摘要:

SUMMARY1. The components of the renin‐angiotensin system exist in many cardiovascular tissues (heart vessels, kidneys, adrenal glands).2. Angiotensin‐converting enzyme (ACE) is similar in somatic cells from all these sites.3. ACE contains two catalytic sites that have different conformation requirements. This suggests that each site may have different substrates and that specific inhibitors could be developed for each site.4. The cardiovascular functions of tissue ACE may include the regulation of regional blood flow, modulation of local sympathetic activity, stimulation of hyperplasia and hypertrophy and the mediation of inflammat

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1992.tb02802.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

SUMMARY1. The effects of angiotensin‐converting enzyme (ACE) inhibitors on the tissue ACE were assessed by quantitativein vitroautoradiography after acute and chronic administrations of the drugs.2. Following acute administration of lisinopril, perindopril or benazepril, ACE was markedly inhibited in the lung, kidney and blood vessels but not in the testis. In the brain, ACE was inhibited mainly in structures with a deficient blood brain barrier.3. High doses of perindopril progressively inhibited ACE in other brain structures. Tissue ACE inhibition persisted after serum levels of the enzyme had returned to control levels. In the case of perindopril, the time course of tissue ACE inhibition correlated with the inhibition of the pressor responses to exogenous angiotensin I.4. After chronic administration of lisinopril or perindopril for 14 days, a similar pattern of ACE inhibition was observed in the kidney, lung and blood vessels. In the lung, however, lisinopril was found to increase total ACE by 30%, while plasma ACE was increased two‐threefold by both lisinopril and perindopril. Testicular ACE remained unaltered by chronic lisinopril treatment.5. Overall, the changes in tissue ACE after the administration of inhibitors more closely parallel the drugs' biological effects than changes in plasma ACE or drug levels. ACE in the testis and brain is protected by permeability barriers that limit access of the dr

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1992.tb02803.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

SUMMARY1. The aim of the study was to examine the effect of the angiotensin‐converting enzyme inhibitor perindopril on the development of atheroma in the cholesterol‐fed rabbit.2. The normal human carotid artery, like most large human arteries, has a preformed diffuse intimal thickening. To model this thickening, the right carotid artery of the 12‐week‐old rabbit had an expanded balloon catheter passed down it to remove the endothelium and partially damage the media.3. Fourteen weeks after this operation, a myointimal thickening similar in almost all respects to the human intimal thickening had developed. The rabbits were then divided into six groups of six rabbits fed on: (i) a 1% cholesterol diet; (ii) a 1% cholesterol diet plus a hypotensive dose of perindopril (0.3 mg/kg per day); (iii) a 1% cholesterol diet plus a non‐hypotensive dose of perindopril (0.01 mg/kg per day); (iv) a normal diet; (v) a normal diet plus a hypotensive dose of perindopril (0.3 mg/kg per day); and (vi) a normal diet plus a non‐hypotensive dose of perindopril (0.01 mg/kg per day).4. After 6 weeks of treatment the animals were sacrificed. There were ameliorating effects of both hypotensive and non‐hypotensive doses of perindopril on the development of plaques, as determined by the area of intima covered by Oil Red‐O‐staining plaque and light microscopy.5. Cell culture studies indicated that perindopril has no effect on smooth muscle proliferation, but increases collagen and non‐collagen synthesis by smooth muscle cells and decreases their binding of the atherogenic lipoprotein beta‐very low density lipoprotein (β‐VLDL).6. The results suggest that perindopril has a beneficial effect in decreasing the severity of atherosclerotic lesions in the cholesterol‐fed rabbit, possibly by affect

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1992.tb02804.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

SUMMARY1. Certain genes drive the blood pressure of young spontaneously hypertensive rats (SHR) to stable hypertensive levels in adulthood.2. Relatively brief blockade of the renin‐angiotensin system in young SHR can reset the track of SHR pressure to a lower level for the life of the animal. This effect appears to be a characteristic of the SHR strain.3. It is proposed that the expression of a particular SHR hypertensive gene depends on angiotensin and is limited to young animals. This hypothesis explains some of the phenotypic abnormalities observed in young SHR and the decremental long‐term blood pressure effects following ACE inhibitor treatment.4. The identity of the gene is unclear, but information from biochemical, physiological and pharmacological studies may direct attention to distinct candidate genes within specific chromosomal regions of interest.5. Understanding these genetic mechanisms may have important implications for future preventive strateg

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1992.tb02805.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

SUMMARY1. It has been suggested that hypertension may be an important determinant of the rate of progression of diabetic microangiopathy.2. Renal microvascular disease as assessed by urinary albumin excretion and glomerular ultra‐structure was evaluated in a model in which streptozotocin diabetes was induced in spontaneously hypertensive rats (SHR).3. Diabetes was associated with increases in urinary albumin excretion, and hypertension resulted in a further increase in albuminuria.4. Various antihypertensive regimens were administered to diabetic SHR, with the angiotensin‐converting enzyme inhibitor perindopril and triple therapy (hydralazine, reserpine and hydrochlorothiazide) being more effective than the calcium antagonist (lacidipine) in retarding the increase in albuminuria in diabetic SHR.5. Antihypertensive therapy appears to ameliorate the development of diabetic renal dise

