Abstract Angiotensin Converting Enzyme Research Articles

Reduction of ischemic events with angiotensin-converting enzyme inhibitors: lessons and controversy emerging from recent clinical trials.

Angiotensin-converting enzyme (ACE) inhibitor therapy has been associated with a substantial (> or = 20%) reduction in the risk of major ischemic events in two recent clinical trials with long-term follow-up: Studies of Left Ventricular Dysfunction (SOLVD) and the Survival and Ventricular Enlargement (SAVE) study. Participants in these studies included patients with a low ejection fraction (< or = 0.35 in SOLVD and < or = 0.40 in SAVE), generally without symptoms of congestive heart failure. Approximately 80% of patients enrolled in SOLVD and all participants in SAVE had histories of ischemic heart disease or acute myocardial infarction (SAVE). In both SOLVD and SAVE the risk of experiencing a major ischemic event such as myocardial infarction was reduced significantly following prolonged ACE inhibitor therapy. In the SOLVD trial, this effect was evident across a range of patient subgroups, including varying concomitant drug therapies. In both studies, several months elapsed before this benefit became apparent, suggesting an effect on underlying ischemic pathophysiology. A third trial of ACE inhibitor therapy postinfarction, the Acute Infarction Ramipril Efficacy (AIRE) Study, demonstrated a 27% reduction in all cause mortality but no effect on myocardial infarction after a 15-month mean follow-up. No effect of ACE inhibition on risk of survival or reinfarction was reported in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS-II), which began the drug within 24 hours of infarction and terminated follow-up at 6 months, a time not likely to demonstrate infarction reduction benefit based on the SOLVD and SAVE observations. Neither AIRE nor CONSENSUS-II had objectively determined left ventricular dysfunction as an entry criterion, as did SOLVD and SAVE, but AIRE mandated "clinical" congestive heart failure prior to randomization. More recently, preliminary results from the third Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3), the Fourth International Study of Infarct Survival (ISIS-4), and the Chinese Captopril Trial suggested that angiotensin-converting enzyme (ACE) inhibitor mortality benefits post-myocardial infarction would be detected in these megatrials as early as 35 days after the event.(ABSTRACT TRUNCATED AT 400 WORDS)

Ramipril and Experimental Vein Graft Intimal Hyperplasia

Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the intimal proliferation in animal models of arterial angioplasty and vein bypass grafting. This study examines the effect of high-dose ramipril, an ACE inhibitor that does not contain a sulfhydryl group, on the development of intimal hyperplasia in experimental vein bypass grafts. Twenty New Zealand White rabbits underwent common carotid interposition bypass grafting. Twelve were treated with ramipril (2 mg/kg/day; po) five days prior to surgery and thereafter until harvest. The remaining 8 animals were used as controls. Vein grafts were harvested at twenty-eight days by pressure fixation (80 mmHg). The grafts were sectioned into proximal, middle, and distal thirds, and the thickness of the intima and the media and the area of the lumen from each segment were determined by videomorphometry. The effect of ramipril on the [H3]thymidine incorporation into DNA of serum-stimulated smooth muscle cells (culture passage 6 to 12) was also assessed. There was a 50% mortality rate in the rabbits that received ramipril, and this was assumed to be related to the high dose of the drug. Ramipril treatment reduced mean vein graft intimal area by 34% (P > 0.05), but this was accompanied by an increase of 73% in the mean medial area of the vein grafts as compared with controls. These changes resulted in a decrease in the mean intimal ratio (intima/[intima + media]) by 39% in the ramipril group as compared with controls. Ramipril did not inhibit [H3]thymidine incorporation into DNA of serum-stimulated smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Captopril on Ocular Irritative Response to Topical Neutral Formaldehyde and Yag-Laser Capsulotomy in the Rabbit

