Vasodilators in the Treatment of I Hypertension

K. O'MALLW, C. O'DOYLE end K. McGARRY ( 7 Blood Pressure Evaluation and Treatment Clinic.

The Charitable Infirmary, Dublin, Eire

Department of Royal College of Surgeons in Ireland, Dublin. Eire

Vasodilator drugs continue to interest r & m h workeis and'clinicians alike. The evaluation of vasodilators in the management of congestive heart failure over the past fcw years has coincided with tbe general acceptance of rbe use of many of t h e .

agents as second and third choia drugs io the management of moderate and sewre hypertension. In this paper we propox a classification of vasodilator antihypertensive drugs. As this group has grown considerably we have elected to conccntrate on some areas of special interest. namely the pharmacology of minoxidil. calcium antagonists as bjpotensivc drugs and pramsin. . . -

I . I

classification : I

Thm is no agmment as to how tbesc drugs should be classified: The narrowest &finition would be to include only those drugs such as bydralazine a d diazoxide which rth vascular smooth muscle but appear not to intcwt with "receptors". On the other hand. many drugs which lower blood pressure do so via receptors or speiSc s i t s on vascuku smooth muscle and these prodm haemdynamic responses no1 very different to those seen witb non-specik vasodilators. We have, therefore, included angiotensin antqonists. calcium antagonists, prostaglandins and a- admoccptor blocking d m g in addition to non-specific vasodilators (Table I). We fatbet arbitrarily excluded tbe converting enzyme inhibitor. captopril, beca w at least ont of its important actions ocrun =mote from the vascular smooth rnuscle. However. .a argument for its inclusion could be made oo tbe basis that the end result is relaxation of vascular smooth alusck. r

Tbe pattern of response to r vasodilator is more importantly determined by tbc setativity shown than by tbc precise mechanism of action. Tbus the hacmodynamic

flw Thmptur iu dlfypwtomh: Roy& Sockzy d kkdicine Inlum(ionrl Congmu and Symposium Ssrisr No. 26. published ,- by A M c R u a Inc. (Lond n) Ud. and th.

mm- ~ ~ . I - R O & & O ~ . ~blbi~~Lq+

- . ' , . 1 . I

Table I

K. O'Maclky, at rl. '

o-admnoceptor Blocking Agcnu

. PoJuynapriE-prazoria . . . Re + postsyaaptic-pknoxyb ctpbalt* . . .

Angiotkin Blocking Agenu . . . . .. - . - 2

sarnlasin Calaum Aotagoaists . .

. . . . .. . . ~fedipinc, venpamil . . . . . Prostaglandins

prostacyclin . . . Non-specific

selmivc-hydraluine. minoxidil. diioxidc noa-sclactive-aitropr~t~idc. totncsoxick .

. . . . 8 -

. . . . ... . . ... . . . .. . . . . % . . . . .

. . '. response to a drug acting &ely on arterioles sucb as hydralazi may be quite different to that observed with a non-selective vasodilator. such as nitroprusside which acts on both resistance and capitant blood verselr With hydraktine, reflex tachycadia and increase in cardiac output accompany Mood pressure lowering, whereas with a mixed arteriolar-venous dilator. .cardiac output tends to m a i n unchanged or. indeed, to fall in hypertensive patients due to r e d u d venous retum. The latter may indetd be associated with postural hypotension The arteriolat selective drugs Qlnclude . '

hydralazine, diazonide and minonidil. The remaining'vasodiIator antihypertensives ' '. are non-selective and vary little in the balance of arteriolar versus venous dTcctcctand from the clinical point of view cannot be readily distin yished;Not surprisingly some of them (prazosin and nitroprusside) haw an application in the management of congestive heart failure because they combine reduction of after-load with diminution in prc-load. In hypertension these drugs do nat have a rnajcrcffact on cardiac output, as stroke volume remains relatively constant in the facc of a fall in outflow resist?ncc (Cohn and Frdnciosa, 1977). b . .. . ,.

Minoxidil . - .

Minoxidil has been under intense clinical scrutiny for the past decade and as it is likely to be approved shortly for clinical use in a number of'countrics it is perhaps timely to review the clinical pharmacology of this effective, ooa-specific vasodilator antihypertensive agent ,.*.

After oral administration the antihypertensive effect of minoxidil i s maximal at .

