Role Of Angiotensin-converting Enzyme Inhibition Research Articles

The concern about ACE/ARB and COVID-19: Time to hold your horses!

Concern about coronavirus 2019 (COVID-19) morbidity and mortality has drawn attention to the potential role of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) because the SARS-CoV-2 uses the ACE2 receptor as its point of entry into the body. It is not clear if and to what degree the SARS-CoV-2 virus affects the renin-angoiotensin system. Early studies from China which speculated on the role of ACE inhibition and ARBs did not evaluate the drug regimens. A vast body of evidence supports the use of ACE inhibitors and ARBs in hypertensive patients and patients with heart failure, and very little evidence has been acquired about their role in COVID-19. There is good evidence in support of the use of ACE inhibitors and ARBs in indicated patients with hypertension and heart failure, and clinicians should be reticent about abruptly withdrawing these drugs based on a paucity of evidence.

Persistent renin-angiotensin system activation after anti-reflux surgery and its management

Purpose To study renin-angiotensin system activation and the role of angiotensin-converting enzyme inhibition (ACE-I) after anti-reflux surgery. Material and Methods Thirty nine children underwent anti-reflux surgery for high grades of primary VUR. Plasma renin activity (PRA), urinary microalbumin, renal scars, split renal function (SRF), glomerular filtration rate (GFR), serum creatinine, blood pressure and episodes of breakthrough urinary tract infection were monitored in the early (5.9 ± 3.9; range 3–9 months) and late (27.1 ± 6.5; range 15–36 months) postoperative phase, before and after therapy with ACE-I (mean period 13.6 ± 2.5; range 10–24 months). Results The early postoperative improvement in renal parameters (rise in SRF and GFR by 11.2% and 7.3%, respectively, and fall in PRA by 68.8%), was not sustained subsequently (minimal improvement in SRF, 7.4%, and GFR, 0.14%, was accompanied by a rise in PRA by 92.3%). After ACE-I therapy, improvement was noted in SRF and GFR by 0.5% and 7.5%, respectively, and there was a fall in urinary microalbumin by 52.3%. Conclusions Significant down regulation of rennin-angiotensin system activation and the accompanying improvement in renal function seen early after surgery is not sustained during follow up. ACE-I aids renal recovery.

The role of angiotensin-converting enzyme inhibition in endotoxin-induced lung injury in rats*

Cardiovascular Research Institute; University of California; San Francisco, CA (Neyrinck) Cardiovascular Research Institute; University of California; San Francisco, CA (Matthay) Departments of Anesthesia and Medicine; University of California; San Francisco, CA (Matthay) The authors have not disclosed any potential conflicts of interest.

Regulation of Cardiac Regeneration by ACE Inhibition Following Donor Heart Myocardial Infarction After Heterotopic Transplantation in Tg Mice

Experimental and clinical evidence have recently shown that pluripotent stem cells can be mobilized using granulocyte-colony stimulating factor (GCSF) and may enhance myocardial regeneration after acute myocardial infarction (MI). The present study investigated the pharmacological role of angiotensin-converting enzyme inhibition on cardiac regeneration after MI using a mouse model of heterotopic cardiac transplantation and coronary ligation. Isogenic heterotopic cardiac transplantations and simultaneous coronary ligations were performed in green fluorescent protein (GFP) mice to produce MI in the donor heart. Five mice in the ligation group were treated with oral perindopril (PE) after the operation. Three mice in the ligation group were treated with subcutaneous GCSF and 4 angiotensin II type1a receptor knockout (AT1aRKO) mice were used as well. At 60 days after the operation, the maximum GFP-positive cell counts in the GCSF group were significantly higher than in the other 4 groups. The maximum GFP-positive cell counts in both the AT1aRKO and ligation & PE groups were significantly higher than in the sham and ligation groups. Pharmacological modification for cardiac regeneration may provide an alternative treatment for subsequent cardiac remodeling in the late phase of MI.

Prevalence and Prognostic Significance of Anemia in Patients With Congestive Heart Failure Treated With Standard vs High Doses of Enalapril