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1992.tb02806.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

SUMMARY1. Large artery dilatation may be produced by angiotensin‐converting enzyme inhibition in hypertensive subjects independently of blood pressure reduction. The resulting increase in arterial compliance may be due to both blood pressure reduction and to arterial smooth muscle relaxation.2. In healthy volunteers and in hypertensive subjects, dosages producing large artery dilatation seem to be even higher than those causing arteriole dilatation with the resulting blood pressure reduction.3. It may be important to consider such findings for the remodelling of the cardiovascular system produced by angiotensin‐converting enzyme inhibit

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1992.tb02807.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

SUMMARY1. Arterial remodelling is an important mechanism in the pathophysiology of hypertension and its complications, being involved in the decrease of vascular reserve, the autoregulation of cerebral blood flow and the development of atherosclerosis. There is now evidence that, in addition to several other growth factors, vasoactive peptides such as angiotensin II may act as vascular smooth muscle growth‐promoting substances. Based on these data, the effects of perindopril, a potent and long‐lasting angiotensin‐converting enzyme (ACE) inhibitor, on structural and mechanical properties of the arterial wall have been studied in animal models of hypertension. Perindopril completely reversed the aortic medial hypertrophy and arterial stiffening observed in renovascular hypertensive rats and in spontaneously hypertensive rats. The effect of perindopril was consistent with the potent inhibition of vascular ACE, and emphasized the potential role of angiotensin II as a vascular growth modulator. Whether the time constant of remodelling is similar or not in the heart and large vessels remains an important question that requires further investig

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1992.tb02808.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

SUMMARY1. We measured the reactivity of 2 mm long ring segments of human resistance arteries dissected from gluteal skin biopsies and mounted on wires in a Mulvany‐Halpern myograph for recording isometric force. Arteries were taken from eight normotensive (N) volunteers (average age 46 years, blood pressure 126/82 mmHg) and eight untreated hypertensives (H; average age 48 years, blood pressure 149/101 mmHg).2. In small diameter arteries (internal diameter500 μm), no response to acetylcholine was noted in either H or N arteries. The sensitivity to serotonin and angiotensin II was similar between these arteries but the EC50 to noradrenaline was less in H than in N arteries (ΔEC50= 0.61 ‐log mol/L).6. Subcutaneous resistance arteries with an internal diameter less than 500 μm from hypertensive patients show enhanced contractility to noradrenaline, serotonin and nerve stimulation despite a lack of detectable medial hypertrophy. These changes may be confined to the medium small arteries acting as pharmacological amplifiers in the circulation. We could not demonstrate a significant defect in neuronal uptake nor in endothelium‐derived relaxing factor in arteries from patients with essenti

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1992.tb02809.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

SUMMARY1. Potential differences among ACE inhibitors include pharmacokinetic and pharmacodynamic factors. The presence of a sulfhydryl group conferring antioxidant properties, the administration as a pro‐drug to delay the onset and prolong the duration of haemodynamic effects, and the route of elimination are examples of possible differences.2. Adverse effects of ACE inhibitors may be mediated by effects on bradykinin metabolism at tissue sites, which may be separable from haemodynamic responses mediated largely by angiotensin II withdrawal.3. Clinically important differences between ACE inhibitors in their adverse event profile have yet to be proven. Evidence is emerging that plasma ACE inhibition and haemodynamic responses are separable, and this may indicate the potential for other organ‐specific effects to differ among ACE inhibitors.4. At present, however, the greatest distinguishing features for one compoundvsanother are the time to onset and the duration of action, which determine the frequency of administrat

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1992.tb02810.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

SUMMARY1. The pharmacokinetic and pharmacodynamic responses to enalapril, perindopril and cilazapril have been studied in essential hypertensives (2, 4 and 8 mg perindopril and 2.5 mg cilazapril, single dose and steady state) and normotensive volunteers (10 mg enalapril, single dose).2. Plasma levels of the active diacid compounds reached similar peaks after single dose administration of the drugs. However, perindoprilat levels persisted for 5 days whereas cilazaprilat levels were not detectable beyond 12 h.3. The higher levels of perindoprilat were associated with a greater inhibition of plasma angiotensin‐converting enzyme (ACE) activity in both acute and steady state studies.4. The potency of the active diacids in inhibiting plasma ACE activity was perindoprilat>cilazaprilat>enalaprilat.5. There was a close relationship between plasma concentration, ACE inhibition and blood pressure decrease. Although both cilazapril and perindopril administration reduced blood pressure in hypertensive subjects, only perindopril exerted 24 h blood pressure control at the doses use

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1992.tb02811.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY