Drugs 35 (SuppL 6): 53-59 (1988)

0012-6667/88/0600-0053/$3.50/0© ADIS Press LimitedAll rights reserved.

Effects of o-Adrenoceptor Blockers on Renal Functionand Blood Pressure Adjustment in HumanHypertension

Gastone LeonettiIstituto Clinica Medica Generale e Terapia Medica, Universita di Milano and Centrodi Fisiologia Clinica e lpertensione, Ospedale Maggiore, Milan

Summary In this paper. the different aspects of the roleplayedby o-adrenoceptors in the controlofrenin secretion from the juxtaglomerular apparatus and renalsodium and water reab­sorption, and the effects of a-adrenoceptor antagonists on systemic haemodynamics, willbe investigated.

Animal experiments suggest that the renal a-adrenoceptors exert a restraining actionon renin secretion while increasing tubular reabsorption of sodium and water. A recentstudy in man has confirmedthe a-adrenoceptor-mediated inhibition of renin secretion.

Previously available ganglion blocking and antiadrenergic agents. while causing a sig­nificant supine bloodpressure reduction. can cause at the same time clinicallyrelevantside effects such as orthostatic hypotension, sedation, drowsiness etc. The advent ofselec­tive «i-adrenoceptor blockers. such as prazosin and urapidil, allow a significant bloodpressure reduction without significant interference on haemodynamic adjustments andonly inducea limited incidence ofside effects.

Many of the drugs that have been used, and arestill being used, in the treatment of hypertensioninterfere in one way or another with sympatheticcontrol of circulation. Extensive interest in the de­velopment of drugs with this mechanism of actionstems from knowledge of the important role playedby sympathetic activity on blood pressure control,on the increasing understanding of the physiolog­ical organisation of sympathetic functions, and onthe widespread opinion that some derangement inthe sympathetic control of the circulation is in­volved, either primarily or secondarily, in thepathogenesis of hypertension.

This review will examine 2 different aspects ofthe a-adrenergic component of the sympatheticnervous system: (a) its relation with renal function ,

and (b) the effects of e-adrencceptor antagonists onsystemic haemodynamics at rest, during dynamicand isometric exercise, and during carotid baro­reflex activation.

1. Renal a-Adrenoceptorst Activation andInhibition

Stella and Zanchetti (1985) stressed that sym­patho-renal interactions may play an important rolein the genesis or maintenance of hypertension, withsome of these interactions having the characteris­tics of a positive feedback mechanism, in whichthe sympathetic system influences several renalfunctions and these, in turn, potentiate sympath­etic activity. Of the renal functions under sym-

a-Blockers in Hypertension 54

Intact Denervated

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Fig. 1. Effect of electr ical stimulation of the vasomotor centre

in the brainstem of the cat. Mean values ± SEM are shown for

renin release (histograms and bars) and for renal blood flow(....) measured just before (C) and at the end (5) of a 5-minute

stimulat ion period . Comparisons were made between intact and

denervated cat kidney (top panel); intact cat kidney and cat kid­

ney injected with phenoxybenzamine [nonselective e-adreno­

ceptor antagon istl (middle panel); before and after the systemic

infusion of prop ranolol [nonselective Il-adrenoceptor antagon­

ist] (bottom panel). Abbreviation: AI =angiotensin I. From Stella

& Zanchetti (1985).

kidney subjected to a-blockade showed no vaso­motor response and had a greater rise in renin se­cretion than the kidney with no a-blockade.

Finally, the influence of ,a-receptors was inves­tigated with the systemic infusion of the non-se­lective ,B-blocker propranolol. Propranolol pre-

1.2 Renin Release

1.1 Renal Vasomotor Function

pathe tic control , the renal vasomotor function,renin release and tubular reabsorption ofwater andsodium are all influenced, though in different ways,by a-adrenergic receptors.

Electrical stimulation of afferent renal nerves hasbeen shown to elicit an increase in arterial bloodpressure in cats and rats; however, in dogs and rab­bits the same manoeuvre causes a decrease in sys­temic blood pressure. As shown in figure lour dataconfirm the neural nature of renal arteries vaso­constriction in that the electrical stimulation of thevasomotor center in the brainstem of the cat causeda fall in renal blood flow in the innervated kidney,whereas no change in blood flow occurred in thecontralateral denervated kidney. The intrarenal in­fusion of a small amount of the o-adrenoceptorblocking agent, phenoxybenzamine, under the sameexperimental condition of brainstem stimulation,induced a slight passive increase in blood flow tothe injected kidney, while the blood flow to thecontralateral kidney was reduced. Finally, the sys­temic infusion of the ,a-adrenoceptor blocking drug,propranolol, did not affect the renal vasoconstric­tor response. Therefore, renal nerves appear tocontrol renal vessel vasoconstriction by an actionof o-adrenoceptor receptors.

