CA2340206A1 - Use of anti-pressor agents for vascular remodeling in genital dysfunction - Google Patents

Abstract

The present invention provides a method of administration of an agent which acts to remodel neuronal or vascular pathways for the long term management of sexual dysfunction in both males and females. In a preferred embodiment, the invention provides a method of ameliorating or reversing pathogenic vascular degradative modeling in the ilio-hypogastric-pudental arterial bed and genitalia comprising administering to a human patient in need of such treatment a therapeutically effective amount of an anti-pressor agent. The anti-pressor agent comprises one or more compounds selected from the therapeutic classes of direct vasodilators such as hydralazine and NO donors, ACE inhibitors, angiotensin-II receptor antagonists, .alpha.1-adrenergic receptor antagonists, .beta.-adrenergic receptor antagonists, calcium channel blockers, and phosphodiesterase inhibitors. The anti-pressor agent may be co-administered with a diuretic compound, and is administered either chronically at low dose, or for short periods of time at doses higher than are typically used for the treatment of hypertension. In certain embodiments of the method of the invention, the anti-pressor agent is co-administered with a diuretic agent and/or prostaglandin-E1.

Description

Methods for Remodeling Neuronal gnd Cardiovascular Pathways Cross Reference to Related Annul ono 'his application claims priority to provisional application Serial No.
b0/098,178 filed August 26, 1998.
The present invention relates to medical methods of treatment, pharmaceutical cornposidons, and use of anti pressor agents to manufacture such phaxmaeeudcal io compositions. More particularly, the present invention concerns the adnou~aistration of an agent which acts to remodel neuronal or vascular pathways for the long terpa management of sexual dysfunction in both males and feimalex.
,s The physivlagy of an erection or sexual arousal in both the male a~ad female involves central nervous system initiation, neural pathway activation, and vascular snoooth nnuscle relaxation. This signaling modiates vasodiladon of the penile.
clitoral labial, and vaginal arterial blood vessels a~oud the trabecular meshwork of smooth muscle. The resulting decrease in vascular resistance promotes an increase in arterial zo inflow and the fllling of the corpora cavernosa in the penis and clitoris.
Subsequent t4 there bein8 ~ appropriate high rate of inflow, the cavernosal "~Iling" results in occlusion of the sub-tuz~i~cal veins and full rigidity. The rate of inflow is critical because if there is not enough volume cbawge, venous occlusion can not take place. A
selective structurally-based increase In penile resistance produces a substantial impediment to zs inflow. That is, if ptnile or clitoral vascular strucaue, or the vascular structure immediately "up-stream" from the genitalia, is more constrained than the rest of the circulation. there would be a "mismatching" of perfusion pressure and selective rcaistanec, i.e. genital arterial insufficiency. On the other hand, it is likely that when hypertension is t3.rst established and there is a generalized up-regulatio~a of so structurally-based vascular resistance iaa all vessels, there would not be any deleterious effect vn erectile fu~activn because of a "matching" between perfusion pressure and PfrT/CA99/00787 resistance. That is, despite the hypertrophy of the penile vaseulature, the arterial pressure is proportionally elevated thereby allowiz~.g for adequate blood flow to the penis.
Pathologtcal changes in the genital vasculature aid alterations in iitnction control s systems have been shown to have a deleterious impact on. erectlle dYsfi~nction. Local factors such as endothelin and sympathetic nerve mediated release of catecholamines have been shown to be ipaportant players in detumcsceaee, but they also are likely tv iuncrease trophic responses in this tissue. The physiology of penile and clitoral erection and the swctural maintenance of the tissue depends upon a balance between control io systems that involve endothelial cells, vascular smooth muscle cells, fsbroblasta, extraccllular matrix, and nerves. A~ay abaft in the balance of these control systems to either towards trophic responses such as vascular hypertrophy, focal fibrosis, or generalized production of the extracellular matrix or to the extrepaes of functional control systems can result in crcctile dysfunction. Further, as structure and funedon are ,s so closely related, it is bxoming increasingly iuaportant in understanding the uxechanisms of ercctile dysfunction that we investigate the reciprocal impact of structural changes on function and of changes in ~netional control systems on structure.
The clitoris is the homologue of the perms, arising from the embryologtcal genital tubercle. As a result, the two organs have similar structural and arousal in response mechanisms. The clitoris consists of a cylindrical, erectile organ composed of three parts: the outermost glens or head, the middle corpus or body, and the innermost crura. 'fhe body of the clitoris consists of paired corpora cavcrnosa of about 2.5 em in length and lacks a corpus apoztgiosuna. During sexual arousal, blood flow to the corpora cavernosa of the clitoris cause their enlargement and tie.
=s The clitoris playa a major role during sexual activity iui that it contributes to local autonozzlic and somatic changes causing vaginal vasoco~agestion, e~agorgetnent, and subsequent effects, lubzicattrig the lntroital canal making the sexual act easier, more comfortable, and morn pleasurable.
Vaginal wall engorgement enables a process of plasma transductton to occur, 3o allowing a flow through the epithelium and onto the vaginal surface. Plasma transductio~n results from the risi»g pressure in the vaginal capiliary bed during the sexual arousal crate. In addition, there is an iwcrease in vaginal length and lumenal diameter, especially in the distal 2/3 of the vaginal canal.
It leas been well established that the generation o~ a penile and clitoral erections s and vaginal and labial engvrgcutent arc greatly dependent on adequate blood flow to vascular beds which feed these organs. Beth smooth muscle relaxation of the corpora cavernosa as well as the vasvdilation of genital arterial vessels mediate the physiological response. One of the nor ftmdamental etiologies of erectile dysfunction is, thus, inadequate genital arterial inflow. If there is an inappropriate structural narrowing in io the supporting vasculaturc that is not associated with an increase iuo.
perfttsion pressure, the blood flow into the organs at maximum dilation may be reduced and therefore be insufficient fox the generation of an erection. 'fLere is increasing recogniaon that erectile dysfunction, although associated with, may appear prior to the onset of clinical signs of cardiovascular disease az~d therefore tray be an early harbiuager of progressing ~s changes.
In both the malt and female human. the aorta bifurcates on the fourth htmbar vertebra into the com~anon iliac arteries. The common iliac arteries pass laterally, bchirwd the common iliac veins, to the pelvic brim. At We lower border of the fifth lumbar vertebra, the common iliac arteries divide into inter~aal and external branches.
xo The internal Iliac artery supplies blood to all of the orga~os withia the pelvis and send branches through the greater sciatic notch to supply the gluteal muscles and perineum.
After passing over the pelvic brim, the internal iliac artery divides into anterior and posterior trunks.
The anterior trunk of the internal iliac artery branches into the superior vesicat zs artery, the inferior vesical artery . the middle rectal artery, the uterine artery. the obturator artery, the internal pudendal artery. and the inferior gluteal artery. The iu0ternal pudendal artery supplies blood to the perineum. The artery passes out of the pelvis around the spine of the isehiutn and back on the inside surface of the ixheal cuberosity and iunferior raznus tv lie in the pudendal canal. The branches from the ao internal puderdal artery are the inferior rectal artery which suPPliey tile az'~ sphincter, skin and lower rectum; the pcrineal artery which supplies the scrotuuc iua the male and the labia in the female; the artery of the bulb which supplies ercctile tissue, the deep dorsal arteries of the perms or deep artery of the clitoris.
It has been demonstr2tted In several forms of expexi~,ental hypertension that s "slow presser mechanisms" such as hypcrtrophic structural changes in the vasculature can atn~ost completely accvwat for the long-term resistan~ee changes associated with the elevated arterial pressure. Based on Poiseuilla's law, it has been shown that vascular resistance in an intact vascular bed is a function of the overall hemodynamic effect of all lumen radii, the number of blood vessels, the length of the vessels a~od the blood io viscosity. In hypertension, increased vascular resistance is most potently conferred by a structurally-based decrease iua the radius of the lumen of arterioles and small arts and also potentially by arteriolar rarefaction whereby even a small cbiange in the average arteriolar radii throughout a vascular bed has a dramatic influence o~o~ the resistance to flow. 1~urther, it has been demonstrated that such structure!
changes can is precede the onset of hypertension and therefore may be an initist~ m~~Sm.
Vascular beds in which there is chronic diuoo~lshed blood flow suffer a degree of pathogenic vascular degradative modeling over time In response to static or circulatory hypoxia. That is, as a normal reaction to diminished blood flow, the lumen in these arteries diminishes in diameter over time, causing decreased blood flow and/or higher zo pressure during periods of peak blood flow. Tbose portions of the ilio-hypogastric-pudendal arterial bed which directly feed blood to the sex organs are examples of such less frequently used arterial beds. Because ineide~ats of major blood inflow to the sexual organs are less frequent than to most other organs, a gradual hypoxic response is seen over tixne iun the vasculature directly feeding these organs and in the organs xs themselves. The body has a self rcgulatiug sm to combat this pathogenic modeling: it is known, for example, that in the human male there are a number of spontaneous nocturnal erections which occur as a result of the body's mechanism for combating hypoxia iua penile tissue. Nevertheless, the arteries in a norncal flaccid pa~ais and the un-enlarged clitoris and labia are constzacted. ,A,s a result, typical oxygen zo concentrations in such tissues are closer to venous rather thaw arterial oxygen levels.