Angiotensin converting enzyme (ACE) -inhibitors inhibit degradation of inflammatory mediators substance P (SP) and bradykinin, which may further stimulate the synthesis of prostaglandins. The resulting increase in inflammatory mediators in tissues is suggested to be the reason for the dry cough, involving sensory C-fiber activation, among patients receiving ACE-inhibitor therapy. In the present study, the effect of an ACE-inhibitor, captopril, on ocular irritative responses was studied in the rabbit. Intravenous captopril decreased markedly the blood pressure and the intraocular pressure (IOP) modestly. Topical neutral formaldehyde elicits an irritative response in the eye mediated through sensory neuropeptides SP and calcitonin gene-related peptide (CGRP). Following topical neutral formaldehyde, the increase in IOP and breakdown of the blood-aqueous barrier were inhibited by captopril, while miosis was not affected. Cyclic AMP (cAMP) content in the aqueous humour was increased by captopril, and this increase was inhibited by indomethacin. Following YAG-laser anterior capsulotomy, captopril inhibited the increase in IOP, breakdown of the blood-aqueous barrier and miosis. The present study demonstrates that use of short-term administration of captopril prior to sensory nerve stimulation or YAG laser anterior capsulotomy does not enhance the ocular responses to these stimuli in the rabbit. In the present study, captopril inhibited these responses, at least partly by decreasing the blood pressure.

Left ventricular size, mass, and function in relation to angiotensin-converting enzyme gene polymorphism in humans

Angiotensin-converting enzyme (ACE) exhibits genetic variation related to insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene. The DD genotype results in high ACE activity and is overrepresented in diseases characterized by left ventricular (LV) hypertrophy and dysfunction. We studied whether the ACE gene polymorphism predicts LV mass or function in the absence of heart disease. Polymerase chain reaction of leukocyte DNA was used to determine the I/D genotype, and M-mode and Doppler echocardiography were used to quantify LV mass and function in 86 human subjects, 36-37 yr of age. All were free of clinical heart disease. The LV mass-to-body height ratio averaged 99 +/- 19 (SD) g/m in subjects with the II genotype (n = 25), 99 +/- 30 g/m in those with the ID genotype (n = 35), and 94 +/- 24 g/m in those with the DD genotype (n = 26; P = 0.790). The indexes of LV systolic and diastolic function were also unrelated to the ACE genotype. We conclude that in the absence of heart disease the ACE gene variation has no major influence on LV mass or function that is detectable at echocardiography.

Effect of the angiotensin-converting enzyme inhibitor, perindoprilat, and of angiotensin-II on the transient inward current of rabbit ventricular myocytes.

Angiotensin-converting enzyme (ACE) inhibitors protect the myocardium from experimental lethal ventricular arrhythmias induced by ischemia or reperfusion. Hypothetically, such arrhythmias may result from the calcium-dependent transient inward current Iti. It is already known that perindoprilat decreased the transient inward current in guinea-pig myocytes [1]. In the same preparation, however, angiotensin-II decreased the transient inward current, an effect opposite to that required to prove that the ACE inhibitor exerted its beneficial effects on Iti by lessening the action of angiotensin-II. We, therefore, selected another species, the rabbit, in which angiotensin-II was known to have a positive inotropic effect. Perindoprilat (1 microM but not 0.01 microM) decreased the transient inward current from -8.93 +/- 0.80 microA/cm2 to -5.33 +/- 0.74 microA/cm2 (p < 0.05). Perindoprilat (1 microM) also protected from the effects of angiotensin-II (0.01 and 0.1 microM), which on its own increased the amplitude of the transient inward current. Based on our results, we conclude that perindoprilat (1 microM) prevents the effect of angiotensin-II in promoting the transient inward current in the rabbit. Hence our data support the hypothesis that the ACE inhibitor, perindoprilat, might in relatively high concentrations have an antiarrhythmic effect, at least in part through inhibition of angiotensin-II-evoked calcium-dependent Iti.

Hemodynamic and morphologic changes after long-term angiotensin converting enzyme inhibition in patients with chronic valvular regurgitation