3-4 h and the duration of action depends intrr dia on tbc severity of hypertcnsioa While many patients can be controlled adequately with onot brily administration, initially the drug shouM be given twice a day. The pattern &antihypertensive action dots not rrlate in a simple manner with plasma kvek the cooantrdtion of pareot dmg being extremely low after 6 h As with otber v d l l o r s . the drug is taken .. up by blood vessels and its persistence therr m y explain the kngthy duration of

I

. Ei"r6' t . H s e m o ~ ~ ~ m i c rksponses to minoxidil ( M ) and the combination of mikxidil i. and popran0101 ( M + P) in patients wit/, u tmt ia l hypertonsion (O'MaLy et aL -

I . . . - . . .. .: . . - . . . . , . : . . , . . . . , . .

. . . . . d o n and lack ofcorrdation 4 t h plasma kvels. T& dose-resvonse ;lationship is. however, relatively simple. iberc being a n t k r narrow range ofslopes and threshold

. % doses. Thus, it is easy to adjust dose and control blood pressure rapidly (O'Malky and McNay. 1975). Wben rapid control of Mood pmsure is required, 50% inmmcnts in dose may be administered every 6 b until goal pressure is reached.

Haemodynamic responses

. The Leernodynamic mponse o b d (Fig. 1) is hmhr to that seen with other

. arteriolar selective vasodilators, most changes k i n g rrfkxogenic in myonx to blood ' press- duction-tachycardia. iocrrasc in stroke volume, increase in plasma m i n

mivity and sodium retention. TbeK changes have t k encct of offsetting the anti- . hypertensive d l i c t ~DCI it ir invariabty narssaq to add a @-adrcnergic blocking drug

Ibd I diluetic. . ; r

. . . . Unwanted effects I

I

lVhik minoxidil has bcen shown to be a highly effative antihypertensive agent, both in our own studies and in those of others (Gilmorc ct d.. 1970; Gottlieb er d.. 1972; Pettinger and Mitchell, 1973) this drug dots have some serious unwanted eflects. It causes liypertrichosis in a very hi& perantage of patients. ln our experience, virtually all patients on tmtment with this drug in a d w of more tban 10 mgiday for more than 6 months developd some &gcc of hypertrichosis. The mason for development of hypertrichosis is n d known. Another vasodilator agent. diamxide, causcs this problem with long-term tlzrapy. Thc hair growth is lanugal in type and is not related to alterations in sex hormones. It may be related in some way to increase in skin blood flow. This unwanted efTect severely h i t s the use of minoxidil in females.

A second unwanted ellict of considerable importance is d i u m retention. The degree of sodium retention is inversely related to rtnal function and many patients with poor renal function may prove quite resistant to treatment. even with high doses of fruxmide. Particular care must k takcn not to precipitate pulmondry oedema as sodium retention can be very marked. . .

There are several possible mechanisms involved io the d& ietmtion including stimulation of the renin-anRiotmsio-aldmterme system and alterations in dirc- tribution of renal blood flow (Zins. 1974). In addition. the marked lowcring of blood pressure possible with this drug. could in itxlf kad to sodium retention in patients with nephrosclerosis and poor renal function.

Sidetffects related to increase in sympathetic estivity are readily controlled by the use of p-adrenergic blocking drugs. In addition. these agents potentiate the anti- hypertensive efrcct of the vasodilator by cutting out the contemporary reflex changes that tend to ofTxt the hypotensive effect of t h vasodilator. While relatively large doses of 8-adrenoceptor blocking d r u g may be required initially, with chronic use the dose rtquirement falls (Brunner et al., i978).

.It .seems likely. in view of the seriousness of the unwanted e h t s of rninoxidil, that it will find a role only in the managemcat of patienu with severe hypertension

'

who arc resistant to conventional antihypenmsive agents.

Prazosin \ . .

Prazosin is one of the newer "vasodilator" compounds and is certainly one of the most interesting. Clinically its effectiveness bas been demonstrated in hypertension and congestive heart failure.

Prazosin was initially synthesized for its phosphd i t c r a sc inhibitory e f f i t . Not only does its structure include the dimcthoxybenzo moiety of papaverine, a potent phosphodiesterax inhibitor. but it also has some features of cyclic AMP and cyclic GMP, both of which are important i a ~ k rrgutation of vascular smooth muscle tone. Initial assessment confirmed its vasodilator activity and hypotensive effect in dogs (Constantine ur uf.. 1973). However. fur tba s tudia in rats. cats and dogs demon- strated the need for an intact sympathetic oerve supply. This finding. coupled with the clinical obxrvutions of an hence of rcflrx tachycardia o r increase in plasma renin activity. indicated that it is [lot a n m p e c i k v d i l a t o r .