Figure I summarises experiments by our group(Stella & Zanchetti 1986) showing the opposite rolesof a- and ,a-adrenergic receptors on the sympath ­etic control of renin release.

Firstly, renin release was compared between theinnervated and denervated kidney of anaesthetisedcats. Electrical stimulation of the brainstem vaso­motor centre stimulated renin release from the in­nervated kidney only.

To define the role played by a-adrenergic re­ceptors, anaesthetised cats, with both kidneys in­nervated , had phenoxybenzamine, a non-selectivea-adrenergic blocker, injected into I renal arteryonly. During central vasomotor stimulation, the

a-Blockers in Hypertension

vented a rise in renin secretion during vasomotorcentre stimulation, while leaving the vasomotor re­sponse present. These 3 experiments suggest thatrenin release after sympathetic nerve stimulationis mediated through the activation of l3-adrenergicreceptors, while a-receptors exert a restraining in­fluence.

Morganti et al. (1982) investigated whether a­adrenergic receptors exert a similar restraining in­fluence on renin release in hypertensive patients.They measured the renin response to an a-adren­ergic receptor stimulating drug, phenylephrine, andto a l3-adrenergic receptor agonist, isoprenaline(isoproterenol), before and after infusion of a non­antihypertensive dose of the selective aI-adrener­gic receptor antagonist, prazosin . It appears that a­

adrenergic receptor blockade by prazosin potenti­ated the renin stimulating activity of isoprenaline(fig. 2). The non-antihypertensive dose ofprazosinused in this study excludes a reduction of renal per­fusion pressure as a possible cause of the potenti­ated renin secretion. Therefore, this study indi­cated that in humans l3-receptor stimulation ofrenin secretion is also inhibited by o-adrenocep­tors.

1.3 Tubular Reabsorption of Sodium

It has been shown in animal experiments(Thames 1984) that the effects of sympathetic renalnerves on different renal functions are mediatedthrough different stimulus frequencies . Renin se­cretion is stimulated at very low frequencies, renaltubular reabsorption of sodium and water is po­tentiated at intermediate frequencies, and renalvasoconstriction is induced at higher frequenciesof renal nerve stimulation. To investigate whethersympathetic effects on tubular reabsorption of sod­ium are mediated through a- or l3-adrenoceptors,Osborne et al. (1983) evaluated the effects of theselective l3-adrenoceptor antagonist, atenolol , andof the al-adrenoceptor antagonist, prazosin, duringlow frequency stimulation of renal nerves. Theyfound that while atenolol suppressed renin secre­tion, it had no effect on the anti natriuretic actionof renal nerve stimulation. Prazosin, on the other

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Fig. 2. The open bars represent the effects of isoprenaline be­

fore prazosin administration and indicate , in the upper panel,

the absolute values of plasma renin activity (PRA) in control con­

ditions (C) and immediately following the infusion of isoprenaline

(ISO). The lower panel shows the isoprenaline-induced incre­

ments in plasma renin activity calculated as percentage of base­

line values . The shaded bars represent the effects of isopren­

aline in comparable conditions, but after prazosin administration.

Values within bars are mean arterial pressure (MAP) observed

before and at the end of each isoprenaline test.

* = p < 0.05; ** = p < 0.02. From Morganti et al. (1982).

hand , prevented the anti natriuretic effect of renalnerve stimulation, but potentiated the renin secre­

tory response . This indicates that sympathetic con­trol of tubular reabsorption, like control of the va­somotor function and unlike control of renin

release, is exerted through stimulation of a-adren­ergic receptors.

a-Blockers in Hypertension

2. Effects of «-Adrenoceptor Antagonistson SJ'mpathetic Adjustment of Circulation

Not surprisingly, the first effective antihyper­tensive drugs to be developed were those interfer­ing with sympathetic adjustment of the circulation(e.g. ganglion-blocking agents). However, the pro­found blockade of sympathetic activity necessaryfor ganglion-blockers to significantly lower supineblood pressure dramatically interfered with the ad­justment of circulation, thus causing posturalhypotension and a fall in blood pressure during ex­cercise. Little progress was achieved when so-calledantiadrenergic drugs, such as guanethidine and be­thanidine, were introduced, because the interfer­ence with the sympathetic adjustment of circula­tion was still too profound.