Angiotensin converting enzyme (ACE) inhibitors decrease preload and afterload and are therefore of potential value in valvular regurgitation. The present study was designed to assess the effects of treatment for 1 year with an ACE inhibitor on myocardial performance. Twenty-four patients with isolated moderate to severe chronic aortic regurgitation or mitral regurgitation who were free of coronary disease were studied before treatment (control) with the ACE inhibitor quinapril and were then followed for 1 year during quinapril therapy (10-20 mg/day). After 1 year of ACE inhibition, the regurgitant fraction fell by 27 and 42%, compared with control values, in the aortic and mitral regurgitation groups, respectively (P = 0.0001). The left ventricular end-diastolic volume was reduced from 150 +/- 33 to 128 +/- 30 ml/m2 in the aortic regurgitation group, and from 146 +/- 26 to 109 +/- 24 ml/m2 in the mitral regurgitation group (P = 0.0001 for each). End-systolic volume decreased from 55 +/- 27 to 44 +/- 28 ml/m2 in the aortic regurgitation group (P = 0.005) and from 63 +/- 43 to 47 +/- 29 ml/m2 in the mitral regurgitation group (P = 0.002). The left ventricular ejection fraction increased slightly at rest and during exercise in patients with aortic regurgitation, but showed no change in the mitral regurgitation patients after 1 year of quinapril treatment. Echocardiographic studies showed that after 1 year of therapy there was a decrease of about 10% in the left ventricular end-diastolic and end-systolic diameter in both patient groups. Moreover, the left ventricular mass was reduced by 35% in the aortic regurgitation group (P = 0.0001), and left ventricular hypertrophy, which was present in all patients, was reversed completely. In the mitral regurgitation group, a mass reduction of 15% was observed after 1 year of quinapril treatment, and the septal wall thickness, which indicated borderline hypertrophy, decreased to normal. These results demonstrate that long-term ACE inhibition in patients with valvular regurgitation reverses left ventricular dilation and reduces left ventricular mass and hypertrophy, thereby improving left ventricular function. Further, they suggest that ACE inhibition may have the potential to delay aortic or mitral valve replacement.

Infarct-related heart failure: The choice of ACE inhibitor does not matter

Angiotensin converting enzyme (ACE) inhibitors are effective across the whole spectrum of heart failure from mild to severe but there are little data on the use of ACE inhibitors specifically in patients with postinfarct heart failure. Pharmacological properties that might potentially be relevant to the choice of drug after myocardial infarction include differences in metabolism, possession of a sulphydryl group, tissue binding, duration of action, and side effect profile. Of these duration of action is probably the most important, as longer acting drugs generally cause more prolonged first-dose hypotension that shorter acting agents and first-dose hypotension is a particular concern in the early postinfarct period. In the SAVE study captopril was effective in reducing mortality and delaying the onset of symptomatic heart failure after myocardial infarction. Similarly, ramipril reduced mortality in the AIRE study. In contrast, enalapril was largely ineffective in CONSENSUS II. These differences result largely from study design and do not indicate an inherent superiority of captopril or ramipril over enalapril. Nonetheless, a short-acting agent should probably be used for the initial dose in postinfarct heart failure to minimize the risks of prolonged hypotension. This aside, the choice of agent is far less important than appropriate patient selection and appropriate maintenance dosages.

Renal morphology and function in dogs after treatment with the angiotensin-converting enzyme inhibitor quinapril.

Angiotensin-converting enzyme (ACE) inhibitors have proven to be effective therapeutic agents for treatment of hypertension and congestive heart failure (CHF). Because of the role the renin-angiotensin system (RAS) plays in maintaining renal homeostasis, the effect these compounds have on renal function has been of interest. We assessed the effect of toxicologically significant doses of the new ACE inhibitor, quinapril, on renal function and morphology in dogs. Groups of 3 male beagle dogs were administered quinapril orally at daily doses of 0, 25, 125, or 250 mg/kg for 13 weeks. After treatment, animals were anesthetized and assessed for clinical pathologic and renal functional disturbances under normal conditions and after volume expansion and diuresis. Renal histopathology was conducted on perfusion-fixed kidney. No adverse effects on sensitive measures of renal function were detected; changes observed were consistent with the pharmacologic consequences of ACE inhibition. Decreased serum Na+ and Cl- (< 10%) and hematocrit at 125 and 250 mg/kg, twofold increases in serum creatinine and blood urea nitrogen (BUN) at 250 mg/kg, and decreased arterial blood pressure (BP) (20%) were observed at all doses. Under baseline conditions, urine flow increased 81-123% in quinapril-treated animals as compared with controls and urine specific gravities decreased 16% relative to controls at 125 and 250 mg/kg. Microscopically, juxtaglomerular hypertrophy was observed at all doses. At 250 mg/kg, minimal, widely scattered cortical tubular alterations were observed; glomerular lesions were not. No significant adverse effects of quinapril on renal morphology or function were observed at doses approximately 250 times the therapeutic dose.

