Effect Of Angiotensin-converting Enzyme Research Articles

A Case of Renin-producing Juxtaglomerular Tumor: Effect of ACE Inhibitor or Angiotensin II Receptor Antagonist

Kashiwabara H, Inaba M, Itabashi A, Ishii J, Katayama S. A case of renin-producing juxtuglomerular tumor: effect of ACE inhibitor or angiotensin II receptor antagonist.We report a case of a renin-producing juxtaglomerular cell tumor and the effects of angiotensin-converting enzyme (ACE) inhibitor captopril or angiotensin II receptor antagonist TCV-116. xsA 19-year-old female visited our clinic because of hypertension (162/122 mmHg). Plasma renin activity (PRA) was 25 ng/ml/h and plasma aldosterone concentration (PAC) was 880 pg/ml. Abdominal sonography revealed a low echoic tumor in the center of the right kidney. The mass was shown to have isodensity on a computed tomography scan, iso- or slightly lower intensity on T1–weighted magnetic resonance imaging (MRI), and low intensity on T2-weighted MRI. Renal angiography disclosed a hypovascular tumor. Plasma renin activity was not decreased in response to oral administration of captopril (50 mg) or TCV-116 (4 mg), which is associated with a marked decrease in PAC and blood pressure. The average of the mean blood pressure determined by an ambulatory monitoring system every hour for 24 h was lowered from 118–t 10.6 (SD) to 85 t 11.4 mmHg by TCV-116. Plasma renin activity did not show any difference between the right and left renal vein. Removal of the tumor successfully decreased PRA to 0.3 ng/ml/h and PAC to 33 pg/ml, resulting in a decrease in 24–h average of the mean blood pressure to 78 ± 16.9 mmHg. The tumor was well capsulated and stained with an antibody against mouse renin. In the tumor, but not normal tissues, renin mRNA was detected at 1.6 kb using rat renin cDNA. The content of active renin in the tumor amounted to 182pg/g tissue, which is 109 times higher than that in normal tissue. The plasma- or tumor-inactive renjn concentration was 3.6- or 1.8-fold the active renin concentration, respectively. These results suggest that the juxtaglomerular tumor had an MRI image of iso- to low intensity on TI and low intensity on T2, and that renin secretion from the tumor may be due mainly to the constitutive pathway and angiotensin II receptor antagonist, as well as to ACE inhibitors, and may be very effective for lowering the blood pressure.

Early administration of ramipril in acute myocardial infarction: neurohormonal and hemodynamic effects and tolerability.

Although several large studies indicate a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction, the optimal timing of therapy in terms of safety and the effects on neurohormones during myocardial infarction are less well known. In order to investigate the effect of ramipril, administered within 24 h after myocardial infarction, on hemodynamics and neurohormones and its safety, 20 patients with a myocardial infarction were studied. Nine patients had an anterior, 10 an inferior, and 1 a non-Q-wave infarction. Fourteen patients received thrombolytic therapy, whereas 6 did not. The initial dose of ramipril was 1.25 mg, but was gradually increased to 5 mg during the next 4 days. Side effects did not occur. The mean arterial pressure decreased 8 h after the first dose from 84 +/- 2 mm Hg (control) to 77 +/- 2 mm Hg (p < 0.05) and remained decreased thereafter. This was accompanied by a reduction in systemic resistance of 8% after 8 h and of 12% on day 2. Heart rate, cardiac and stroke indexes, and pulmonary artery and wedge pressures did not change. The ACE activity decreased within 1 h of ramipril administration with a maximum of 71% at 4 h after the second dose and remained at this level throughout the study. Angiotensin II decreased by 34% (day 2) and by 41% (day 5). The renin activity gradually increased from 33 +/- 7.5 to 75.4 +/- 11.5 microM/ml on day 5, whereas epinephrine was reduced from day 2 onwards, with a maximal reduction of 71% on day 5. Arginine vasopressin was significantly reduced 5 h after ramipril administration until the end of the study, with a maximum of 77% on day 3. Moreover, a late but significant decrease in norepinephrine occurred on day 5. Thus, oral ramipril results in early ACE inhibition, followed by progressive attenuation of the neuroendocrine activation and a reduction in afterload during the acute phase of myocardial infarction. It is well tolerated, also in combination with nitroglycerin and thrombolytic therapy.