Periodic vasvdilation of the penis and clitoris increases oxygen levels in these tissues.
'fhe higher oxygen levels supplied to tissue in the pe~ais and clitoris, as well as vasodilatlon itself, shut down adverse metabolic processes such as TGF-~i production and pathogenic vascular wall modeling which result in long ternoi tissue damage.
s Therefore, it is differential changes in genital vascular resistance that is likely to be a critical issue in ercctile function. That is, if such vascular structural changes take piece In the genitalia i~a tlae absence of hypertensio~a ox systemic changes in vessel structure them would trot be the increase in arterial pressure required to compensate foe the iuncreased resistance. It may be that this condition could occur as an early indicator ~o of progressing cardiovascular disease. The appearance of erectile dysfunction preceding the global clinical signs of hypertension may, in fact, suggest azt increased susceptibility of this vascular bed to pathological changes.
~ummarv of the hventi~on ~s In its principal embodiment, the presc~at invention provides a method for the long term management of sexual dysfunction in males and females by administcriuag a therapeutic agent which remodels n~euxonal or vascular pathways. 1n a preferred embodinnent, the invention provides a method of ameliorating, inhibiting or reversing pathogenic vascular dcgradative modeling in the ilio-hypogastric pudendal arterial bed and genitalia comprising administering to a human parietal 'ua need of such treatment a therapeutically effective amount of an anti-pressor age~ot. In one embodiment, the present invention provides the use of an anti-prcssor age~ot fox the manufacture of pharmaceutical compositions for am~elioratuag, itabibidng or roversing pathogenic vascular degradative modeling iw the ilio-b~ypogastric-pudendal arterial bod and is genitalia.
The ants-pressor agaat is adauinisaered chronically at low doses ranging txtween about one-twentieth to about one-half the dose requtred to evoke vasodilation in a patient exhibiting no~nooal ei~cculatio~a oat, alternatively, is administered over a period of time ranging between about five days to about 21 days at higher doses ranging between about 1.5 to about 3 times tb~e dose required to evoke vasodilation in a patient exhibiting nortn~al circulation.
Brief Description of the Drawins~ iaures IN TEIE DRAWING:
s FIGURE 1 is a representative cumulative a,-adre~noreceptor concentration-responx curve for administration of xveral doses of ~aaetboxamine (MXA) to a spontaneously hypertensive rat. Arrows indicate the point of drug delivery to the penile vascular bed at the concentrations labelal iua, the Figure. Each concentration of MXA was in~uscd for a period of ten minutes, at which time a ~o plateau was reached. The point marked "yield" in the Figure represents the pressure at maximum constriction of the blood vessels in the vascular bed.
This maximum constriction was achieved by administratio~a of a "cocktail"
co~ataiwittg a znfxture of vasopressin (20 g/mL), angiotensin-II (Z00 g/mL), and rrxethoxamfne (64 g/mL.).
~s FIGURE 2 shows tine average a,-adrcnoreceptor cozr~xntratxoa-xesponse curves for administration of methoxamine (MXA) to both the penile vascular bad and hindlimb vascular bed perfusion preparations of the spontaneous hypertensive rat (SHR) and the normotensive Sprague~Dawley rat (SD). Figure 2a and 2b represent, respectively, the curves for administration to the penile vascular beds zo of the SHR and SD rat stiraiuas. Figures 2c and 2~ xep~resent, respectively, the curves for administration to the hlndlimb vascular beds of the SHR and SD rat 5trainS.
FIGURE 3a shows the structurally-based vascular resistance asserted at unaucimum dilation for the penile and hlndlimb perfusion vascular preparations for the a spontaneously hypcrtensive rat (SHR) and the normotensfve Sprague-Dawley rat (SD).
FIGURE 3b shows the corresponding structurally-based vascular resistance asserted at maximum constriction for the penile and hlndlimb perfusion vascular preparations for the spontaneously hypertensive rat (SI-1R) and the r~ot7motensive Sprague-Dawley rat (SD).

~1GURE 4 is a schematic reprcseutation depicting structural differences in blood vessels in the spontaneously laypertensive rat (SHR) and the nor~axotensiv~ Sprague-Dawley rat (SD) and ttae expected impact on resistance to blood flow.
p~lgiled Description The present invention contemplates the use of aud-pressor agents to remodel vasculature in the arterial beds supplying blood to the sex organs, and iu the vascularity of the sex organs themselves. There has been some controversy in the literature as to she correct definition of the term "vascular remodeling," as oviden~cod by the exchange m of letters in the ,journal of Hvnertension, 15: 333-337 (199. The controversy iun the nomenclature centers, iua part, around the use of tb~e terms "hypotrophic,"
"eutrophie,"
and "hypcrcrophic" as modifiers for the tenoa "remodeling" as well as the uae of the prefix "re-" in the word "re~ooiodeli~tlg."
The "trophic" terms have been objected to because of their suggestion that some ~s sart of growth change accot~apacties the observed vascular changes. The term "remodding" was inntialJy~applied in the literature to the observation in spontaneously hypertcnsive rats aztd izt hypertensive humans that the interior lume~a radius (r,) of blood vessels was greatly diminishod while vessel wall ~aaass (w) remained constant.
The rexuit was an observed increase in the ratio of wlr, which correlated with blood pressure zo elevation. The term "re~octodcling" was applied to the observed phenomenon, primarily because of the surprising consistency in total wall xuass. It was thought that somo sort of remodeling of the internal cellular structure of the blood vessel had occurred which permitted a change in lumen radius without a corresponding change in vessel wall mass.
The "re-" prefix has beets objected to mainly bocause of the suggestion that is some sort of "modeliag" of the vasculature has already occurred, and subseduent changes (for good or ill) result in a "re-"modeling of those changes.
Lacking a general consensus of the tcrz~a "vascular remodeling" in the medical community, the term "pathogenic vascular degradative modeling" will be applied, throughout this specification arid the appended claims, to denote the pathogenic or 3o degradative increase in the ratio w/r, of vasculaturc, irrespective of the cause. The term "vascular re~oaodeliuag" a: used throughout this spxifieation and the appended claims will mean the amelioration, inhibition or reversal of pathogertic vascular degradadve modeling; that is the amelioration, inhibition or reversal of the decrease in the redo of vascular w/r,.
s 'The tertn "anti-pressor agent" as used ltereln denotes a thorapeudc agent which acts either directly or indirectly w lower blood pressure. Tlne term and-pressor agent is chosen, rather than the more spocific term "antihypertensive" agent, because the invention contemplates the use of agents which are effective to increase vascular flow Ia both hypertetxsive and notzttotensive patients. Anti-pressor agepts contemplated for use to in the tnechod of the present invention, Include agents which act to bring about a lowering of blood pressure by any of a number of different physiological mechanisms.
Anti-prcssor agents iuo~clude compounds belonging to a nmouber of therapeutic classes bard upon their mechanism of action, even though the therapeutic outcome is the same.
Anti-pressor agents suitable for the method of this invention include compounds which is arc direct-acting vasodilators such as NO donors and hydralazine. Other suitable anti-pressor agents are compounds which act to inhibit the enzyme which converts the kss potent decapeptide vasoconstrictor, angiotcnsin-I, to the more potent octapepdde vasoconstrictor, angiotensin II (so-called angiotensin-II converting enzyme inhibitors or "ACE inhibitors"), as well as agents which block the bindiun~g of angioie~nsi~a-II to the m AT, receptor ("angloteusin-II receptor autagonitts"). And-pressor agents useful in the method of the present invention also include vasodllating agents which act at a,-adcenergic receptors or p-adzenergic receptors in the axnovth ~oauscla of vascular walls ("a,-adrenergic receptor antagonists" and "(3-adrenergic receptor antagonists"), as well as agents which act to decrease intracellular calcium ion concentration in arterial Smooth xs muscle ("calcium channel bloekers"). Suitable and-pressor agents for use in the present invention also include activators of the enzymes guanylyl cyclax and adettyl cyclase such as YC-1 and forskolin, respectively. PGE, (prostaglandin-E~), which acts both as an anti-prcssor agent and as a sexual responx initiator, is also suitable for use in the invention. Also contcmplatod as falling within the scope of the invention for use as 3o anti-pressor agents are phosphodiesterase inhibiting agents, particularly type-3 and type-5 phosphvdiestcrase inhibitors. Antagonists of PDE-S (phosphodicsterase type 5), the cnzyxne primarily responsible for the degradation of cyclic guanosine monophosphate (cflMP), produce an increase in levels of cCiMP, wbieh. by way of ~cross-talk," also decreases the activity of PDE-3, the enzyme primarily responsible s for the degradation of cyclic adenosine monophospb~ate (CAMP). Thus.
increasing levels of eGMP acts to inhibit the PDE-3 enzyme, tb~exeby blocking the degratlatio~o of cAMP and causing an increase in cAMP levels. Thus, inhibition of eitbex PDE-S
o:
PDE-3 results in an overall iuacrease in concentrations of cAMP and eC3MP.
Specific examples of NO donors include glyeexyl trinitrate, isosorbide 5-io uxononltrate, isosorbide dinitrate, pentaerythritol tetranitrate, sodium nitroprussidc. 3-morpholinosydnonixnime, wolsid~nomine, S-nitroso-N-acerylpenieilhunine. S-nitrosoglutathione, N-hydroxyl-L-arginine, S,S-dinitrosodtbaol, and NO gas.
ACE inhibitors include benz:azapine compounds such as benazepril, and libenzapril; 6N pyridazino[1,2-a]diazcpine derivatives such as cilaxapril: 2,3-dlhydro-m 1N indene compounds such as delapril; L proiine derivatives such ss slac~pril.
captopril, ccronapril, enalapril, fosinopril, lisinopril, moveltipril and spirapril;
oxoimidazoline derivatives such as imidapril; 1,4-dihydrapyridine compounds such as lacidipiuxe; iso-quinoline carboxylic acid derivatives such as moexipril and quinapril;
1 hl-indole carboxylic acid derivatives such as pentopzil arid pexindoprit;
xo hexahydroindole carboxylic acid derivatives such as trandolaprll;
cyclopenta[b]pyrrole carboxylic acid derivatives such as ramipril; and 1,4-thiaupine compounds such as temocapril.
Angiatensin-II receptor antagonists useful as aaa-pxessox age~ats is the method of this invention include eprosartan, lrbesartan, losartan, and valsartan.
zs a,-Adrencrgic receptor antagonists include substituted phenyl derivatives such as midrodrine, phcnoxybeazamlac, tamsulosin; subatitutod naphthyl derivatives such as naphazoline; axninoquinazoline derivatives such as alfuzosin, bunazosin, doxazosin, prazosin, terazosin and ttimazosin; benzamide compounds such as labctolol;
carbazolc derivatives such as carvedilol; dimethyluracil derivatives auch as urapidil;
so itnidazolidinyl derivatives such as apraclonidine, clonidine;
dihydroimidazole derivatives such as phentolamine; indole derivatives such as indora~oo~ira;
and 1,2,4-triazolo[4,3-a]pyridiuae compounds such as dapiprazole.
Calcium channel bloekers include benzothl,azepine eon~ounds such as diltiazenu;
dihydropyriditte compounds such as nicardipine, nxfedipinc, and nimopidiuae;
phcnylalkylamine compounds such as verapatnll; dlarylaminopropylamine ether compounds such as beprldil; and bcnimidazole-substituted tetralin compounds such as niibrefadii.
Phosphodiesterase inhibitors include bipyridone compounds such as amrinone;
and di~hydrvpyra~olopyrimidinc compounds such as sildenafil. Sitdenafil fttnctions as a ~o selective type-5 (i.e. c-QMP specific) phosphodiestcrase inhibitor, and acts to decrease the merabolistn, of c-GMP, the second messenger in nitric oxide mediated erectile response. An oral formulation of this medication has proven to be safe and effective in improving erectlle duration and rigidity. In fetnalea, nitric oxide/NOS exists in human vaginal and clitoral tissue. SildenafU, alone or in combination with other vasoactive ~s agents, is effective for the long tennu ~onanage~ment of sexual dysfunction for the treatment of vasculvgenic mule or fe~oaale sexual dysfttnetion.
pharmaceutical Comt~ositions Pharmaceutical compositions which arc useful in the method of the present zo invention comprise one ox ~onore compounds defined above formulated together with one or more non-toxic phartnaeeutieally acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for vagiu~al or rectal administration. The formulations may, for example, contain a single therapeutic agent selxted from ACE
inhibitors, zs angiotensin-1 (AT,) receptor antagonists, a,-adrenoreeeptor antagonists, ~i-adrenergic receptor antagonists, direct-acting vasodilators, NO donors, calcium channel Mockers, phosphodiesterase inhibitors, or a combination of two or more agents selected from the same or different therapeutic categories. Moreover, a combination of one or more therapeutic agents fro~an the groups listed above may be combined witb. a diuretic agent of the class well known in the art.
to To enhance delivery to genital vaseulature, combtnod systemic delivery with topical administration of an ercctogenic initiator is also co~atemplated within the seeps of this invention. In this manner the anti-presser drug is delivered to target regions at a markedly enhanced rate. Siuace prostaglandin-E, acts both as an anti-presser and as a direct sexual response initiator, one or more therapeutic agents from the groups listed above caz~ be administered in combination therapy with prostaglandin PGE,. The co-administered PGE, may be administered by a~ay of the routes discussed below, with topical application being a preferred mute.
The pharmiaceutitcal compositions of this invention can be administered to either io systemically or locally to humans and other animals. Systemic routs include oral, parenteral, intraeistexital, intraperitoneal, traps-eutaneous (bY injection or patch), buceal, sub-Iinguai administration, or by means of an oral or nasal spray. The term "parenteral" administration as used herei~o~ refers to ~ouodes of ad~oo~inistration which include intravenous, intramuscular, inuaperitoneal, intrastcrnal, subcutaneous and a intraarterial injection and int~tsion. Local administration routes include vaginal, rectal, intxaurethral, traps-urethral, by infra-cavemosal insjaction, or topical administration.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nvnaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile zn idjcctable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous careers, dilucnts, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and it~octable organic esters such as ethyl oleate. proper fluidity can be maintained, for example, by the use of coating materials z3 such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various and bacterial and antifungal au agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like, It may tt also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostcarate and gelatin.
to some cases, in order to prolong the effect of the drug it is desirable to slow the release or absorption of the drug following subcutaneous or intramuscular rejection. This may be accomplished by the use of a liquid suspension of crystalhirte o;
amorphous material with low water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
u~ Alternatively, delayed absorption of a parenterally administered drug for~tn is acconn~plished by dissolving or suspending the drug in an oil vehicle.
lnjectable depot forms are made by forming microcncapsttle matrices of tbc drug in biodegradable polyrrters such as polylactide polyglycolide. Dependlszg upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug ~s release can be controlled. Examples of other biodegradable polymers include poly(othocsters) and poly(a~ohydridea). Depot injectablc formulations are also prepared by entrapping the drug in liposomes or mierocmulsions which are eounpatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration tluough xo a bacterial-retaining filter, or by incorporating steriilizuag agents in the form of sterile solid compositions which can be dissolved or dispersed iua sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration iuuclude capsules, tablets, pills, powders, and granules. In such solid dosage forms the active cmoapound is mixed with zs at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalciurn phosplxate ar~d/vx a) fillers or extenders such as starches, lactose, sucrose, glucose, znanxuitol, and silicic acid, b) bindera such as, for example, caxboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) huxttectants such as glycerol, d) disitieegrating agents such as agar-agar.
calcium x~ carbonate, potato or tapioca starch, alginic acid, certain silicates, a~ad sodium carbonate, e) solution retarding agents such as paraffin, fj absozption accelerators such as ~2 quaternary ammonium compounds, g) wetting agents such as, Por example, cctyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and 1) lubricants such as talc, calciumi stcarate, magnesium stcarate, solid polyethylene glycols, sodium iauryl sulfate, and mixtures thereof. In chc case, of capsules, tablets and pills, the dosage fonoca caay also comprise buffering agents. Solid compositions of a similar type naay also be employed as fillers iut soft and hard-flllcd gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be u~ prepared with coatings and shells such as enteric coatings and other coatings weU
known is the pharmaceutical formulating art. T>aey may optionally contain opaeifying agents and can also be of a composition that they release the active ingredien;t(s) only, or preferentiaily, in a certain part of the intestinal tract, optionally, in a delayed ma~uner. Examples of embedding compositions which can be used include polymaerie ~s substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentiv~aed excipients.
Liquid dosage forms for oral administration Include pharaaaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In additio~a to the active compounds, the liquid doaagc forma may contain iuacnt dilucx~ta commonly usad in the zo art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, be~azyl alcohol, bcnzyl benzoate, propylene glycol, 1,3-butylene glycol, dintethyl formamide, oils (in particular, cottonseed, ground nut corn, gene olive, castor, and sesame oils), glycerol, tctrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and zs mixtures thereof. Resides inert diluents, flat oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuioaing agents.
Suspensions, in addidvn to the active compounds, may contain suspending agents as, fir example, etbvxylated isosteaxyl alcohols, polyoxyethylcne sorbitol and xa sorbitan esters, microcrystalline cellulose, aluuainum metahydroxide, bentonite, agar-agar, and tragacanth, and miuttures tb~eiceof.
Compositions for rectal admuaistratiozt axe preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating s exclplents or carriers such as cocoa butttr, polyethylene glycol Qr a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in rite rectum and release the acdve compound, Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes arc generally derived from phospholipida ~o or outer lipid substances. Liposomes are formed by mono- or mufti-lamcllar hydratod liquid crystals that are dispersed iua an aqueous medium. Axty non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, pxeservadves, excipients, and the like. The prcferrod m lipids arc the phospholipida and the phosphatidyl cholines (lecltbans), both natural and synthetic. Methods for the formation of liposomes are known in the art. See, for example, Prescott, Ed., Methods In Cell Hlology, Volume Xl'V Academia Press, New York, N.Y. (1976), p. 33 ct scq.
Actual dosage levels of active ingredients in the pharmaceutical compositions of sa this invention may be varied so as to obtain an amount of the active cotnpound(s) that is effective to achieve the desirod therapeutic response for a particular patient, compositions. and mode of administration. The seieetod dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient befng is treated. However, it is well known within the medical art to determine the proper dose for a particular patient by the "dose tluatlon" method. In this method, the patient is started with a dose of the drug compound at a level lower than that required to achieve the desired therapeutic effect. The dose is then gradually increased until the desirod effect is achieved. Startiag dosage levels for an already comnaerciaIly available ~o kkterapeutic agent o~ the classes discussed above can be derived from the information already available on the dosages employed for the use of the compound as an antihypertensive agent. In a cbxouic, ox lotlg-term dosing regimen to remodel the vasculature In the genitalia and inn vascular beds feeding the genitalia, lower doses ranging between about 1/20 to about 1/2 the doses normally given to combat s lxyporte~nsion are used. In short term, acute, ox "burst mode" therapy, the compounds are admi~nustexed in doses ranging between 1 to 3 threes the auxou~lts generally prescribed for hypertension. In these situations, however, appropriate precautions should be takezt by the aaending physician to closely monitor untoward side-effxts peculiar to each particular therapeutic agent.
io For the preferred tlie~rapeutic agents in the method of the present invention.
namely ACE inhibitors, ge~aerally dosage levels of about 1 mg to about 300 mg, more preferably of about 5 mg to about 150 mg of active compound per kilogram of body weight per day are aduxi~aistexed orally to a padent, with the dose levels appropriately adjusted if the route of ad~oouuaisbtation is other than oral. If desired, the effective daily is dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
piological Data Demonstration lthat the Scx Organs are Not Protected from Pathology zo Vascular Degradative Modeline Methodoloav 'Male spontaneously ltypertenslve (S~ rats weighing between 24&31.3 g, and norrnoteztsive Sprague-Dawley (SD) rats weighing between 246-440 g were vbtaiz~et!
from Charles River laboratories (Mo~at~real, Quebec, Canada). The animals were zs maiuttaiued in iuxdividual cages with a 12 hour light / 12 hoax darlc cycle, and a room temperature of 22-24°C.' They were provided with sta~odaxd rodent cb~ow and tap water ad llbitum and were acclimated to the room for at least two days before the experiments. All procedures were carried out in accordance with the guidelines set out by the Canadian Council on Animal Care.
so is 2. ntnile vascular resistance prop",e es Penile perfusion preparations were made using the procedure established by Ranting, J. D., et al., "lsoladozt and Perfusion of the Pudendal Vasculanrre in Mala Rats. J Uro~.,, 2: 587-590 (1995). A heated chamber served to maintain the ambient s temperature and the entire preparation at 37-38°C. The pcrfusate was held in a reservoir and passed through a heating and a bubble trapping/mixing chamber connected to a single peristaltic pump (Mitaipuls 2 Pump, ~llson, Inc., 3000 W. Beltline Highway.
Middleton, W1 USA 53562) . Au irtjecdon port was located distal to the pump fvc tlxe introduction of phazxnacological agents to minimize dead volume. Drugs were ~o administered via a Harvard Apparatus, Inc. i~otfusion pump (Harvard Apparatus, Inc., 84 October Hill Road, Holliston, Massachusetts 01746) . The perfusate was a Tyrode-dcxtran solutio~a consistax~.g of a mixture of 20 mg of KCI, 32.3mg of CaCI=~HzO, 5.1 mg of MgCiz~6Hi0, 6.2 mg of NaH2P0,~2I-IzO, 1.55 »ag of NaHCO,, 100 mg of glucose, and 800 mg of NaCI iua each 100 mL of fluid. The solution was ~ s maintained at pH 7.4, and a temperature of 37-39°C, and oxygenated with 95 °6 Oz and S~ rc~=. The rata were a»ae~etheti~.ed (snAi~~m rentnharhitai fi0 mg/kg hcuiy weight i.p.) and txepazi~ed (1000 IU/kg, i.v.). The bilateral isolation of penile vasculature was achieved by ligating ail of the branching arteries except for the pudendal; then the abdominal aorta was cannulated proximal to the iliac bifurcation with a single h:men Zo catheter. The catheter was connected to the perfusion apparatus via a pressure transducer for arterial pressure recvrdirag. After sectiotxing the v~erra cave aad spinal cord to remove venous resistance and to oliminate neural influences, a flow of perfusata ( 1 mL/min per kg body weight) through ehe abdominal cannula was initiated.
The pertEtsion pressure was continuously recorded on a data acquisition system (MacLab, zs AD Instruments, Houstoil, TX). The pcrfusatc was infused for twenty minutes to flush the penile vasculature of blood and obtain a stable pressure before the beginning of any experiment. Following this, sodium nitroprusside (20 g/mL) was infitsed to induce maximum vasodllation. The flow rate-perfusion/pressure relationship was determined by measuriztg the pressure at tztiniuttuna vascular resistance at flow rates of 0.5, 1.0, 2.0, 30 4.0 mL/min per kg of body weight. A cumulative a,-adrenoreceptor t6 concentration-response curve to methoxapai~ne (2.5, S, 10, 23, 50 g/mL was then generated. Each concentration of methoxamine was infused for a duration of 10 minutes, at which time a plateau was reachod. Subsequently, a continuous itljxtion of a cocktail containing a supramaximal con~cen~txation of vasoconstrictors (vasopressin, 20.5 s g/rnL, angiotensin-Il, Z00 ng/mL; methoxamhie, 64 ghoaL.; Sigma, St. Louis, MO, 63178) was given to ensure that aon~aximmn constrktor response that was not dependent upon the activation of a single receptor type was achieved. A second injection of the constrictor cocktail was administcrad to ensure the tissue "yield" was maximum constriction. This "yield" induced by the ~multi-vasoconstrictor cocktail has been io demonstrated to correlate directly with the bulk of medial vascular smooth muscle cells in the resistance vasculamre. A, typical perftzsion pressure tracing from this pzotocol can be aeon in Figure 1. At the cad of the concentration-respou~se relationship, the aorta was cut distal to the catheter, and a baseline flow pressure cuz<re was recorded again. This was done to ensure that pressure fell to zero and to account for any false t, pressure readings drat may have resulted due to movement of the catheter during the experiment.
Flindlimb vascular resistance propeztics The hindlimb perfusion preparation was adoptrd from a technique origiuually designed by Folkow et al., Acta Physiol Scend., 80: 93-106 (1973), as modified by Adams zu et al., Hvaereension ,14: 191-202 (1989). The perfusion experiment was performed as dexribed above. Drugs were adr~ainnsterod into the mixing chamber via a Harvard Apparatus infusion pump. The rats were anaesthetized (Inactin, 100 mg/kg of body weight, i.p.) and heparinizcd (1000 IU/lCg of body weight, i.v.). Following a midline abdominal incision, the abdouaitzal aorta was cannulated proximwl to the iliac bi(urcatio~n z~ with a double lume~a catheter (Stozx, St Louis, MO, USA), and the catheter was extended down the right common iliac artery. One lumen of the catheter was connected to the perfusion apparatus, while the other was connected to a pressure transducer for arterial pressure recording. The rat was perfused at a constant flow rate (2 mL/min per 100g of body weight) and the experiments were carried out as dexribed above.
The so flow rate/perfusion~ pressure relationship was recorded at flow rates of 0.5, 1.0, 2.0, m 4.0 mL/naiux per 100 g of body weight. ,A cumulative a,-adreuoreceptor coz~cantration-response curve to methoxaminc {0.5, 1. 2, 4, 8, 16, 32, 64 g/mL) was then gcneraced. Each eonecatration of ~methoxamine was infused for a duration of 5 minutes, at which timc a plateau was reached. Subsequently, a bolus injection of a s cocktail containing a supramaxinxai concentration of vasocvz~strictors was given as above. At the cnd of the concentration-response relationship, the iliac artery was cut distal to the catheter, and the flow pressure curve was monitored again.
1~low rafts for the hindlimb perfhsio~a experiments wen detcrtui,~o~ed based on expected flow rates of exercising akelctal muscle at maximum dilado~a. The flow rate io used resulted in a perfusion pressure at maximum dilation between. 20-25 mm Hg which is well within the expxted range. After checking several flow rates iua the penile perfusion, a rate was obtained that resulted in a similar perfusion pressure at maxiaxum;
dilation. The flow rates chosen also allow for the assessment at maximum constrkdon;.
This allowed for couiparison between strains.
~s 4. ~,,~ysis of Data All values in the figures and tables were expressed as mean t standard deviation. Results comparing penile and hindlimb vasculature were analyzed using the Student's t-test. Differences were co~asidered as signifleant at p <0.05.
io i'i '1'kxere was no signuficant difference in the body weight of the spontaneously hypertensive rats in the penile assessment group (267 f 29 g, n=5) and in the hindlinab assessment group (270 t 5.7 g, n=3). The average body weight of the tlormotettsive zs Sprague-Dawley rats in the hiuadlimb assessment group (375 ~ 41 g, n=8) was significantly higher than 'that of the of the ixormotensive Spraguo-Dawley rats in the penile assessment group (284 t 32 g, n=5). However, this was not considered relevant because in norrnotensive adult rats there has been shown to be very little correlation between body weight and blood pressure (Adams, M. A., er aL, Hvnertcnsion, so 14: t 91-zo2 ~ t 989).
a This bemodynaulic analysis had similar effects in most parapaeters between the penile and hindlimb vascular beds witban each rat strain. The flow-pressure curve assessed at maximal dilation was similar in both tile petlile and the hindlimb vasculatures of spontaneously hypertensive and nortuotensive rats as shown in Tabie 1.
s These curves were monitored to ensure a linear increase lit perfusion pressure with an increase in flow rate. The increase in the flow rate exerted a radial pressure against the vessel wall and resulted iu1 increased pressure. The spontaneously hypertensive r8ts trended towards a higher baseline pressure than the normotensive rats. This was observed in both penile and hindlimb vascular beds. Tbese data suggest that ~o spontaneously hypcrtcnsive rats ~oaay have a smaller lumen thus causing them to operate at a higher pressure than normotcnaive Sprague-Dawley rats wan when there is no constrictor tone on the vessel.
Table i Group lope Mas,intum __ ~g-~C~ . -_ Slope - .