Improving Patient Care: Some Unresolved Issues in Heart Failure

Angiotensin-converting enzyme (ACE) inhibitors are considered as the cornerstone of the treatment of congestive heart failure with systolic dysfunction, proving beneficial in all grades of heart failure, from I to IV on the New York Heart Association scale. However, despite these positive results, a brief glance at the published mortality data or an hour spent in any heart failure clinic easily demonstrates that the problems of heart failure are far from being solved. Among the unresolved issues that will be addressed in this brief review are: the high incidence of deaths due to pump failure and sudden death in patients receiving ACE inhibitor therapy; methods of further improving exercise tolerance and quality of life, and, finally, current views regarding prevention of heart failure.

Angiotensin converting enzyme in renal ontogeny: hypothesis for multiple roles

Angiotensin converting enzyme (ACE) has multiple effects both as the enzyme which cleaves angiotensin II from angiotensin I and as that which breaks down bradykinin. The present study examines ACE mRNA and protein expression in the rat kidney during development. Changes in distribution and expression during development are consistent with suggestions that the renin angiotensin system is important in growth modulation, vascular development and regulation, and protein reabsorption.

Life-Threatening Hyperkalemia Associated With Captopril Administration

Angiotensin converting enzyme (ACE) inhibitors have become commonly used medications for hypertension and congestive heart failure. These agents are noted for their low incidence of adverse effects; but in certain cases, these effects can be life-threatening. Severe hyperkalemia is one of the potentially dangerous effects of the ACE inhibitors. While cases of life-threatening hyperkalemia associated with the use of ACE inhibitors have been described previously, in no instance was dialysis required. Herein, we report a case of acute hyperkalemia in a patient with congestive heart failure and renal insufficiency, the resolution of which required hemodialysis. The hyperkalemia in this case occurred without an increase in the patient's azotemia. In addition, the patient did not respond to attempts to effect the intracellular shift of potassium. This suggested that there may have been a defect in internal potassium homeostasis.

Pharmacokinetic Drug Interactions with ACE Inhibitors

Angiotensin converting enzyme (ACE) inhibitors which have active moieties excreted mainly in urine require adjustment of either the dose or the interval between doses in patients with moderate to severe renal dysfunction or severe congestive heart failure. Those agents such as temocapril (CS 622) and fosinopril, excreted both in urine and bile, may not require such adjustment. Renal clearance of ACE inhibitors may be reduced and some accumulation may occur in elderly patients with mild renal dysfunction or congestive heart failure. The bioavailability of ACE inhibitors is reduced by concomitant food or antacids which may slow gastric emptying and raise gastric pH. Pharmacokinetic interactions with ACE inhibitors are unlikely in patients receiving thiazide or loop diuretics. When ACE inhibitors are given hyperkalaemia may occur in patients with renal insufficiency, those taking potassium supplements or potassium-sparing diuretics, and in diabetic patients with mild renal impairment. While no pharmacokinetic interaction precludes use of this combination, the pharmacokinetics of some ACE inhibitors are subject to greater variability when patients also receive beta-blockers. Calcium antagonists and ACE inhibitors have additive anti-hypertensive effects and pharmacokinetic interactions between these agents are unlikely. One report exists of a significant effect of coadministered hydralazine on the pharmacokinetics and urinary excretion of lisinopril. Data on interactions between ACE inhibitors and digitalis are contradictory. There is no evidence that the concomitant use of ACE inhibitors and digoxin is associated with an increased risk of digitalis toxicity. ACE inhibitors are mainly excreted by glomerular filtration and renal tubular secretion. Possible interactions between ACE inhibitors and probenecid have been noted, with renal and total body clearance of ACE inhibitors being potentially reduced in the presence of probenecid. Probenecid pretreatment may enhance the pharmacodynamic response of ACE inhibitors. Few but contradictory data exist on the effects of H2-blockers on ACE inhibitor pharmacokinetics and little information is available on interactions between ACE inhibitors and hypoglycaemic drugs. Some case reports link ACE inhibitors with the induction of lithium toxicity. Coadministration of lithium should be undertaken with caution, and frequent monitoring of lithium concentrations is recommended with all ACE inhibitors. Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the haemodynamic actions of ACE inhibitors. NSAIDs reduce renal excretion of ACE inhibitors, with a corresponding increase in circulating drug concentrations. There is little information available on the pharmacokinetic interaction with ACE inhibitors and cyclosporin, but caution should be employed when they are used together.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of Enalapril on Renal Sodium Handling in Healthy Subjects on Low, Intermediate, and High Sodium Intake

