Br Heart Jf (Supplement) 1994; 72: 33-37 Role of ACE inhibitors in hypertension complicated by vascular disease Gordon T McInnes Hypertension is an important risk factor for vascular disease. Therefore, it is not surprising that many patients with hypertension have widespread atherosclerotic disease. Treatment with conventional antihypertensive drugs can be problematic in such patients. In this article I consider the use of angiotensin converting enzyme (ACE) inhibitors in managing hyper- tension complicated by vascular disease, pay- ing particular attention to cerebrovascular disease and peripheral vascular disease affect- ing the legs. Coronary artery disease and atherosclerotic renovascular disease are considered only briefly. ACE inhibitors reduce blood pressure in hypertensive patients by decreasing peripheral resistance with little effect on cardiac output or heart rate. The lack of reflex tachycardia is likely to be due to downward resetting of baroceptor reflexes, though ACE inhibitor induced venodilatation or modification of parasympathetic activity may contribute. The increase in arterial compliance due to ACE inhibition can influence regional haemo- dynamics, with redistribution of blood flow in favour of vital organs. ACE inhibitors increase blood flow and decrease vascular resistance in the regions supplied by the renal, carotid, and brachial arteries both in healthy subjects and in patients with hypertension. Unlike some other antihypertensive agents, such as P blockers, ACE inhibitors do not interfere with the normal haemodynamic responses to stress or exercise while blood pressure reduction is maintained. As a conse- quence of these haemodynamic properties, ACE inhibitors might be particularly suitable for the treatment of hypertension complicated by atherosclerosis. The beneficial haemodynamic effects of ACE inhibitors in hypertension are mediated primarily by inhibition of ACE and the conse- quent withdrawal of the vasoconstricting action of endogenous angiotensin II. Since ACE can also affect bradykinin degradation, some of the vascular actions of some ACE inhibitors might be mediated by changes in concentrations of vasoactive kinins and prostanoids. Although the effects of captopril may depend partly on such mechanisms, studies with other ACE inhibitors have failed to show changes in prostaglandin metabolism. Animal studies suggest that tissue ACE and angiotensin II (particularly in the vasculature) may be more important than plasma concen- trations in determining the haemodynamic effects of ACE inhibitors. It is unclear whether the local effects of ACE inhibitors are entirely due to inhibition of local angiotensin II or interference with other peptide systems. Locally produced angiotensin II may exert a significant effect on vascular tone directly by contracting smooth muscle and indirectly by releasing catecholamines from surrounding nerve endings. Direct clinical evidence suggests that tissue actions may influence regional blood flow. Thus, enalapril, at a dose which did not induce significant humoral or systemic haemodynamic effects, reduced left ventricular inotropic state and increased coronary blood flow when infused into the coronary bed and increased forearm blood flow when infused into the forearm.' Vascular angiotensin II may be a major pathological factor in the development of atherosclerosis (figure), mediating the pro- liferation of arterial smooth muscle cells by many mechanisms, including a direct effect on growth factor production and reciprocal sup- pression of arterial bradykinin concentrations. The effects of ACE inhibition on pro- gression of atherosclerosis has been reviewed recently by Sharpe.2 Early studies showed no beneficial effect on aortic atherosclerosis in rabbits fed cholesterol, but in more recent work captopril was effective in Watenabe rabbits, which have an inherited tendency to secondary hyperlipidaemia, without affecting serum cholesterol concentration; total aortic surface involvement and the cellularity of athero- sclerotic lesions were reduced. In cynomolgus monkeys fed cholesterol, low and high doses of captopril reduced atherosclerotic lesions in carotid arteries by 80% and 95% respectively; coronary arteries were almost free of athero- sclerosis after ACE inhibition. Continuous