The Role of Angiotensin II Regulation of Glomerular Filtration Rate During Pregnancy

Objectives: This paper examines the effect of angiotensin-converting enzyme (ACE) inhibition in the maintenance of glomerular filtration rate during primate pregnancy.Study Design: Twenty timed mated pregnancies were studied in 10 baboons receiving either enalapril 7.5 mg/day or placebo for each pregnancy in a prospective, randomized crossover design. Animals were studied nonpregnant, then at 8, 12, 16, 20, and 24 weeks gestation. Tests included arterial pressure, plasma creatinine, serum ACE activity, plasma electrolytes, plasma osmolality, hematocrit, and hemoglobin.Results: Serum ACE activity was significantly reduced for active versus placebo treatments (P < 0.001) throughout all phases. Maternal mean arterial pressure was decreased by 8 weeks gestation in all animals, accompanied by significant fall in plasma sodium, plasma potassium, and plasma osmolality (P< 0.01). In placebo-treated animals plasma creatinine fell significantly (P < 0.01) with pregnancy. A similar fall was also seen in active treated animals (P < 0.05).Conclusion: ACE inhibition had no deleterious effect on maternal renal function in pregnancy, despite decreased renal perfusion pressure. The result provides evidence that maintenance of glomerular filtration rate in pregnancy is not angiotensin II dependent.

Is there an internal cardiac renin-angiotensin system?

The beneficial effects of angiotensin converting enzyme (ACE) inhibitors in heart failure appear to be independent, at least in part, of their effect on blood pressure. The existence of a local cardiac renin angiotensin system is often suggested as an explanation. It has been known for some time that a substantial proportion of arterially delivered angiotensin I is converted to angiotensin II by ACE of the coronary vascular endothelium. The levels of angiotensin II in cardiac tissue are several times the levels of angiotensin II in circulating blood. Recent evidence suggests that most of the angiotensin II in the heart is not derived from angiotensin I in the circulation, and that most of the angiotensin I in cardiac tissue is generated in the tissue itself. On the other hand, renin mRNA levels are very low or undetectable in the normal heart. In addition, studies on the effects of bilateral nephrectomy on the cardiac tissue levels of renin, angiotensin I, and angiotensin II in pigs have indicated that cardiac renin originates from the kidney and that cardiac generation of angiotensin I and angiotensin II depends on renin from the kidney. Intracardiac synthesis of renin may occur under pathological conditions and during fetal development. The fact that angiotensins are generated by the heart raises the possibility of local mechanisms to regulate the concentrations of these peptides at certain tissue sites. For example, preliminary evidence suggests that binding of renin to cardiac membranes is a mechanism by which renin is taken up by the heart. A specific renin binding protein has been identified in cardiac tissue. Cardiac ACE levels may also influence local angiotensin II formation and are, in part, determined by the so called insertion/deletion ACE gene polymorphism. More detailed knowledge on the site of angiotensin generation and on its regulation will improve our understanding of the role of the renin-angiotensin system in cardiac function, hypertrophy, and postinfarction remodelling.

Vascular hypertrophy and albumin permeability in a rat model combining hypertension and diabetes mellitus: Effects of calcium antagonism, angiotensin converting enzyme inhibition, and angiotensin II-AT 1-receptor blockade

The aim of this study was to compare the effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II (AII) AT 1-receptor blockade, and dihydropyridine calcium antagonism on hypertrophy and on vascular albumin permeability in kidney, heart, and mesenteric artery in a model combining genetic hypertension and diabetes mellitus. Diabetes mellitus was induced by streptozotocin in 8-week-old spontaneously hypertensive rats. The animals were randomized to receive no treatment, the angiotensin converting enzyme inhibitor ramipril, the AII AT 1-receptor blocker valsartan, or the dihydropyridine calcium antagonist lacidipine for 3 weeks. Vascular albumin permeability was measured as the tissue content of intravenously injected Evans blue dye (EB) in kidney, heart, and mesenteric artery and the tissue/plasma EB ratio was calculated. Systolic blood pressure was reduced by all three antihypertensive regimens. Glycemic control was similar in all diabetic groups. Kidney hypertrophy was not affected by any of the antihypertensive drugs. Hypertrophy of the mesenteric artery was enhanced by lacidipine but was not affected by ramipril or valsartan. Relative heart weight was also increased by lacidipine. Vascular albumin permeability, expressed as EB content in micrograms/gram dry weight or as tissue/plasma EB ratio, was higher in the kidneys of lacidipine-treated rats than in any other group of diabetic rats, There was a positive correlation between kidney weight/body weight and kidney/plasma EB ratio in the diabetic rats. These findings indicate that the dihydropyridine calcium antagonist lacidipine is associated with an unfavorable effect on vascular hypertrophy and on vascular albumin permeability in the kidneys in rats with hypertension and diabetes mellitus. Furthermore, there seems to be a coupling in the diabetic kidney between hypertrophy and increased vascular albumin permeability.