Flow PressureConstriction Methozamitte Wtth Methozamine (mm Hg) SHR, penile 7.15 ~ 2.0 17z t 32 0.95 f0.19 1.64 f0.21 bed SHR, indlimb6.68 t 0.38253 t 25"' ~ 0.79 t 5.19 t 3.0"
0.15 bed SD, penile 7.34 t 2.3 171 t 36 0.63 t 0.242.03 t 0.68 bed SD, billdlimb6.99 t 3.4 191 t 55 0.7810.12 3.0 t 0.99 bed T atatlstlcally stgrlutcant.
~s Table I shows there was a statistically significant difference in maximum constrictiv~n with a supramaximal, dose of xnetb~oxal~u;iro~ (50 g/mL for penile slid 64 g/anL fox hindlitnb vasculature) between spontaneously b~ypextensive rat hLudlil>ab vasculature (253 * 25 rnmHg) and spontaneously hypertensive rat penile vasculature (172 * 32 aouztHg). Thus difference was not observed ua iao~nnaote~asiva Sprague-Dawley xo rats. The discrepancy is novel and requires further assessment. It is expected that higher responses would be seen in the spontaneously hypertensive rats in both arterial beds, however only the lliuadliuulb vasculature showed a significant difference between spontaneously hypertensive and normotensive rats. Average cortcetttratlon response curves for mcthoxamine of the two strains in both beds are shown in Figures 2a-2d.
The EC,~ of the concenuation response curve shown in Table 1 gives the concentration of drug at which there is a 5096 response to a~-adrenorcceptor stinnulatiorw. This value would be an iuadication of the sensitivity of the tissue to this receptor activation. The logs ECM of the methoxamine concentration-response curves were not different for penile and hindlimb vasculature in both the spontaneously hypertensive and normotensive rats thus fndlcating similar sensitivity to leis receptor stimulation.
io The steepest slope of this curve is given in Table 1. Irx normot~asive rats, them was no statistically significant differenee in slope between penile vascttlature (2.03 t 0.68) and hi~diiuaub vasculature (3.0 t 0.99). The parameters showod a statistically significant difference between spontaxteously hypertensive rat penile (1.64 t 0.21) and apotxtauneously hypcrGensive rat hindlimb (5.19 t 3.0). This was expxted siurce the ~s maximal constriction with methoxam~e was lower iut penile vasculamre while the EC,o, remained the same.
Figure 3 depicts the structurally-basod vascular resistance properties assessed at both maximum dllation and maximum constriction. There was no signiftca~ot difference in perfusion pressures at ~cta~ciz~ounca dilation within the rat strains.
Hetwocn the two xn strains of rats, the penile vasculature trended towards higher pressures in the hypertensive rat as compared to the normotensive Sprague-Dawley rats, however it did riot reach a level of significance as in the hindlimb. Spontaneously hypertensive rats rcaehed a point of maximal constrietio~a with a cocktail at a perfusion pressure that was 20 96 higher than notmotcnsivc rats in each vascular bed. Titers was no statistically is significant diffcrenec between the two beds withiut strain, suggesti~og that the penile and hindlirnb vasculature uztdexgo similar structural changes in genetically hypertcnsive rats.
This point demonstrates the increased medial thickening that occurs iua the hypertcnsive rats that allows for the rttai~utenance of higher arterial operating pressures.