The belief that antihypertensive drugs acting onthe sympathetic system unavoidably interfere withcardiovascular homeostasis to a disturbing extentwas shown to be erroneous when agents with a siteof action in the central nervous system, such as 0'­

methyldopa and 'clonidine, were introduced in thetreatment of arterial hypertension. Mancia et al.(1978) showed that a-methyldopa significantlylowers blood pressure without markedly affectingthe haemodynamic changes induced by isometricand dynamic exercise, the only differences beinglower pre-exercise levels of blood pressure and totalperipheral resistance. Furthermore, a-methyldopawas shown to not interfere with the blood pressuredecrease induced by stimulation of the carotid sinusreflexes by the neck-chamber technique, whereasthe increase in blood pressure caused by reflexdeactivation of the carotid sinus was somewhat re­duced. This may explain why a-methyldopa gen­erally induces a greater blood pressure fall in thestanding, rather than the supine, position.

Centrally acting antihypertensive agents, whilerepresenting a considerable advance on ganglion­'blockers and antiadrenergic agents, also producesignificant side effects such as drowsiness and dry­ness of the mouth. These have limited their use­fulness, especially in mild hypertension.

More recently, interest has shifted to peripher­ally active drugs. Although it has long been known

56

that sympathetically induced vasoconstriction ismediated through a-adrenergic receptors, the pos­sibility of reducing blood pressure by using a-ad­renergic receptor blockers was scarcely investigateduntil recently, because the available non-selectivea-blockers, phenoxybenzamine and phentolamine ,had been shown to interfere with cardiovascularhomeostasis during standing, rest and exercise.

Prazosin, a selective al-adrenoceptor antagon­ist, is an improvement on non-selective a-blockers,as it significantly lowers blood pressure by reduc­ing peripheral vascular resistances without affect­ing cardiac output or increasing heart rate, andwithout interfering with haemodynamic adapta­tions to dynamic and isometric exercise (Manciaet al. 1979). Furthermore, reflex responses to ac­tivation and deactivation of the carotid sinus re­main intact with prazosin. The ability of prazosinto modulate sympathetic tone without interferingwith baseline sympathetic activity may be due to

.its selectivity of al-adrenoceptors without any ant­agonism on a2-postsynaptic adrenoreceptors. Thismeans that cardiovascular homeostasis remains in­tact even when blood pressure is reduced. How­ever, the preservation of homeostasis is seen onlyunder long term therapy when the effective doseof prazosin is carefully titrated over several days;too large an initial dose or too brisk a change ofthe dose can cause a transient impairment of car­diovascular control, a phenomenon known as 'first­dose effect' (Graham et al. 1976).

Urapidil, an al-adrenoceptor antagonist with anadditional central action, has to be considered inthe light of our experience with previous a-block­ers in hypertension. In our study (Leonetti et al.1986a) urapidil caused a similar reduction in bloodpressure to the .a-blocker metoprolol in both thesupine and upright position (fig. 3). Furthermore,urapidil, while selectively limiting the blood pres­sure rise induced by phenylephrine without affect­ing the pressure response to angiotensin II (Leo­netti et al. 1986b), [fig. 4), did not interfere withthe homeostatic rise in blood pressure and heartrate during dynamic exercise (fig. 5), All these datasuggest that (1) the antihypertensive efficacyby ur­apidil is similar to that of .a-adrenergic blocking

a-Blockers in Hypertension

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Fig. 3. Supine (e) and upright (0) systolic and diastolic bloodpressure before placebo (PI) and after 4 weeks on urapidil 30mgtwice daily and metoprolol 100mg twice daily. From Leonetti et

al. (1986a).

agents, indicated by the WHO committee as thefirst choice drug for the treatment of arterial hyper­tension; (2) urapidil interferes with peripheral a,­adrenoceptors; and (3) urapidil does not interferewith the haemodynamic adjustments to dynamicexercise.

3. Conclusions

a t-Adrenoceptor antagonists, by their vasodi­lating property , their ability to lower resting va­somotor tone without interfering with physiologi-

Fig. 4. Increases in systol ic and diastolic blood pressure in­

duced by standard doses of phenylephrine and angiontensin IIbefore and at fixed times after urapidil25mg intravenously. Ab­

breviation: asp =change in blood pressure. •• =p < 0.01. From

Leonett i et al. (1986b).

cal modulation, and their antagon ism of thesympathetically induced renal reabsorpt ion of sod­ium, can be considered effective antihypertensiveagents. The data available for urapidil indicate thatit shares the favourable features of other ai-block­ers, with the added advantage that initial titrat ionof urapidil may be unnecessary or easier than withprazosin (Pozenel 1986).

There is a further aspect of a t-adrenoceptor ant­agonists that deserves comment. Various interven-

a-Blockers in Hypertension 58

Fig. 5. Exerc ise-induced increases in systolic blood pressure(li SSP) and heart rate (6HR) dur ing placebo. urapidil and me­topr olol treatment of hypertensive patients . 0 = placebo; • =

urapidil, J. = metoprolol. •• = p < 0.01 vs place bo.