Effects of inhibition of the maternal renin–angiotensin system on maternal and fetal responses to drainage of fetal fluids

To find out which of the effects of angiotensin converting enzyme (ACE) inhibitors on the fetus are due to their actions in the mother and which are direct effects due to blockade of the fetal renin-angiotensin system, enalapril (150 mg twice daily i.v.), which does not readily cross the sheep placenta, was given for 3 days to nine chronically catheterized pregnant ewes, 5 days after fetal urine and lung liquid had been continuously drained and while drainage of these fetal fluids continued. Drainage of fetal fluids was carried out so that a net sodium deficit would be incurred, and the dependency of the ewe on the activity of her renin-angiotensin system (RAS) for maintenance of her arterial pressure and fluid and electrolyte balance would be increased. During drainage of fetal fluids ewes drank more and increased their net water balance (p < 0.025). With enalapril, ewes became hypotensive (p < 0.005), but heart rate did not change. Maternal plasma potassium (K) levels increased (p < 0.05) and the plasma sodium to potassium ratio (Na:K) decreased (p < 0.005). Enalapril did not reduce maternal water intake nor change her urine output. After 5 days of drainage, fetal plasma K levels (p < 0.05) were higher and plasma Na:K (p < 0.025) was lower. After maternal enalapril, lung liquid flow and electrolyte excretion were transiently reduced (p < 0.05). Fetal plasma K levels increased further (p < 0.025) and plasma Na:K ratio decreased (p < 0.025 - p < 0.01). Fetal arterial PO2 was reduced 2 h after enalapril (p < 0.005) and was low on the last 2 days of treatment. Although fetal fractional reabsorption of K fell (p < 0.01) by the last day of enalapril treatment, the increase in fetal K excretion was not significant, because by this time sufficient enalapril was present in the fetal circulation to reduce glomerular filtration rate (GFR, p < 0.025 - p < 0.001). It is concluded that the toxicity of ACE inhibitors may be related to those effects in the ewe that lead to reduced fetal arterial oxygen levels and increased fetal plasma K levels. In the latter case it is postulated that inhibition of the maternal RAS may leave ewe and fetus deficient in aldosterone, leading to the rise in K levels. Thus the toxic effects of ACE inhibitors can be mediated through their effects on the mother, but their ability to cause fetal renal failure and oligohydramnios is due to their direct effects on the fetal RAS.

Peripheral artery structure and endothelial function in heart failure: effect of ACE inhibition.

Chronic heart failure (CHF) induces peripheral vasoconstriction and impairs endothelium-dependent relaxation of large arteries. We investigated in a rat model of CHF (coronary artery ligation) 1) whether endothelial dysfunction also exists in resistance arteries, 2) whether this is associated with vascular morphological changes, and 3) the effect of angiotensin-converting enzyme (ACE) inhibition on these parameters. After 1 mo or 1 yr, CHF reduced the vasodilatory response to acetylcholine of isolated, perfused femoral and mesenteric artery segments. This impairment was more marked in femoral than in mesenteric arteries. However, CHF did not induce any arterial remodeling. Chronic treatment with the ACE inhibitor perindopril improved the response to acetylcholine and reduced media cross-sectional area and collagen density. Thus at the level of small peripheral arteries, CHF induces an endothelial dysfunction but does not affect vascular structure. ACE inhibition prevents the CHF-induced endothelial dysfunction and induces vascular remodeling. These changes could contribute to the observed beneficial effects of ACE inhibitors on hemodynamics and survival in CHF.