The bulk of evidcnce now points to an a-adrcnoceptor blocking mechanism of

action although direct vascular smooth muscle relaxation may occur at very high d o s e in animals. In addition to the nced for an intact nerve supply Tor prazosin to decrease vascular resistance (Wood er 01.. 1975) it has been shown that pramsin attenuates the pressor response to noradrenaline and cifezoliae. a specific a-agonist (Cavero and Lcfevre, 1976). and sympathetic stimulation, but docs not reduce the pressor mponse to serotonin. vasopressin (Wood er d., 1975) or angiotensin I1 (Graham et 01.. 1977; Stokes and Oatcs, 1977). suggesting an a-adrcnoceptor kvel of action rather than direct vasodilation. Reversal of the pressor response t o adrenaline. which m r s uith a-adrenoccptor blocking agents has been demonstrated with prazosin (Stokes and Oates, 1977; Graham cr d., 1977). IIS adrcnoceptor- blocking action is confirmed by abolishing its erect by prior blockade with conventional a-adrenoccptor blocking agents such as phentolamine (Stokes.and Oates. 1977) and phenoxqbenzamine (Cornmarato et 01.. 1978).

Although prazosin fulfils the criteria .for an a-adrcnoceptor blocking agent. and is more potent than phcntolamine in this respat, it does not demonstrate the typical reflex changes of conventional a-adrenoceptor blocking agents. Langer's (1974) concept of presynaptic a-receptors prompted further studies of the nature of the a-blockade associated with prazosin.

Cambridge er a/. ((1977) compared the etTm o r pramsin and phmoxybenzamine on the airnulation-induced overflow of tritiated noradrenaline ('HNA) in rabbit pulmonary artery. Prazosin. in concentrations which produced similar antagonism of postspapric function to that seen with phenoxybenzamine, caused no significant increase in tbe overflow of 'HNA. white phenoxybenzaminecauxd a marked increase in overflow. Graham er al. (1978) demonstrated a disproportionately greater (300"/) i m a s e in plasma noradrenaline response to equipressor doses ofphenoxybenramine and prazosin. tbereby confirming a relaiive selectivity of prazosin for postsynaptic adrenoceptors. .- . .

Prazosin does not causs an overflow of noradmnaUne owing to lack of interference with prrsynaptic inhibition of noradrenaline release, which is the postulated theory ror the absence of reflex tachycardia and rise in plasma rcnin activity. Similarly, ia the majority of animal studiq, prazcsin causes tither no change or a reduction in plasma renin activity. Massingham and Haydco (1975) demonstrated DO significant increax in plasma renin activity in conscious hyperrtnsive dogs, given i.v. or oral prazosin. In anaesthetited dogs given prazosin i.v., plasma mnin activity was significantly lowered to 62Y; of the control value with prazqsin, in contrast to a rise in activity of 180"/, ofcontrol value when dimoxide was administered. Similar findings apply in man (Roscnthal 1978).

Although the selectivity of a-blockade exhibited by prazosin may r t d u k circulating amdrenaline. this is not the only pathway for reflex eff'ecls. broreceptor reflex function should normally compensate for falls in blood pmsure., As demonstrated by Bun to (1978J sympathetic responsiveness m a i n s intact in the face of a challenge but yet the hypotension M u d by pramsin is inadequatc,to stimulate the expected . . mponsc. . .

It would seem from irr ritro and in vim animal st& that pratosin is a xkctive portsynaptic a-adrcnocxptor blocking agent in doses studid, although t bc pharmaco- dynamic picture is not oompkte. It is of interest that the selectivity varies among speck. Its lack of Hest on plasma rcnin activity axxi heart rate ore suggestive. but nor conclusive proof. ofits selative postsynaptic a-adrmoceptor blocking action in man. a probabk explanation that hrrs so far been difficult to prove. in any event t k absence of an inrrurx in sympathetically mediated m p o n x accounts. partly nt kast. for the greater cfkacy of prluosin compared to older a-adrenoceptor blocking drugs such as phentolamine and phcnoxybenutminc in esxntial hypertension.

Calcium Anatagonists in Hypertension .