treatment with cilazapril or captopril prevented neointimal proliferation after carotid endo- thelial denudation injury by balloon catheter- isation; this was not primarily due to blood pressure reduction as verapamil was ineffec- tive. Similar findings have been reported with lisinopril and perindopril in various animal models of atherosclerosis. These actions are likely to be due to blockade of angiotensin II since the same effect has been seen with an AT1 receptor antagonist.3 Preservation of Hypertension Vascular injury Induction of vascular ACE Increase in local angiotensin 11 Vascular remodelling Vascular angiotensin II as a pathological factor in the development of atherosclerosis. University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow G T McInnes Correspondence to: Dr G T McInnes, University Department of Medicine and Therapeutics, Gardiner Institute, Westem Infirmary, Glasgow G1 1 6NT. S 33 on May 24, 2020 by guest. Protected by copyright. http://heart.bmj.com/ Br Heart J: first published as 10.1136/hrt.72.3_Suppl.S33 on 1 September 1994. Downloaded from
Transcript
Br Heart Jf (Supplement) 1994; 72: 33-37
Role of ACE inhibitors in hypertensioncomplicated by vascular disease
Gordon T McInnes
Hypertension is an important risk factor forvascular disease. Therefore, it is not surprisingthat many patients with hypertension havewidespread atherosclerotic disease. Treatmentwith conventional antihypertensive drugs canbe problematic in such patients. In this articleI consider the use of angiotensin convertingenzyme (ACE) inhibitors in managing hyper-tension complicated by vascular disease, pay-ing particular attention to cerebrovasculardisease and peripheral vascular disease affect-ing the legs. Coronary artery disease andatherosclerotic renovascular disease areconsidered only briefly.ACE inhibitors reduce blood pressure in
hypertensive patients by decreasing peripheralresistance with little effect on cardiac outputor heart rate. The lack of reflex tachycardia islikely to be due to downward resetting ofbaroceptor reflexes, though ACE inhibitorinduced venodilatation or modification ofparasympathetic activity may contribute. Theincrease in arterial compliance due to ACEinhibition can influence regional haemo-dynamics, with redistribution of blood flowin favour of vital organs. ACE inhibitorsincrease blood flow and decrease vascularresistance in the regions supplied by the renal,carotid, and brachial arteries both in healthysubjects and in patients with hypertension.Unlike some other antihypertensive agents,such as P blockers, ACE inhibitors do notinterfere with the normal haemodynamicresponses to stress or exercise while bloodpressure reduction is maintained. As a conse-quence of these haemodynamic properties,ACE inhibitors might be particularly suitablefor the treatment of hypertension complicatedby atherosclerosis.The beneficial haemodynamic effects of
ACE inhibitors in hypertension are mediatedprimarily by inhibition of ACE and the conse-quent withdrawal of the vasoconstricting actionof endogenous angiotensin II. Since ACE canalso affect bradykinin degradation, some of thevascular actions of some ACE inhibitors mightbe mediated by changes in concentrations ofvasoactive kinins and prostanoids. Althoughthe effects of captopril may depend partly onsuch mechanisms, studies with other ACEinhibitors have failed to show changes inprostaglandin metabolism.Animal studies suggest that tissue ACE and
angiotensin II (particularly in the vasculature)may be more important than plasma concen-trations in determining the haemodynamiceffects ofACE inhibitors. It is unclear whetherthe local effects of ACE inhibitors are entirelydue to inhibition of local angiotensin II orinterference with other peptide systems.
Locally produced angiotensin II may exert asignificant effect on vascular tone directly bycontracting smooth muscle and indirectly byreleasing catecholamines from surroundingnerve endings. Direct clinical evidencesuggests that tissue actions may influenceregional blood flow. Thus, enalapril, at a dosewhich did not induce significant humoral orsystemic haemodynamic effects, reduced leftventricular inotropic state and increasedcoronary blood flow when infused into thecoronary bed and increased forearm bloodflow when infused into the forearm.'
Vascular angiotensin II may be a majorpathological factor in the development ofatherosclerosis (figure), mediating the pro-liferation of arterial smooth muscle cells bymany mechanisms, including a direct effect ongrowth factor production and reciprocal sup-pression of arterial bradykinin concentrations.The effects of ACE inhibition on pro-
gression of atherosclerosis has been reviewedrecently by Sharpe.2 Early studies showed nobeneficial effect on aortic atherosclerosis inrabbits fed cholesterol, but in more recentwork captopril was effective in Watenabe rabbits,which have an inherited tendency to secondaryhyperlipidaemia, without affecting serumcholesterol concentration; total aortic surfaceinvolvement and the cellularity of athero-sclerotic lesions were reduced. In cynomolgusmonkeys fed cholesterol, low and high dosesof captopril reduced atherosclerotic lesions incarotid arteries by 80% and 95% respectively;coronary arteries were almost free of athero-sclerosis after ACE inhibition. Continuoustreatment with cilazapril or captopril preventedneointimal proliferation after carotid endo-thelial denudation injury by balloon catheter-isation; this was not primarily due to bloodpressure reduction as verapamil was ineffec-tive. Similar findings have been reported withlisinopril and perindopril in various animalmodels of atherosclerosis. These actions arelikely to be due to blockade of angiotensin IIsince the same effect has been seen with anAT1 receptor antagonist.3 Preservation of
Hypertension Vascular injury
Induction of vascular ACE
Increase in local angiotensin 11
Vascular remodellingVascular angiotensin II as a pathological factor in thedevelopment of atherosclerosis.
UniversityDepartment ofMedicine andTherapeutics,Gardiner Institute,Western Infirmary,GlasgowG T McInnesCorrespondence to:Dr G T McInnes,University Department ofMedicine and Therapeutics,Gardiner Institute,Westem Infirmary,Glasgow G1 1 6NT.
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Table 1 Possiblemechanisms of effect ofACE inhibitors onatherosclerosis
Mechanism
Reduction in blood pressureReduction in arterial
permeability andlipoprotein entry
Inhibition of growth factors:Angiotensin IIPlatelet derived growthfactorFibroblast growth factorEpidermal growth factorTransforming growthfactor a
Free radical scavenging(SH group) andantioxidant for low densitylipoprotein cholesterol
Anti-inflammatory effects
endothelial function with ACE inhibitors hasbeen shown in the aortic segments of rabbitson a long term atherogenic diet,2 possiblythrough accumulation of bradykinin, whichenhances release of endothelial derivedrelaxing factor and production of cyclic AMP(cAMP). Thus ACE inhibitors may prevent orretard the development of atherosclerosis.Table 1 lists potential mechanisms.
Peripheral vascular diseaseIntermittent claudication is the primarysymptom of chronic occlusive peripheralvascular disease of the legs. Like hypertension,its prevalence increases with age. Its pattern issimilar to that of angina but it occurs 10 yearslater; 3-20% of subjects over 65 years areaffected.4 Atheroma is a generalised disease,and intermittent claudication might beexpected to coexist with coronary arterydisease and cerebrovascular disease. About50% of sufferers have evidence of myocardialischaemia; a smaller proportion have cerebro-vascular disease. About 15% have myocardialinfarction and 5% a stroke within five years.Only two approaches have been shown to be
of benefit in improving symptoms: stoppingsmoking and regular exercise. Angioplasty orreconstructive surgery offers good relief ofsymptoms if there is continuous serioushandicap for at least one year despite con-servative measures; pain at rest; or gangrene.Medical treatment of coexistent hypertension,hyperlipidaemia, and diabetes mellitus may berequired, but there is no evidence that thisleads to symptomatic improvement.The optimal choice of treatment for hyper-
tension complicated by peripheral vasculardisease is limited by the unwanted effects onperipheral vascular resistance and regionalhaemodynamics of many of the most effectivedrugs currently available. Antihypertensivedrugs should not lower blood flow to the legsas symptoms of peripheral vascular diseasemay be exaggerated. In peripheral vasculardisease arterioles in the leg may already bedilated maximally because of local productionof muscle metabolites. Atheromatous bloodvessels may also be so sclerotic that they areunable to dilate further, and use of a vaso-dilator may divert or "steal" blood flow awayfrom the worst affected areas. Thus generalisedvasodilatation does not improve intermittentclaudication and may even make it worse. Bycontrast, 3 blockers reduce blood flow duringexercise perhaps because of diminished bloodpressure, reduced cardiac output, or blockadeof 32 receptors in the vessels supplyingworking muscles. No change in claudicationwas seen with atenolol, which does notantagonise P2 receptors, but patients could notwalk as far when the cardioselective , blockerwas combined with nifedipine.5 This tendsto support the notion that drugs with vaso-dilating properties may direct blood flow tounaffected vascular beds.