PROTECTIVE EFFECTS OF PERINDOPRIL, AMLODIPINE, METOPROLOL AND INDAPAMIDE ON HYPERTENSION INDUCED LEFT VENTRICULAR HYPERTROPHY IN RENOVASCULAR HYPERTENSIVE RATS: BIOCHEMICAL AND HISTOPATHOLOGICAL STUDY

The objective of this study was to evaluate the efficacy of 6 weeks daily oral administration of different classes of antihypertensive drugs in renovascular hypertensive adult male rats. The effects of angiotensin converting enzyme (ACE) inhibitors perindopirl, 0.08 mg/kg), calcium channel blocker (amlodipine, 0.15 mg/kg), s-blocker (metoprolol, 0.005 mg/kg) and a diuretic indapamide, 0.5 mg/kg) were studied on elevated blood pressure and hypertension induced left ventricular hypertrophy (LVH), the latter was measured as left ventricular wall thickness and left ventricular nuclear density. Also, the effect of the mentioned drugs on some metabolic variables such as lipid profile represented by serum cholesterol, triglyceride (TG) and high density lipoprotein (HDL) as well as on serum blood glucose and serum Na+ and K+ levels was examined. All of perindopril, amlodipine metoprolol and indapamide significnatly decreased the elevated blood pressure and protected against hypertension induced LVH, but non of these drugs could affect left ventricular nuclear density. Indapamide significantly reduced blood glucose level and serum Na+ and K+ levels, whereas, perindopril markedly elevated serum Na+ level. Neither amlodipine nor indapamide could affect the lipid profile but perindopril benificially affected serum lipid profile by increasing HDL. Conversly, metoprolol increased cholesterol and TG and decreased HDL significantly. In conclusion, periondoproil in the present model (2 kidneys, one clip renovascular hypertensive rats) Would seem to have some advantages over the other used antithypertensive drugs in terms of lowering the elevated blood pressure and protecting against hypertension induced LVH. It laso improved the lipid profile as it increased HDL and seemed to have neutral effect on blood glucose level.

BLOOD PRESSURE LOWERING IN PATIENTS WITH CEREBROVASCULAR DISEASE: RESULTS OF THE PROGRESS (PERINDOPRIL PROTECTION AGAINST RECURRENT STROKE STUDY) PILOT PHASE

1. Among patients with cerebrovascular disease, there is a direct and continuous association between blood pressure and the risk of stroke, but previous trials of blood pressure lowering in this patient group have been inconclusive. 2. PROGRESS (Perindopril Protection Against Recurrent Stroke Study) is a multicentre, randomized, placebo-controlled trial that aims to determine reliably the effect of angiotensin converting enzyme (ACE) inhibitor-based blood pressure lowering on stroke risk in patients with a history of cerebrovascular disease. If a 4 week run-in period on active perindopril is well tolerated, participants are randomized to either perindopril (4 mg) +/- indapamide (2.5 mg) or matching placebo(s). The primary study outcome is stroke and follow-up is for a minimum of 4 years. 3. For the pilot study nearly 5000 medical records were screened and 60 patients with recent cerebrovascular events were approached directly in hospital or at a clinic visit. Sixty-seven patients entered the run-in phase (52 from retrospective screening and 15 by prospective approach) and 60 patients proceeded to randomization. Treatment with perindopril was well tolerated; only three patients were withdrawn due to side effects and four were withdrawn for other reasons. The mean age of randomized patients was 68 years; 70% were male and 55% were 'non-hypertensive'. The mean entry blood pressure was 142/83 mmHg and following pre-randomization treatment this was reduced by 7/4 mmHg. 4. Most patients were identified by retrospective review of medical records, but this was less efficient than prospective methods. Blood pressure lowering was well tolerated by both hypertensive and non-hypertensive patients with cerebrovascular disease. The small numbers of patients and the non-randomized nature of the data reported limit the conclusions that can be drawn, but the results confirm the feasibility of the main study.