While vasodilating drugs have lo'ng baen of use in the treatment of systemic hypertension. the mechanism of action of thcse d r u g is still unclear. It h& becn suggcstcd t b t hydralazinc (Koch Weser, 19768) and diszortidc (Koch W a r , 1976b) exert their effect by chelating certain trace metals required for smooth muscle contradork. It has also k e n postulated that diazoxiOccompctcs withcalcium to lower smooth muscle t o w (WON et al.. 1867). Minoxidil may exert its effect by blocking '.

calcium entry at the plasma membranes. M u m n i t r o p w i d e is thought to eitbcr inhibit cakiurn release in the cell or calcium activation oo the contractile protein.

In view of the putative links between the established vasodilatingdrugs and c a l c i u ~ . . . it is not surprising that there has been interest in the hypotcnsive effect of the calcium:!': .'.: antagonist group of drugs. The most commonly used calcium antagonist drugs arc S" nifedipine. a pyridine derivative. and verapamil. a synthetic papaverine derivative: ..: ,. . These drugs combine a peripheral and coronary artery vasodilatingeffect 'with a negative inotropic effect on the heart. thus diminishing myocardial oxygen require- ment (Nayler, 1%7: Nayler and Szeto, 1972: Ross and Jo rgnxn , 1967). These drugs are in common w for the treatment o r angina (Andreasen et aI.. 1975) and are particularly useful in the tkatment of coronacy';rrtery spasm or Rinzmetals angina, where 6-adrenoccptor blocking drugs may be contraindicated (Hansen et al.. 1978). Theoretically, the calcium antagonist group of drugs should be f m of some of the side-effects of the established vasodilating drugs and tbercfore might be of particular value in the treatment of hypertension w h m it is associated with angina pectoris.

Splitting of ATP is required for the energy delivery process of muscle contraction '

and this process is dependent on calkium. Calcium antagonists act by blocking the passage orextracellular calcium from the superficiatly located membrane storage areas of the sarcoplasmatic reticulum into the cell p!asllla, where the ATP-asc of the . . ,

myofibrils is located. Ln the heart. inhibition of cakium displacement produck a '.

ne~ative inotro~ic effect. In addition. reductictu of the amount of calcium available at&e myofibrii. leads to a dinlinutidn in turnover or high energy phosphates, thus reducing myocardial oxygen demand. ..

I

Mifedipine 1

Nifedipine has a rapid onset of byp~tcnsiie action after both oral (20 min) and . . sublingual (5 min) administration (Guazzi el d.. 1977). The hypotensive efCect is . accompanied by increses in heart rate (21%). stroke index (7%) and cardiac index ,

(WA) with a 40% reduction in total peripheral mistance. No change occun in mean right atrial pressure suggesting that nifcdipine does not sipificantly diminish venous tone. In chronic dosing (Olivari er d.. 1979) the pattern is rdther similar with the response to each dose lasting 8-12 h. Sideeffects include headache and palpitations

7 8 but postural hypotension is not seen, Of particular interest' is the failurn of nifedipine to markedly perturb the renin-

angiotcnsin system. Modest increases (WQ in p lasm rcnin activity have been observed (Lederballe-Pedersen et d.. 1979). This contrasts with the five- to ten-foM increases observed with minonidil (O'Malky et al.. 1975). In addition to reflecting a slightly smaller hypotensive effect. these differences most likely indicate that nifedipine attenuates renin responsiveness

Vasodilarom in the trsrtnmnt of nypsriension

Tbe antihypertensive cf6cacy of verapamil in the acute situation is documented in a number of studies as reviewed by Lcwis ( 1978). LederbaUe-Pcdersoo (1978) studied the antihj-pmensive cfTect of verapamil on six hypertensive patients whose diastolic pressures were greater than 100 mmHg. and found that the drug given i.v., produced a significant reduction in blood pmsure ahich was accompanied by an incrtasc in beart rate. Chronic dosing ( 3 2 W rng,'day) produced a modest reduction in blood pressure (mean reduction 14/12 mmHg) but it is obvious that full evaluation of the hypotensive potential of this drug would require more extensive studies. There is insufficient information available at present to assess the clinical potential of verapamil in hyperteq~i . In addition. the marked effect on impeding A-V

)conduction (Husaiai. .& s e n after veraparnil. but not with niredipine (Rowland cr a]., 1979) may preclude its use in palienu with conduction disturbanm. Fatal bradyarrhythmias have been rrponed following the use of verapamil i.v., especially when it is combined with the use of/3-adrcnoceptor blockinp drugs (Ben& 1972. It seems likely. therefore. that verapamil may havelittk to ofler over other vasodilators becaw of this troublesome erect. There arc studies currently under way on various other calcium antagonists, including RO 11-1781 which rwmbles vcrapamil in its antiarrhythmic qualities. -

Summary . .. . . . , . . . . .. . . , . - . .. . The major advantage of tbe use of dl& antagmist drugs in the treatment of hypenension lies in their use io the patient with concomitant ischaemic hean disease, in whom the use of conventional vasodilators may te contraindicated:ln addition, the lack of a major efTcct of these drugs on the renin-angiotensin system and sodium balance requires further long-term study. as &is may prove to be an important advantage over older vasodilators and raise the possibility that these drugs may be used as moootherapy.