isc s io The major findings of the data presented above demonstrate that the penile vasculamre is not protected from the structural changes tb~at take place in the other vascular beds of spontaneously hypertensive rats relative to normotensive strains.
increased medial thickening and narrowing of the vascular lumen have been found irn blood vessels of a wide range of vasculaz beds of spontaneously hypertensive rats.
Therefore, the overall results of the present series of experiments have spawn that the genetic disposition appears to dominate the struchure regardless of the vascular bed.
In the present study a he~oaody~narnie methodology was used to compare and in contrast structurally-based vascular resistance in two vascular beds. The hindliuib bed was chosen for comparison since tb~e vascular resistance properties are well establishod and anatomically the fender vessels of the two beds arc common.
These results demonstrate that the resistance properties at maxfmum dilation were similar in the two beds within strains. A general finding of studies comparing ~ s vascular resistance at minimum tone is that a higher perfusion pressure is normally obtained in SHR compared to ~aormotrnsive rats. Thus, findings of elevated resistance properties at maximum dilation are consistent with there being an overall narrowing of the vascular lumen. ftesistanee properties were further assessed by determining the slope of the flow-pressure curve at maximum dilation. This relationship was used to ~o decern~ine whether there were any differences in the passive vascular wall elements such as the extracellular matrix components, i.e. if distensibilzty was altered there would be a differential effect on the flow-pressure curves. Fuz~thex, a thicker medial wall could also result in a stiffer vessel which would exhibit less compliance with increasing flow. The lack of difference in all of these values suggests that there has been no differential zs change in the components of the vessel wall wlthi~a the penile vasculature.
Assessment of the active components of the vessel walls was determined by inducing a state of ma7cinoal vasoconstrictor tone using a cocktail of vasoconstrictor agonists. The supramaxitnal, multiple agonist stimulus produces a maximum constrictor response which is independent of individual receptor population changes 3o thereby reflecting only the overall contractile bulls of the medial smooth muscle cells.