Effect of Angiotensin‐Converting Enzyme Inhibition on Bronchial Responsiveness

The effect of angiotensin-converting enzyme (ACE) inhibition on bronchial responsiveness has not been clearly established. Because ACE degrades bradykinin and substance P, inhibition of the enzyme may lead to accumulation of these potent bronchoconstrictors in the lung, potentially leading to enhanced bronchial reactivity or bronchospasm. Previous studies of the effect of ACE inhibition on airway responsiveness have yielded conflicting results. A randomized, double-blind, placebo-controlled study was therefore conducted to evaluate the effect of a 14-day course of oral lisinopril (10 mg for days 1-3, 20 mg for days 4-14) on bronchial responsiveness to inhaled methacholine in a group of healthy volunteers. No significant change in methacholine responsiveness occurred in any of the participants receiving lisinopril. The mean ( +/- SD) concentration of methacholine producing a decrease in FEV1 of 20% from baseline (PC20; mg/mL) was 23.3 +/- 5.0 before the study and 23.5 +/- 4.5 at the end of the study for the lisinopril group, and 23.0 +/- 4.6 before the study and 21.8 +/- 6.9 after the study for the placebo group. The 14-day course of ACE inhibitor therapy did not enhance nonspecific bronchial responsiveness in healthy volunteers.

Attenuation of reperfusion arrhythmias by selective inhibition of angiotensin-converting enzyme/kininase II in the ischemic zone: mediated by endogenous bradykinin?

We studied the effects of angiotensin-converting enzyme (ACE)/kininase II inhibition selectively in the ischemic zone on reperfusion arrhythmias, and the role of bradykinin versus angiotensin II (produced locally in this zone) in modulating the severity of such arrhythmias. Isolated rat hearts (n = 12 per group) were subjected to independent perfusion of left and right coronary beds. The left coronary bed received the ACE/kininase II inhibitor ramiprilat, alone or in combination with either HOE140 (bradykinin B2 receptor antagonist) or angiotensin II, before induction of regional ischemia (10 min) by discontinuation of flow to the bed. Ramiprilat (1, 10, or 100 nM) did not significantly alter the incidence of reperfusion-induced ventricular tachycardia (VT) or fibrillation (VF), but reduced the incidence of sustained VF from 83% in controls to 75, 50, and 25% (p < 0.05). The protective effects of 100 nM ramiprilat were abolished by coinfusion of HOE140 (10 or 100 nM) but not affected by coinfusion of angiotensin II (1 nM). HOE140 (10 nM), when infused alone into the left coronary bed before 7-min ischemia, increased the incidence of sustained VF from 42 to 100% (p < 0.05). Although HOE140 caused vasoconstriction in the left coronary bed when given alone or in combination with ramiprilat, its proarrhythmic effects were not due to a reduction of flow to the bed. We conclude that selective inhibition of ACE/kininase II in the ischemic zone moderately attenuates reperfusion arrhythmias and that enhanced bradykinin availability rather than reduced angiotensin II in synthesis contributes to such an effect.

Effects of losartan on the cardiovascular system, renal haemodynamics and function and lung liquid flow in fetal sheep.

1. The angiotensin type 1 (AT1) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125-132 days gestation). Losartan reduced the fetal systolic (P <0.01) and diastolic (P <0.01) pressor response to 5 microg angiotensin II (AngII) i.v. from 27.4 +/- 1.5 to 7.4+/-0.9 and from 17.5 +/- 1.3 to 5.4 +/- 0.6 mmHg, respectively, after 1 h and to 6.1 +/- 0.5 and 4.4 +/- 0.5 mmHg, respectively, after 2 h. Maternal pressor responses to 5 microg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P <0.05) after losartan administration, but fetal heart rate did not change. 2. Fetal haematocrit increased (P <0.05), fetal PO2 decreased (P <0.01), PCO2 did not change and pH decreased (P <0.01), as did plasma bicarbonate levels (P <0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. 3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P <0.01) and an increase in blood flow (P <0.05). Glomerular filtration rate decreased (P <0.05); thus, filtration fraction decreased (P <0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P <0.01) and became negative. Urine flow decreased (P <0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium: potassium ratio decreased (P <0.05). There was a decrease in lung liquid flow (P <0.05) following losartan. 4. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT1 receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels.