Patients with hypertension and peripheralvascular disease might be expected to respondwell to ACE inhibitors, which are associated
with decreased sympathetic drive and increasedcompliance of large vessels. The vasodilatingaction of ACE inhibitors on peripheral vesselsmight lead to improved blood flow to thelimbs. Ancillary actions such as inhibition ofplatelet aggregation and thromboxane A2release after captopril may be particularlyadvantageous since hyperaggregability ofplatelets may contribute to the atherogenicprocess and to formation of mural thrombiand platelet emboli.
In healthy subjects ACE inhibitors havebeen reported to increase blood flow to thearms and legs. Blood flow to skeletal muscleand skin is augmented because of an action onlarge arteries and arterioles and because ofimproved compliance.6 By contrast, otherstudies have indicated no change in limbblood flow with captopril in hypertensivesubjects.7 Peripheral vasodilatation is offset bylowered perfusion pressure and flow isunaltered; the normal response to exercise ismaintained. These effects may not beaccompanied by clear clinical advantages.Herrick et al found no difference betweenenalapril and atenolol in exercise duration,subjective dyspnoea, or tiredness in hyper-tensive patients.'Anecdotal reports suggest that the symp-
toms of peripheral vascular disease seen with3 blockers may improve dramatically byswitching to treatment with an ACE inhibitor.Properly conducted studies of ACE inhibitorsin hypertensive patients with peripheralvascular disease are difficult to find. Uncon-trolled observations in 20 patients treated withcaptopril 50 mg daily for eight weeks indicatedimprovement in ankle/arm pressure index atrest and after exercise, in absolute pain freeinterval, and in reduction in blood pressure.9Libretti and Catalano also compared captoprilat the same dose with chlorthalidone 25 mgdaily in 20 hypertensive patients with Fontainestage Ila and Ilb peripheral vascular disease.'0Only captopril reduced blood pressuresignificantly, increased ankle/arm arterialpressure index at rest and on exercise, andincreased relative and absolute pain freeintervals on exercise. This study had severalshortcomings: only subjects previously shownto be "responders" to captopril were included;the treatments do not seem to have beenallocated at random and were open labelled;the groups were not well matched at outset;and the drugs were not compared directly.Inspection of the data suggests no significantdifferences between captopril and chlorthali-done for any of the variables.