The findings that sensitivity (ECM aztd reactivity (slope) to a,-adrenorectptot stimulation were not different between vascular beds ox strains likely indicates that there is a similar stimulus-response coupliuog of the noradreacrgic innervativn in all of these vessels; i.e. there is a consensus of nonoaal vascular biology. In the schematic diagram of Figure 4, the concept of atxuccuxak changes dominating function is depicted. Thus, the curves show that, at any given level of vasoconstrictor tone, the hypexte~ive circulation will always have iuacrcased vascular resistance compared to normotensivc circulation. Another way of looking at this concept would be that at tb~e same level of constrletor tone, the normotensive circulation would be able to achieve the same inflow ~o at a proportionately lower perfusion pressure thaw the hypertensive circulation.
Taken together, the findings indicate that the penile vaseulature has an increased average medial mass coupled with decreased average lumen. The generation of an erection is based vn the flow when vessels are in a dilated state. Although there was a significant difference in the perftxsion pressure at maximum dilation in the hindkimb is vasculaturc of spontaneously hypertensive rats (SHR) when compared to the normotensive Sprague-Dawkey (SD) rats, this was not detected in the penile vascuka~r bed. There was however a trend toward significance which may be aee~a iu future studies when animals arc used that arc genetically closer to the spontaneously hypertensive rat, such as the Wistar-Kyoto rat (laconic, 273 Hover Avenue, zo C3en;nantown, NY 12326) which Is a more appropriate ~aonnotensive control.
Tha penile vasculature is more complex than that of the ktindllmb and therefore it mvay be that differences at maximum dilation are more difficult to detect. It is also unknown whether the size of the penis differs between the suauns examined in this study. The length of the vessels changes bascli~ resistance more than the maximum constriction zs response because the maximum dilation is flow~ependent, as there is no constrictor tone on the vessel. In contrast, gum constriction responses are based oxt the bulk muscular tissue. Therefore although the point of maximum dilation is expected to be higher in the penile vasculature of SCR as compared to a normot~asive control it may not be detectable using tine Spxague-Dawley rats as a comparison based on the suspected 3o differences between the strai~o~s, z2 B_, Therapeutically Induced Vascular Remodeling ~ Penile Vasculatt~re Iy o~odolor~_c Adult spontaneously hypercensive rats (SHR) were ucated for I or two weeks s with either eaalapril (30 mglkg of body weight per day) or hydralazine (45 mg/kg of body weight per day). Following this txeatmcnt, structurally-based resistance to blood flow in the perfused penile vascular bed and hindllmb vascular bed models were measured using the methods detailed above. Cumulative a,-adrenoreecptor concentration-response curves in response to mctboxamine were ~oaeasured as descn'bed ~o above, and the "yield" poiuat determined, following the achievement of maximal vasoconstriction using the vasopressin, angiotcnsin-11, methoaamine cocktail described about. The anittial hearts were excised and weighed. The data are presented in Table 2 below.
Table 2 G~~p gape --M~mum Log ECeo Left Flow ConsMctloo Ventricle PreseuureWlth Weight (g)/