Effects of angiotensin-converting enzyme and neutral endopeptidase inhibitors: influence of bradykinin

These experiments compare the effects of a neutral endopeptidase inhibitor, retrothiorphan, 1-[(1-mercaptomethyl-2-phenyl)ethyl]amino-1-oxopropanoic acid, a converting enzyme inhibitor, enalaprilat, and the combination of the two inhibitors on changes in blood pressure and renal function induced by exogenous and endogenous bradykinin in deoxycorticosterone acetate (DOCA)-salt rats. Enalaprilat potentiated the exogenous bradykinin-induced hypotensive responses while retrothiorphan potentiated the effects on urinary cyclic-GMP (cGMP) and bradykinin. The combination potentiated the exogenous bradykinin-induced hypotensive effects and the bradykinin-induced urinary excretion of cGMP, bradykinin and prostaglandin. The bradykinin B 2 receptor antagonist, Hoe 140, had no effect on the enalaprilat- and retrothiorphan-induced changes in blood pressure and renal function. In conclusion, while angiotensin-converting enzyme and neutral endopeptidase are involved in the vascular and renal catabolism of exogenous bradykinin, the effects of the peptidase inhibitors do not appear to depend on the protection of endogenous bradykinin under acute conditions in DOCA-salt rats.

Effects of ACE inhibition and beta-blockade on collagen remodelling in the heart of Bio 14.6 hamsters.

1. The effects of angiotensin converting enzyme (ACE) inhibition and beta-blockade on collagen in the heart and on plasma catecholamines and tissue angiotensin (Ang) I and II were examined in Bio 14.6 Syrian hamsters. Male hamsters (76-79 days old) were given low-dose enalapril (3 mg/kg per day), high-dose enalapril (30 mg/kg per day), atenolol (50 mg/kg per day) or vehicle for 65 days. Age and sex matched healthy F1b hamsters were used as controls. Collagen concentration was determined by measuring hydroxyproline content and the relative proportion of type I, III, and V collagens was obtained by non-interrupted sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE). Per cent collagen area (PCA) was measured by pixel counting in myocardial tissue by a personal computer. 2. Although heartweight (HW) and bodyweight (BW) in F1b controls were significantly higher compared with drug-treated groups and vehicles, the HW/BW ratio in cardiomyopathic Bio 14.6 hamsters tended to be high compared with F1b controls and was decreased by each drug treatment. 3. Collagen concentration, total collagen content and PCA in the heart of Bio 14.6 hamsters were significantly higher than F1b controls. Collagen concentration and total collagen content were significantly decreased in all drug-treated groups compared with vehicles. 4. The proportion of type I collagen tended to decrease while that of type III collagen tended to increase in all drug-treated groups compared with vehicles. Type V collagen in vehicle-treated group was significantly higher than in F1b controls, while it tended to decrease in all drug-treated groups compared with vehicles. 5. Plasma concentrations of catecholamines (adrenaline and noradrenaline) were decreased significantly by atenolol and high-dose enalapril, but not by low-dose enalapril. Tissue AngI remained unaltered in any of the drug-treated hamsters. Tissue AngII was decreased by the high-dose enalapril and beta-blockade, and tended to be decreased by low-dose enalapril treatment. 6. These results reveal that enalapril and atenolol produced similar beneficial effects on collagen remodelling in Bio 14.6 hamsters by decreasing the total amount of collagen, and also by changing collagen phenotypes through the inhibition of the renin-angiotensin system. Both drugs also improved myocardial morphological integrity.

Effects of inhibition of the maternal renin–angiotensin system on maternal and fetal responses to drainage of fetal fluids