Roberts et al conducted one of the fewadequate studies on this subject." In arandomised, placebo controlled, crossovertrial they compared captopril 25 mg twicedaily, atenolol 100 mg once daily, labetalol200 mg twice daily, and pindolol 10 mg twicedaily for one month in 23 patients with mildto moderate hypertension and chronic stableintermittent claudication. Peripheral arterialdisease was confirmed by clinical observation(including pedobrachial systolic pressure ratio<0.9) and aortofemoral angiography. Three
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Role ofACE inhibitors in hypertension complicated by vascular disease
patients were withdrawn from the studybecause of other cardiovascular events (twowith non-fatal myocardial infarctions and onewith transient ischaemic attacks), reflectingthe high morbidity of this condition. All treat-ments were equally effective in reducing bloodpressure, and there were no differences betweentreatments in resting blood flow measured byocclusion plethysmography. Postexercise calfblood flow was reduced by labetalol andpindolol, and all a blockers improved therecovery in calf blood flow after exercise,which was reduced by captopril. Labetalol andpindolol reduced pain free walking distance;atenolol reduced total walking distance.Captopril did not alter either walking distance.Increases in the frequency and severity ofsymptoms of intermittent claudication wereseen only with labetalol and pindolol. Therewere no correlations between calf blood flowindices and walking distances. This studyindicates that captopril has advantages over[ blockers, regardless of their ancillaryproperties. The lack of effect on resting calfblood flow suggests little (or no) direct orcompensatory action on vessels distal to thearterial obstruction, probably because of medialatrophy in the arterial wall. The preservationof limb flow with captopril strongly supportsan action of this drug in maintaining thecollateral circulation.ACE inhibitors may be appropriate anti-
hypertensive agents in peripheral vasculardisease, particularly if this is associated withgood collateral flow. The incidence ofcoexisting renal artery stenosis in such patientsis, however, high, with consequent risk ofacute renal failure induced by ACE inhibition(see later). A prospective study of renalarteriography in 100 patients referred forinvestigation of peripheral vascular diseasefound that many patients had bilateral renalartery stenosis; seven had a single functioningkidney.'2 Peripheral vascular disease is thebest clinical marker of anatomical renal arterystenosis. Normal renal function has beenassumed to preclude renal artery stenosis,but as most patients in this study hadnormal serum creatinine concentrations thisis clearly not the case. In patients withperipheral vascular disease ACE inhibitorsshould be used with caution. Considerationshould be given to coexistent renal arterystenosis.
Cerebrovascular diseaseHypertension and other risk factors foratheroma such as smoking, diabetes, andhyperlipidaemia predispose to cerebrovasculardisease. If hypertension is long standing, therisk of development of stenosis in extracranialand intracranial segments of major arteriessupplying the brain is increased.'3 As a result,cerebral blood flow is reduced; the decline isparticularly well documented in elderlypeople.
Cerebral blood flow is usually auto-regulated.'4 It is kept constant during widechanges in perfusion pressure by an intrinsic
mechanism mediated by variations in thecalibre of cerebral arterioles and small arteries,which respond to increases in perfusionpressure by constriction and to decreases inperfusion pressure by dilatation. Below acertain perfusion pressure, autoregulatoryvasodilatation is inadequate; flow decreaseswith the risk of ischaemia. With acuteincreases in blood pressure beyond a certainlevel, autoregulatory vasoconstriction is over-ridden, with consequent increase in cerebralblood flow. Thus, there is an upper andlower limit of autoregulation. Atheromatousnarrowing of intracranial arteries, either withinor outside the cranium, may limit auto-regulation in response to a fall in perfusionpressure, and, at regional level, fixedobstruction (due to vascular disease) in thelarger intracranial vessels may lead to localischaemia when blood pressure falls.'3
In chronic hypertension the absolute valueof cerebral blood flow is the same as that innormal subjects, but autoregulation of cerebralblood flow is adapted to higher pressure. Thelower limit of autoregulation is shifted to theright on the blood pressure axis in proportionto the severity of hypertension. '4 Thisincreases the risk of ischaemic effects as bloodpressure falls. The shift is probably due tostructural changes in hypertensive resistancevessels, which are narrowed and havethickened walls and thus have a restrictedcapacity for vasodilatation. A shift in the upperlimit probably explains tolerance to very highblood pressures, which would precipitatehypertensive crises in normal subjects. How-ever, the shift towards higher pressure of theupper limit of autoregulation may be lessobvious than the shift in the lower limit, suchthat the autoregulatory plateau may be shorterin some patients with hypertension than innormal subjects. Resting cerebral blood flow isnearer the threshold for cerebral ischaemia,particularly in elderly patients.