References

Cambien F. Plou in PF. Prazosin does not alter levels of plasmalipids. glucose and insulin. Journal of Cardiovascular Pharma­cology 7: 516-519. 1985

Graham RM. Thornell IR. Gai n JM. Prazosin: the first dosephenomenon. British Medical Journal 3: 1293-1297. 1976

Leonetti G. Mazzola C, Boni S. Guffanti E. Meani A. et al. Com­parison of the antihypertensive effect of urapidil and meto­prolol in hypertension. European Journal of Clinical Pharm a­cology 30: 637-640. 1986a

Leonett i G. Terzoli L. Rupoli C. Gradnik R. Zanchett i A. Effectsof intravenous urap idil on blood pressure. renal "plasma flowand responsiveness to vasoconstrictor agents in hypertensivepatients. In Amery (Ed.) Treatment of hyperten sion with ur­apidi l: preclinical and clinical update . pp. 11-18. Royal Societyof Medicine Services. London. 1986b

Liebau H. Haehn KD, Behr H. Wurst w. Antihypertensive actionofurapidil : results ofa mult icenter trial. In Amery (Ed.), Treat­ment of hypertension with urapidil : preclinical and clinical up­date. pp. 165-171, Royal Society of Medicine Services. Lon-don . 1986 "

Mancia G. Ferrari A. Gregorini L. Leonett i G. Terzoli G, et al.Effects of treatm ent on basal hemodynam ics and on neuralcirculatory control. In Zanchetti (Ed.) Methyldopa in hyper­tension. pp. 50-62. Rahway. New Jersey. 1978

Mancia G. Ferrari A. Gregorini L, Ferrari MC, Bianchini C, etal. Regulation of the circulation during antihypertensive treat­ment with prazosin. In Rawlings et al. (Eds) European pra­zosin symposium. pp. 15-21. Excerpta Medica, Amsterdam 1979

Morganti A. Sala C, Palermo A. Turol o L. Zanchetti A. et al.Dissociat ion of the effects of alpha j-adrenergic blockade onblood pressure and renin release in pat ients with essentialhypertension. Journal of Cardiovascular Pharmacology 4: S158­S161. 1982

the cholesterol abnormalities caused by diuretics(Cambien & Plouin 1985). Urapidil seems to havesimilar properties (Liebau et aI. 1986).

The relevance of changes in serum lipids duringantihypertensive therapy is still unclear, but 2 re­cent trials draw further attention to them. The firstis a large American study on cholestyramine treat­ment which showed that reduction in serum chol­esterol could indeed reduce coronary mortality. Thesecond, and perhaps more relevant, is an Austra­lian trial on mild hypertension. Analysis of thisstudy shows that the hypertensive patients whobenefited least from therape utic lowering of bloodpressure were those in whom serum cholesterol waselevated. It seems likely from these studies that ifthe usefulness ofantihypertensive therapy is to ex­tend beyond mere stroke prevention, a multiple riskstrategy will be necessary, and attention will need 'to be concentrated simultaneously on blood pres­sure and cholesterol control.

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tion trials in which active antihypertensive drugshave been compared with placebo have shown thatantihypertensive drugs have a clear beneficial ef­fecton cerebrovascular disease, but little beneficialeffect on coronary disease. The reasons for this arenot clear and several hypotheses have been sug­gested, one being that the drugs most widely usedin trials (i.e. diuretics) may cause a reduction inserum potassium and a rise in serum cholesterolconcentrations. It is interesting that prazosin , of allantihypertensive drugs, has the unique property oflowering serum cholesterol and of partly correcting

a-Blockers in Hypertension

Osborne JL, Holdaas H, Thames MD, Di Bona GF. Renaladrenoceptor mediation of antinatriuretic and renin secretionresponses to low frequency renal nerve stimulation in the dog.Circulation Research 53: 298-304, 1983

Pozenel H. Antihypertensive effect of two doses of urapidil at restand during exercise. In Amery (Ed.) Treatment of hyperten­sion with urapidil: preclinical and clinical update , pp. 143-150,Royal Society of Medicine Services, London, 1986

Stella A, Zanchetti A. Interactions between the sympathetic nerv­ous system and the kidney: experimental observations. Journalof Hypertension 3 (Suppl, 4): S19-S25, 1985

Stella A, Zanchetti A. The renin-angiotensin system: physiologi-

59

cal regulation of renin release. In Zanchetti & Taraz i (Eds)Handbook of hypertension , vol. 8, Pathophysiology of hyper­tension: regulatory mechanisms, pp. 365-388, Elsevier SciencePublishers B.V., 1986

Thames MD. Renin release: reflex control and adrenergic mech­anisms . Journal of Hypertension 2 (Suppl. I): 57-68, 1984

Author's address: Prof. G. Leonetti, Centro di Fisiologia Clinicae Ipertensione, Ospedale Maggiore. Universita di Milano, ViaSforza 35, 1-20122, Milano (Italy).