To find out which of the effects of angiotensin converting enzyme (ACE) inhibitors on the fetus are due to their actions in the mother and which are direct effects due to blockade of the fetal renin-angiotensin system, enalapril (150 mg twice daily i.v.), which does not readily cross the sheep placenta, was given for 3 days to nine chronically catheterized pregnant ewes, 5 days after fetal urine and lung liquid had been continuously drained and while drainage of these fetal fluids continued. Drainage of fetal fluids was carried out so that a net sodium deficit would be incurred, and the dependency of the ewe on the activity of her renin-angiotensin system (RAS) for maintenance of her arterial pressure and fluid and electrolyte balance would be increased. During drainage of fetal fluids ewes drank more and increased their net water balance (p < 0.025). With enalapril, ewes became hypotensive (p < 0.005), but heart rate did not change. Maternal plasma potassium (K) levels increased (p < 0.05) and the plasma sodium to potassium ratio (Na:K) decreased (p < 0.005). Enalapril did not reduce maternal water intake nor change her urine output. After 5 days of drainage, fetal plasma K levels (p < 0.05) were higher and plasma Na:K (p < 0.025) was lower. After maternal enalapril, lung liquid flow and electrolyte excretion were transiently reduced (p < 0.05). Fetal plasma K levels increased further (p < 0.025) and plasma Na:K ratio decreased (p < 0.025 - p < 0.01). Fetal arterial PO2 was reduced 2 h after enalapril (p < 0.005) and was low on the last 2 days of treatment. Although fetal fractional reabsorption of K fell (p < 0.01) by the last day of enalapril treatment, the increase in fetal K excretion was not significant, because by this time sufficient enalapril was present in the fetal circulation to reduce glomerular filtration rate (GFR, p < 0.025 - p < 0.001). It is concluded that the toxicity of ACE inhibitors may be related to those effects in the ewe that lead to reduced fetal arterial oxygen levels and increased fetal plasma K levels. In the latter case it is postulated that inhibition of the maternal RAS may leave ewe and fetus deficient in aldosterone, leading to the rise in K levels. Thus the toxic effects of ACE inhibitors can be mediated through their effects on the mother, but their ability to cause fetal renal failure and oligohydramnios is due to their direct effects on the fetal RAS.

Quality of Life with ACE Inhibitors in Chronic Heart Failure

The randomized trials assessing the effect of angiotensin-converting enzyme (ACE) inhibitors in chronic heart failure (CHF) are reviewed. The Minnesota Living with Heart Failure Questionnaire has demonstrated the benefits of enalapril in some but not all circumstances and the Yale Dyspnea-Fatigue Index improves with lisinopril. A recent trial of both cilazapril and captopril vs. placebo employed the Sickness Impact Profile and supports the concept that ACE inhibitors have a small (and in this trial nonsignificant) beneficial effect on mobility. Other vasodilators and inotropes may also have small benefits on quality of life, such that comparisons of an ACE inhibitor with vasodilators, as was done in the V-HeFT II trial, fail to reveal any different effects on quality of life.

Clinical benefit of angiotensin-converting enzyme inhibitors in chronic heart failure.

The ideal therapy for patients with chronic heart failure should reduce symptoms related to pulmonary congestion or low perfusion, prevent the progression of left ventricular dysfunction and, ultimately, should reduce mortality. Extensive studies in humans have investigated the effects of angiotensin-converting enzyme (ACE) inhibitors on these goals of therapy. As an example, the ACE inhibitor cilazapril significantly improved exercise tolerance, as borne out by a meta-analysis of six placebo-controlled, randomized 3-month trials. Comparison of the effects of cilazapril and captopril vs. placebo in one of the trials documented similar improvement in exercise tolerance (14 vs. 17%). Results from other randomized comparative trials suggest that the improvement in symptoms represents a class effect of ACE inhibitors. A beneficial effect of ACE inhibition on the progression of left ventricular dysfunction has also been demonstrated in the SOLVD trial, and a reduction of mortality has been amply documented in several mortality trials (CONSENSUS I, SOLVD, V-HeFT-II, SAVE, AIRE, SMILE) in patients with or without preceding myocardial infarction. Reports that ACE inhibitors also reduce the incidence of reinfarction after myocardial infarction have not been confirmed in all studies but raise the interesting concept that ACE inhibition may interact, in a beneficial but thus far not well-understood way, with key processes in the development of atherosclerosis, thereby preventing plaque rupture, thrombus formation, and myocardial infarction. Taken together, a large database convincingly demonstrates that ACE inhibitors are effective not only in improving symptoms but also in the prevention of progression of left ventricular dysfunction, in the reduction of mortality, and possibly in stabilizing the atherosclerotic disease process.