Antihypertensive treatment protects againstcerebrovascular events. In most cases thebenefit is much greater than the risk ofischaemia from lowering blood pressure.Although the autoregulatory curve is shiftedupwards, there is still a considerable reservebetween resting pressure and the lower limit ofautoregulation and between resting pressureand the even lower pressure at which clinicalsymptoms of brain hypoperfusion are seen.The cerebral circulation might also readaptduring long term treatment, with consequentshift of the lower end of the cerebral bloodflow autoregulation curve towards normal. Inanimals the shift in the lower limit iscompletely reversed by antihypertensive treat-ment. This finding may be relevant in treatingyoung or middle aged patients who havehad hypertension for a short time. Whethermore longstanding hypertensive adaptation ofcerebral circulation with degenerative changesin cerebral vessels could be reversed by anti-hypertensive treatment is unknown, althoughat least partial reversal would be expected.Reversal of the shift in the upper limit ofautoregulation has not been shown.
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Table 2 Possiblemechanisms of protectiveeffect ofACE inhibitors oncerebral vessels inhypertension
Mechanism
Normalisation of cerebralvascular reserve
Decrease in vascularhypertrophy
Increase in external diameterNormalisation of:
Endothelial functionVascular mechanisms
Antiatherosclerotic effect:Decrease in proliferationof smooth muscle cells*Prevention of endothelialinfiltration ofmacrophages*t
*Characteristic steps of earlyphase of atherosclerosis.tLater form "foam cells," inwhich cholesterol accumulates.
Evidence in humans is sparse. Observationsduring long term treatment of patients withhypertension suggests similar changes in auto-regulation, at least in some. 14 Groups atparticular risk of cerebral ischaemia includethose with malignant hypertension during theearly phase of treatment, those with acutestroke with high blood pressure, and elderlypeople with hypertension. Although elderlypeople are at particular risk of stroke, theyoften complain of increased dizziness aftertreatment, and occasional strokes follow over-zealous treatment. Elderly people cannot beexpected to show noticeable readaption ofhypertensive vascular changes, and treatmentshould probably be conservative.Numerous studies in experimental models
of hypertension have shown that treatmentwith ACE inhibitors normalises blood pressureand restores autoregulation of cerebral bloodflow. Thus cerebral blood flow is maintainedat normal levels despite a measurable decreasein perfusion pressure, although there remainsdoubt about distribution of blood flow withindifferent brain areas. ACE inhibitors seemto influence cerebral blood flow uniquelysince both lower and upper limits are shiftedto lower pressure. These changes improvetolerance to acute hypotension and, if con-firmed in humans, might explain why ACEinhibitors are seldom associated withorthostatic hypotension. As yet, studies of longterm treatment are awaited.
After ACE inhibition in healthy humanvolunteers the diameter of and flow in carotidarteries increase in a dose-dependentmanner. ' Despite reduction in bloodpressure, ACE inhibitors do not significantlyaffect cerebral blood flow.'6 The mechanismof action of ACE inhibitors on cerebral bloodflow may include inhibition of local angio-tensin II at the luminal membrane of cerebralarteries, which leads to dilatation of thearteries and large cerebral resistance vessels,with compensatory constriction of smallercerebral arteries; this explains a shift mainly ofthe lower limit of autoregulation of cerebralblood flow towards lower blood pressures."
Changes in carotid artery haemodynamicsafter ACE inhibition in hypertensive patientsare similar to those seen in normal subjects.'7Clinical studies of short and long termACE inhibition show total and regionalcerebral blood flow is unchanged eventhough blood pressure is reduced.7 '7 There-fore autoregulation seems to be intact, but noconsistent effect on the lower limit of auto-regulation has been shown.