Angiotensin-converting enzyme (ACE) inhibitors have a modest natriuretic effect, but the responsible changes in tubular sodium (Na) handling are not fully known. We therefore studied the effect of a single dose of 20 mg enalapril on Na excretion in 8 healthy subjects, using lithium clearance and maximal water diuresis to analyze tubular Na handling. Because the natriuretic effect may depend on the volume state, the same subjects were studied during low (20 mmol Na/day), medium (200 mmol Na/day), and high (400 mmol Na/day) salt intake. Enalapril caused natriuresis during the 20-mmol Na diet (from 51 +/- 9 to 81 +/- 14 mumol/min, p < 0.05) and the 200-mmol Na diet (from 190 +/- 24 to 230 +/- 31 mumol/min, p < 0.05), but not during the 400-mmol Na diet. The increase in Na excretion was not accompanied by consistent changes in glomerular filtration rate (GFR), free water clearance data, maximal urine flow, uric acid clearance, or lithium clearance. Instead, the increase in Na excretion was positively related to the increase in Na concentration in the maximally diluted urine (r = 0.75, p < 0.01). Regardless of diet, enalapril reduced the filtration fraction, but a significant increase in effective renal plasma flow was noted only during the 20-mmol Na diet. The data suggest that a decrease in Na reabsorption in the diluting segment, perhaps related to renal vasodilatation, participates in the natriuretic effect of ACE inhibition in humans.

Do ACE inhibitors delay symptoms of aging?

Angiotensin-converting enzyme (ACE) inhibition may delay, but not prevent, the first signs of aging. This interesting effect was demonstrated in the Aging Processes and Perindopril (APRIL) study, an animal study conducted by the Groupe Recherche Servier in France. The investigation also highlighted the importance of differentiating between the effects of normal aging and age-related disease before embarking on the development of preventative strategies. Results of the study were presented at the 15th World Congress on Gerontology held earlier this month in Budapest, Hungary.

Angiotensin II Receptor Blockade After Myocardial Infarction in Rats

Angiotensin-converting enzyme (ACE) inhibitors are widely used for treatment of heart failure after myocardial infarction (MI). The beneficial effects consist of a combination of hemodynamic effects and interference with cardiac structural alterations. These effects are believed to depend on inhibition of angiotensin II (AII) formation and thus diminished angiotensin receptor stimulation. We administered the angiotensin II-1 (AT-1) receptor antagonist losartan during and after completion of the repair phase of an MI to investigate involvement of the AT-1 receptor in the above described effects of captopril. MI reduced cardiac output (CO) (sham 94 +/- 4 ml/min, MI 78 +/- 5 ml/min) and maximal CO (sham 154 +/- 4, MI 107 +/- 5 ml/min, respectively). Losartan (15 mg/kg/day) resulted in a rightward shift of the AII pressor dose-response curve by a factor of 32-40. Neither CO nor COVL,max was affected by losartan treatment in either phase (late treatment CO = 78 +/- 5, COVL,max = 118 +/- 9 ml/min). Although early treatment with losartan reduced cardiac hypertrophy measured as heart weight, DNA synthesis was reduced only slightly. In contrast, collagen deposition was inhibited completely. The results suggest that the effects of captopril in rats after MI are not dependent on AT-1 receptor-mediated mechanisms.

Angiotensin-Converting Enzyme in Cortical Tissue in Alzheimer's and Some Other Neurological Diseases

Angiotensin-converting enzyme (ACE), choline acetyltransferase and acetylcholinesterase were measured in seven cortical regions from the brains of 11 neurologically normal controls, 15 cases of dementia of the Alzheimer type, 6 cases of Parkinson dementia, and 12 cases with other neurological diseases. The groups did not differ significantly in age or postmortem delay. As expected, the cholinergic enzyme activities were significantly correlated with each other and were both markedly reduced in the Alzheimer and Parkinson dementia groups. Overall, ACE activity was not correlated with either of the cholinergic enzymes, and was not significantly affected by clinical category. The activity did, however, show significant regional variation and appeared somewhat higher in females than in males. The mean cortical ACE activity showed a statistically significant increase with age.