Adrearen. F., Boye, E., Christo~crsea, E., D a l s p d . P.. Henneberg. E.. Kallenbach. A.. Ladefogad S.. Lillquist. K.. Kilkdsen. E. Nordero. E.. Olsen, J.. Pedersen. J. K., Pcdmen. U, F'ederxn. G. B.. Schroll. J., Scbultz, H. and Seidelin, 1. (1975). hscssmcnt of verapvoil in tbe treatrnent'of angina poctoris. Ewopcm Jonrnol of CPrdiology Y4.443-452.

Bcnaim. M. E. (1972). Asytok lfter -1. BritirJI Mrai'cal Journol2. 469-110. Brunncr. H. R, J q . P.. Ferguson. R K, laquicr. E..'Turini. G. and Gevpr. H. (1978).

Nccd for &bloclro& in hypertension reduced with long-term minoxidil. British Mrdical J o d 2 383-388.

B-. L.. Stoik. J. M. and Lownnein. J. (1979). Effect of pratosin on mponws to insulin- induced hypoglycaanin. =&S oj' the lntrrnatiowl Swicty of Hype trnrion (Puru) u ( a t s m I. k

Cambridge. D., D a n y . M. J. and Masingham. R (1977). The pharmacology of anti- hypertensive drugs with spacial dcrem to vasodilators. a-rdrcnergic blocking ngen~s and puosin. Mrdicd,Juurtml u j Arrrtrulia 2 (Suppl.). 2-6.

\

Cavero. I. and tefevrc. F. (1976). Cardiovascular cKects of p a o r i n in spontanmurly hypertensive rats (SHR). Clinical curd Erprrimmtd Phonncudogy and P~I-sidogy 3 (Suppl.). 6144.

Coho. I. N. and Franciosa. J. A. (1977). vasodilator t h m p y of cardisc failure. ,h fig!& Journal of Medicine 297. 27.

Cornmarsto. M. A. Landcy. A E.. Dugaa. D. H.. Lattimc E. c. Smith R. D.. T a m = D. K. and Kaplao. H. R. (1978). Raroria and phentokminc: comp;uative cardiovascular and autonomic pro*. CILu'cal ad Erprimentd Hyper- tension 1. 191-217.

Constantine.. J. W.. McShanc. W. K, Scriabiac A and Hess. H. J. (1971). Analysis &the' hypotensive action of p r a m i n In 'Hypcrtensioa: Mechanisms and Management" (Eds G. k t i . K. E. Kim and J. Moyer). p. 449. Grune B; Stratton. New York.

Gilmore. E.. Weil. J. and Chidsty. C. (1970). Treatment of essential hypenension wi& a new vasodilator in combination with 8-adrenergic blockade. New Ljlgland Journal of .Uudicinc 282. 52.

Gottlicb. T. B.. Katz F. H. and Chidsey. C. A (1972). Combined therapy with vasodilator drugs and 8-adrcnergic blockade in hypertension: a comparative study of

a

minoxidil and hydralazine. Circulation 45. 571. Graham. R. M.. Oat- H. F.. Stoker. L. and Stokes. G. S. (1977). a-blocking actioo of the

antihypertcnsiw agent. prazosin. Journal ojPharmacolog~ and Erperimm~al Thuraprurics 201. 747-752.

Graham. R. M.. Kennedy. P.. S~ephenson, W. a d Petdnga. W. A. (1978). In vho evidence for the presynaptic a-adrcncrgic receptor controlling norepioephrine release. FtCrarion Proceedings 37. 308.

Guani. M., Olivari. M. T.. Polex. A.. Fioren~ini. C.. Magrini, F. and M o d . P. (1977). Nifedipine: a new antih>pertensive with tapid action. Clinical Pi~armacology and Thirapr ics Z2. 528.

Hanxn. J. F. and Sandoe. E. (1978). Treatment of Prinzmetal's angina due to coronary artery spasm using vcrapamil. E w o p n Journal of Cardiologj S(d), 327-335.

Husaini. M. H.. 1.. Ryden, L. and Holmberg. S. (1973). Action of vcrapamil - on sinus node. atrioventricular and i n t r a v e n i r conduction. British I Heart Journal 35. 734-737.

Koch-We-. J. (1976). Hydralazinc. Ncr fixland Journal qf Medicine 295. 320. Koch-Weser. J. (1976b). Dizoxide. New figland Jownal of Medicine 294. 1271. Langtr. S. L. (1974). Presynaptic rrguLatiw of catecholamine release. Biockmicml

Pharntocology 23. 1793-1 800. LederbaUe-Pederxn. 0. (1978). Does venpamil have a clinically signik.int antihypertensive

effect? European Journal of Clinical Phartacology 13, 21-24. Lederballt-Padenen. 0.. Mikkelscn, E.. Christtnscn. N. J., Kornerup. H. J. and Pederscn.

E. B. (1979). Effect of nifedipine on plasma renin. aldosterone and catecholamines in arterial bypehension. European Journal of Clinical P h a r m u c o l ~ 15. 235-240.

Lewis. G. R. J., Morlcy. K. D.. k w j s . M. B. and Bowcs. P. 1: (1978). The treatment of hypertension with verapami). New Ztaland Medical fournd 87. 351-354.

Massingham R. and Hayden. M. L. (1975). A comparison of the effects of prazosin and hydralazine on blood pressure. heart rate and plasma rrnin activity in conscious rend hypertensiw dm Ewopcun Journal of P h u m u c o l ~ 88. 121-124.

Nayler. W. G. (1967). Calcium exchange in card'i murk. a basic mechanism of drug mion. Amuric* Heurr Journul IS. 37?-394.

Nayler. W. G. md Szcto, J. (1972). Eflirt of m p a m i l on contractility, oxygen utilization and Ca- - cxchwgeability .on rrmmmalian hart muscle. Curdiov~~~culur Ru.uurch 6. 120.

Olivari. M. T.. hrtorelli. C.. Polhe. A.. Fiomntioi. C.. Moruni. P. and G u d . M. D. (1979). Treatment of hypertension with niiedipinc. a calcium antagonistic agent. .

Circuluriun 59. 1056- 1062.

Vasodilaton in the treatment of hypertension 81

.O'Malley. K. and McNay. J. L. (1975). A method for achieving expeditious blood pmsure ; control using cumulative minoxidil dosing. Clinical Phormacolng?. and

fh~rapeurirs 18. 39. ' . . Pettinger. W. A. and Mitchell. H. C. (1973). MinoxidilIan dternntive to nephmorny for

refractory bypenension. h'cu. England Journal of Medicint 239. 167. Rosenthal. I.. Jaegcr, M. and Arlan. 1. (1978). EfTccts of prazosin on Mood prssurc d

plasma rrnin activity in man. Proc~dings oj' rha h t t m a r r o ~ l Socury of Hypcrr~mion (Paris) 224 abstract).

' Ross, G. and Joqenue C. R. ( I 9 6 ~ d i o v a s c u l u actioL of lproverntrit. Phurmocolog? cmd Erp~rimenral 77rerapcurics 199. 504.

. Rowland. E.. Evans. T. S. and Krikla. D. (1979). Effects of nifedipinc on alrioventricular . ~

conduction as compared && ve pamil--inrraca;diac clatrophysiologic study. 8~ uL q3- : lw+ -

e J 5 - Stoker G. S. and Oates. M. F. (1977). Comparative and interaction studies with peripherally

acting hypotcnsive agents. Medical JorunolojAwrralia 2 (Sp. Suppl.). 9-10. Wohl. A. I.. Hausla. W. M. +d Roth. F. E. (1967). Studies on tbe mechanism of anti-

hypertensive action of diazoxide: in rirro phamacodynamics. Journal of Pharmacologj. and 7Xcrapeurics 198. 531.

Wood. A. J., Phelan. E. L. and Simpson. F. 0. (1975). Cardiov'sscular effects of prazosin . in nomotensivc and generically hypertensive rats. CIinicaland Lrperimmral Pharmacology and Phj-siofogx 2 27-3M. '

Zins. G. R. (1974). Alterations in rtnal function Advances in Renal Physiology FaneUi). University Park Rcn. Baltimore.