Patients presenting with acute stroke areparticularly prone to develop further ischaemiaduring acute antihypertensive treatment sinceautoregulatory capacity is lost in the partiallyischaemic areas of brain surrounding theinfarcted area. ACE inhibitors do not changeischaemic regional cerebral blood flow in acutestroke. '7
Elderly patients and those with severeatheroma have rigid vessels, which make themparticularly sensitive to hypotension. Thedevelopment of stroke after reduction in blood
pressure with ACE inhibitors is well recog-nised in these circumstances. Symptomatichypotension is no more common in elderlysubjects than in the overall population treatedwith ACE inhibitors."' The cautious use ofmost antihypertensive agents in elderly people,however, does not compromise cerebral bloodflow. 1'
In addition to the above properties, ACEinhibitors may have an advantage in inhibitingthrombosis and the atherosclerotic processin patients with cerebral atherosclerotic disease.Platelet angiotensin concentration is increasedafter cerebral infarction, and at least some ACEinhibitors reduce platelet angiotensin II in thiscontext. Recent animal studies support a pos-sible beneficial effect of ACE inhibitors on thecerebral vasculature in hypertensive patients.ACE inhibitors may protect cerebral vessels bya number of mechanisms (table 2).
Coronary artery diseaseCoronary artery disease is the most commonvascular complication of mild to moderatehypertension. Plaques in coronary vessels areparticularly likely to be symptomatic since themyocardium in hypertension has an increasedoxygen demand because of hypertrophy andincreased afterload. Some antihypertensivedrugs such as 1 blockers and calciumantagonists have well recognised antianginalproperties, but the reflex tachycardia and non-specific coronary vasodilatation caused byarterial vasodilatators such as hydralazine mayprecipitate or worsen angina.A series of controlled studies has failed to
show a difference between ACE inhibitors andplacebo.'9-2' More recently, a comparison ofplacebo and captopril in patients with heartfailure and angina suggested that the ACEinhibitor may exacerbate the symptoms ofangina and increase nitrate consumption;exercise performance was reduced and thusincreased mobility could not account for thedeterioration in symptoms.22 This topic isexplored further in this supplement byDavies.23
Beneficial effects on coronary events havealso been shown in studies of long termoutcome in patients with heart failure,24suggesting that ACE inhibitors may havesecondary protective effects in humancoronary artery disease. A series of large out-come trials are currently under way to test thishypothesis, the most important of which is thequinapril ischaemic event trial (QUIET). TheQUIET study has several substudies, whichwill investigate various aspects of coronaryvessel structure and function, as well asproduce cost-benefit analyses.
In conclusion, ACE inhibitors may be usefulin the treatment of hypertensive patients withcoronary artery disease. It is premature toconsider these drugs as an alternative treat-ment for coronary heart disease. Publishedwork is heavily weighted by poor qualitystudies. Properly conducted, randomised,double blind clinical trials are required tosettle the issue.
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Renal vascular diseaseRenovascular hypertension probably accurs inno more than 2-5% of hypertensive patientsbut is a frequent cause of drug resistant hyper-tension. Such patients often have widespreadvascular disease, of which renal vascularatheroma is only one component. Furtherconsideration is given to this topic in thissupplement by Fluck and Raine.25
ConclusionsTheoretical considerations support a role forACE inhibitors in hypertension complicatedby vascular disease, particularly in themanagement of cerebrovascular disease, whereACE inhibitors seem capable of preservingautoregulation of flow. Few patients, however,are at risk of cerebral underperfusion, andmost antihypertensive drugs are well toleratedif used sensibly. ACE inhibitors do not seemto worsen symptoms in most hypertensivepatients with angina, but their antianginaleffect is modest at best. 1 Blockers or calciumantagonists are more effective options inpatients with symptoms. Although ACEinhibitors are widely advocated as anti-hypertensive agents in patients with peripheralvascular disease, there is a high risk ofunsuspected renal artery disease in suchpatients and renal function, as for patientswith known renal artery stenosis, must bemonitored carefully.ACE inhibitors have the potential to cause
regression of atherosclerosis or even prevent it.If preliminary findings in animals areconfirmed in humans the application of ACEinhibitors in hypertensive patients withvascular disease will be greatly widened. Suchpatients are at great risk of vascular events,and even a modest benefit would have anenormous clinical impact. Clinical con-firmation, or otherwise, awaits the outcome oflong term trials. In the meantime, there is adearth of good quality evidence to guideclinical decisions. Well controlled clinical trialsof ACE inhibitors in hypertensive patientswith all forms of vascular disease are needed.
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