Recovery of Renal Function in Undifferentiated Connective Tissue Disease After Treatment With Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitor therapy has been reported to improve patient survival and promote recovery of renal function in the renal crisis of systemic sclerosis. In addition, an ACE inhibitor and a calcium channel blocker have been reported to control hypertension and reverse dialysis-dependent renal failure in a patient with undifferentiated connective tissue disease. We treated a patient with undifferentiated connective tissue disease who developed hypertension, pulmonary compromise, and renal failure requiring prolonged dialysis therapy. Due to allergy, the patient's hypertension could not be treated with ACE inhibitors initially, yet pulmonary function improved and renal function partially recovered with tenormin and minipress. When blood pressure became refractory to tenormin and minipress after 14 months of peritoneal dialysis, the patient was treated with lisinopril alone. Pulmonary function has remained stable and the patient has been off renal replacement therapy for 26 months, with a further substantial increase in creatinine clearance following treatment with lisinopril. The delayed and sustained recovery of renal and pulmonary function in the present case suggests undifferentiated connective tissue disease, like systemic sclerosis, may benefit from therapy with ACE inhibitors.

Angiotensin-Converting Enzyme Inhibition

Angiotensin-converting enzyme (ACE) is a widely distributed dipeptidyl carboxydipeptidase. Using computer analysis of the binding of radiolabeled ACE inhibitors, we have mapped the distribution of ACE in normal animals and in models of disease, and have studied the tissue effects of ACE inhibitors. In the myocardium, ACE is located in vascular and valvular structures as well as in the atria and ventricles. Its concentration is increased in myocardial hypertrophy in the infarct model of heart failure. Chronic ACE-inhibitor therapy prevents myocardial hypertrophy. In the brain, ACE is localized in multiple specific sites where its role is unknown. Following oral ACE-inhibitor treatment, effects are restricted predominantly to areas devoid of blood-brain barrier. Early studies suggest ACE inhibitors enhance cognition. In the testis, ACE is located in the seminiferous tubules where its function is unknown. It is not inhibited following oral ACE-inhibitor treatment. In the kidney and gastrointestinal tract, ACE is in high concentration in the epithelial brush border where its function is unknown. In clinical use ACE inhibitors primarily affect the cardiovascular system. With pharmacological developments, ACE inhibitors targeted for specific organs may have effects predominantly in the brain, heart, reproductive system, or gastrointestinal tract.

Severe Angioedema Related to ACE Inhibitors in Patients With a History of Idiopathic Angioedema

Angiotensin converting enzyme (ACE) inhibitors have been associated with the onset of angioedema in a small subset of treated patients. The angioedema commonly involves the face and oropharyngeal tissues and may result in life-threatening airway compromise. The mechanism by which ACE inhibitors precipitate angioedema has not been well-defined, and retrospective analysis of reported cases has failed to identify a group of patients at high risk. We report four cases of ACE inhibitor-related angioedema that required immediate medical intervention. All four cases occurred in patients with a prior history of idiopathic angioedema, an otherwise uncommon clinical entity. These observations suggest that patients with a history of idiopathic angioedema are at increased risk for the development of ACE inhibitor-related angioedema and should be treated cautiously with this class of drugs.

Age-related variations in tissue angiotensin converting enzyme activities: comparison between spontaneously hypertensive and Wistar-Kyoto rats

Angiotensin converting enzyme (ACE) activity was measured by fluorimetry in the plasma, lung, heart, aorta and kidney (cortex and medulla) of 3-, 5-, 8- and 11-week-old spontaneously hypertensive rats (SHR) and compared with that of age-matched Wistar-Kyoto rats (WKY). In the plasma, lung and kidney (cortex and medulla), ACE activity was lower in SHR than in WKY. This was evident as early as the age of 3 weeks. In contrast, there were no differences between SHR and WKY in the aorta and the heart. Age-related variations in ACE activities differed in each tissue and in both groups of rats, but no major modifications were correlated with the development of hypertension. A binding assay was performed with [3H]ramiprilat; affinity (KD) and the maximum number of binding sites (Bmax) were determined in plasma and tissues of 3-week-old SHR and WKY. The KD values were identical in the two groups but Bmax was lower in all SHR tissues except in the heart; these results might be related to the decrease in ACE activity. Our results probably reflect genetic differences in ACE activity between SHR and WKY, and suggest that ACE regulatory mechanisms act differently in each tissue.