Cocktail Body "Yield" Wd~ht (cum (~) l~lti0 SHR-E," 6.45 t 335 t 23 8.73 t 2.13 t 1..31 0.2b 0.08 (n =
~) SHR-E,' 6.10 t 358 t 20 7.33 f 2.17 f 1.5 1.39 0.05 (n=5) SHR-H~ 6.63 t 353 t 1l 13.56 t 2.37 t 0.86 5 0.12 n~7 Control 7.13 f 381 t 21 11.95 t 2.46 t 0.63 5.51 0.08 (n =
9) ' Enalapril-treated animal:.
z Hydralazine-treated animals ~s The data appearing in Table ~ show that enalapril treatment progressively regressed so (remodeled) cardiac and pudendal vascular suucture over the 2-week perfod of treatunent. The "yield" value decreased on average by 12.1'9b t 6.O~o, while left ventricular mass dxreasod. by 13.b 96 t 3.2 9b . Hydralazizae treatment was somewbat less effective, decreasing the "yield" point by 7.396 ~ 2.9~, and had uo signiNeant effect on left ventricular weight (decreased of 3.7fb t S.0°6).
While there have been shown and described what are believed at ~rescnt to be the preferred eonbodiments of the prexnt ~uaveution, it will be obvious to those of ordinary skill in the art that various modifications can be made in the preferred embodiments without depaxtitag fxotn the scope of the iuavention as it is defined by the appended claims.

Claims (13)

WE CLAIM:

1. A method of remodeling an ilio-hypogastric-pudendal arteriel bed comprising administering to a human patient in need of such treatment a therapeutically effective amount of an anti-pressor agent at a dose that is from about one-twentieth to about one-half the dose required to evoke vasodilation in a patient exhibiting normal circulation, wherein said anti-pressor agent comprises one or more compounds selected from the group consisting of prostaglandin-E1, ACE inhibitors, angiotensin-II receptor antagonists, .alpha.-adrenergic receptor antagonists, .beta.-adrenergic receptor antagonists, calcium channel blockers, direct acting vasodilators, activators of adenyl cyclase, hydralazine, amrinone and sildenafil.

2. The method of claim 1 wherein said anti-pressor agent is an activator of adenyl cyclase.

3. The method of claim 2 wherein said activator of adenyl cyclase is forskolin.

4. The method of claim 1 wherein said anti-pressor agent is hydralazine.

5. The method of claim 1 wherein said anti-pressor agent is an angiotensin-II
receptor antagonist selected from the group consisting of eprosartan, irbesartan, losartan, and valsartan, and mixtures thereof.

6, The method of claim 1 wherein said anti-pressor agent is an ACE inhibitor selected from the group consisting of alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, fosinopril, imidapril, lacidipine, libenzapril, lisinopril, moexipril, moveltipril, pentopril, perindopril, quinapril, ramipril, spirapril, temocapril, and tandolapril, and mixtures thereof.

7. The method of claim 1 wherein said anti-pressor agent is an .alpha.1-adrenergic receptor antagonist selected from the group consisting of alfuzosin, apraclonidine, bunazosin, carvedilol, clonidine, dapiprazole, doxazosin, indoramin, labetolol, midrodrine, naphazoline, phenoxybenzamine, phentolamine, prazosin, tamsulosin, terazosin, trimazosin, and urapidil, and mixtures thereof.

8. The method of claim 1 wherein said anti-pressor agent is a calcium channel blocker selected from tho group consisting of bepridil, diltiazem, mibrefadil, nicardipine, nifedipine, nimopidine, and verapamil, and mixtures thereof.

9. The method of claim 1 wherein said anti-pressor agent is co-administered with a diuretic compound.

10. The method of claim 1 wherein sand anti-pressor agent is co-administered with prostaglandin-E1.

11. The method of claim 1 wherein said anti-pressor agent is administered for a period ranging between about three days to about twenty-one days.

12. The method of any one of the preceding claims wherein said anti-pressor agent is administered on a chronic basis at a dose ranging between about one-twentieth to about one-half the dose normally given to a hypertensive patient.

13. The method of any one of the preceding claims wherein said anti-pressor agent is administered to a normotensive patient.