Kinin and angiotensin II receptor antagonists in rats with chronic renal failure

To assess the potential of the kallikrein-kinin and renin-angiotensin systems in mediating the cardio- and renoprotective effects of angiotensin converting enzyme (ACE) inhibitors in rats with chronic renal failure. Spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto (WKY) rats subjected to five-sixths nephrectomy were randomly assigned to treatment with vehicle, a kinin antagonist (Hoe 140) or an ACE inhibitor (cilazapril) or both drugs, intraperitoneally via osmotic minipumps for 4 weeks. In addition, the effects of a chronic infusion of a specific angiotensin receptor antagonist (losartan) alone or in combination with an ACE inhibitor (enalapril) were also investigated in nephrectomized SHR for 2 weeks. In nephrectomized SHR and WKY rats, cilazapril alone significantly reduced systolic blood pressure, urinary protein excretion, heart weight and serum creatinine. In nephrectomized SHR, Hoe 140 alone or cilazapril in combination with Hoe 140 (7 or 70 mu g/kg per day) induced no changes in these parameters, other than those associated with the effects of cilazapril alone. In nephrectomized WKY rats, cilazapril in combination with Hoe 140 (70 mu g/kg per day) slightly, but not significantly, attenuated the antihypertensive effect of cilazapril but did not affect the other parameters. These results were confirmed by morphological analysis of kidneys. All the drug regimens provided effective protection against an increase in focal glomerular sclerosis. Enalapril did not modify the antihypertensive and renoprotective effects of losartan in nephrectomized SHR. The present results indicate that the kallikrein-kinin system might not be a major factor in the cardio- and renoprotective effects of ACE inhibitors in rats with chronic renal failure.

Vascular changes in the diabetic kidney: Effects of ACE inhibition

The effects of angiotensin-converting enzyme (ACE) inhibition with perindopril on renal vascular structure were studied in control and streptozotocin diabetic male Sprague-Dawley rats after 3 weeks. After kidneys were perfusion-fixed at systolic blood pressure, morphometric analysis of vascular structural changes in the media of the renal vasculature at the cortico-medullary junction was performed. Vascular hypertrophy was present in the diabetic vessels, as assessed by an increase in medial cross-sectional area for a given lumen size. This relative increase in medial area was prevented by perindopril treatment, consistent with an antitrophic effect on diabetic kidney vessels by ACE inhibition. The diabetic kidney had an increased proportion of small vessels less than 50 μm diameter at the cortico-medullary junction, perhaps representing diabetes induced angiogenesis. This subpopulation of vessels was reduced in number after perindopril treatment. Our data support a role for increased activity of angiotensin converting enzyme as a mechanism for vascular hypertrophy, which may be involved in the pathogenesis of diabetic vasculopathy and nephropathy.

Putative mechanisms of cough after treatment with angiotensin converting enzyme inhibitors.

A dry cough is the most common adverse effect of angiotensin converting enzyme (ACE) inhibitors, even if it is not particularly serious. Controlled studies have suggested that the incidence may eventually be as high as 20% and the problem seems to occur much more often in women. The mechanism of the cough associated with ACE inhibitor treatment is unrelated to inhibition of the renin-angiotensin system because treatment with angiotensin receptor blockers and renin inhibitors has not caused similar problems. Other substrates of ACE have been implicated, and the side effect has been linked in particular to an accumulation of bradykinin or tachykinins in the airways with consequent stimulation of vagal afferents that subserve the cough reflex, particularly the non-myelinated or C fibres. Some of the effects of bradykinin in particular may be due to secondary activation of prostaglandins (PG), especially PGE2 and PGI2. Anecdotal evidence that cyclooxygenase inhibitors prevent the cough has not been sustained in well controlled clinical trials, but recent evidence suggests that inhaled cromoglycate may have a significant inhibitory effect. The mechanism of action of cromoglycate is not well understood but evidence of inhibition of local neural reflexes has been inferred, mostly from animal studies. The observation seems unlikely to have much practical benefit for it is difficult to envisage routine use of an inhaled agent to prevent a drug side effect. The question of whether ACE inhibitors are safe in patients with asthma is still open, and most rechallenge studies have shown little effect on lung function. Data from one large-scale surveillance study suggest that a few individuals may experience dyspnoea and wheezing but no causal relationship has been established. Delineation of the mechanism of the ACE inhibitor cough may lead to a better understanding of the mechanism of cough in inflammatory airways disease.