Anemia is common in patients with congestive heart failure (CHF), although its etiology and pathophysiology remain largely unexplained. The purpose of this study was to examine the prognostic significance of a low hematocrit (Hct) in patients with CHF and the possible role of angiotensin-converting enzyme inhibition in anemia development. Hct was measured at the time of enrollment of 160 patients with CHF, mean age 56 +/- 12 years, in New York Heart Association (NYHA) functional class 2.6 +/- 0.7 and with left ventricular ejection fraction of 20 +/- 9%. They were randomized to standard (mean: 17.9 +/- 4.3 mg/day) or high (mean: 42 +/- 19.3 mg/day) doses of enalapril. The follow-up duration was 2 years. Cox regression models were used to identify prognostic factors, and correlations among individual variables were tested. Mean baseline Hct was 42.7 +/- 5%. In multivariate analyses, low Hct (p = 0.036), older age (p = 0.022) and low systolic blood pressure (p = 0.032) were independent predictors of death within 2 years. A correlation was found between baseline Hct and NYHA class (Spearman's correlation coefficient: -0.183, p = 0.008). A significant decrease in Hct from 43.2 +/- 4.9% at baseline to 40.7 +/- 4.4% at 2 years was observed in the group treated with high doses of enalapril (p < 0.001). Low baseline Hct predicted poor 2-year prognosis in patients with CHF. Enalapril administered in high doses increased the incidence of anemia in this population. The underlying pathophysiologic mechanism and effects of maintaining a normal Hct on clinical outcomes remain to be determined.

The potential role of angiotensin-converting enzyme inhibition in peripheral arterial disease.

Peripheral arterial disease (PAD) is associated with significant morbidity and mortality, and yet remains under-recognized and under-treated. Atherosclerosis is the most common cause of lower extremity PAD and pharmacological interventions that alter this central pathogenic role of atherosclerosis may alter the natural history of PAD. There is growing evidence that the renin-angiotensin system (RAS) is a significant mediator of this disease process and that treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with vasculoprotective effects that are independent of the antihypertensive properties of these agents. Numerous lines of evidence suggest that ACE inhibitors directly inhibit the atherosclerotic process and improve vascular endothelial function. In patients with PAD, ACE inhibitors have been shown to improve peripheral circulation as measured by peripheral arterial blood pressure and by increases in peripheral blood flow. Preliminary evidence suggests that ACE inhibitors might improve clinical symptoms in patients with PAD. Recent evidence has confirmed that ACE inhibition is associated with a decrease in morbidity and mortality in patients with arterial disease without left ventricular dysfunction; this benefit was at least as great for the subset of patients with PAD. Overall, these data support a significant role for the RAS in the pathogenesis of all atherosclerotic diseases (including PAD) and suggest that the benefit is independent of the blood pressure lowering properties of these agents. These studies suggest that ACE inhibitor therapy should be considered in the routine management of individuals with PAD, regardless of whether they have hypertension or left ventricular dysfunction.

Intravenous nesiritide vs. nitroglycerin for treatment of decompensated congestive heart failure. A randomized controlled trial

The possible role of angiotensin-converting enzyme inhibition in preventing or minimizing tolerance to intravenous nitroglycerin in severe congestive heart failure (CHF) was studied by quantitating the degree of tolerance in 12 patients receiving nitroglycerin (group 1) and in 9 patients (group 2) receiving nitroglycerin and concurrent treatment with captopril (60 ± 29 mg/day). At peak effect, nitroglycerin produced almost identical hemodynamic changes in both groups, with significant decreases in right atrial and pulmonary arterial wedge pressure, systolic blood pressure and systemic and pulmonary vascular resistances. Cardiac index increased.The extent of nitrate tolerance was calculated for each hemodynamic parameter as the percentage loss of the peak effect achieved by the drug. At 24 hours, 98 ± 80% of the benefit achieved with respect to right atrial pressure was lost in group 1 and 61 ± 74% in group 2 (group 1 vs 2, difference not significant). For pulmonary arterial wedge pressure, 51 ± 31% (group 1) and 85 ± 53% (group 2) (difference not significant) of the effect was lost, and for cardiac index, 53 ± 58% (group 1) and 54 ± 44% (group 2) (difference not significant). Tolerance was also almost identical regarding systolic blood pressure and systemic and pulmonary vascular resistance. Thus, the extent of tolerance to high-dose intravenous nitroglycerin in CHF was unaltered by administration of captopril, indicating that in clinical dosage, counter-regulatory neurohumoral mechanisms involving the renin-angiotensin system appear to be unimportant in its development.

Role of angiotensin-converting enzyme inhibition in glucose metabolism and renal injury in diabetes

The role of angiotensin-converting enzyme (ACE) inhibition in glucose metabolism and renal injury in diabetes has been extensively investigated in diabetic humans, as well as in animal models of diabetes. Accumulated data indicate that ACE inhibitors have either no adverse effect on glucose control or insulin sensitivity or may even improve them. ACE inhibitors also appear to have neutral or positive effects on lipid metabolism. The variability of results between studies may relate to differences in experimental design, the degree of glycemia or insulin resistance, potassium balance, and dose or duration of ACE inhibitor treatment, among others. In contrast, ACE inhibitors have proved effective in limiting proteinuria and retarding renal function loss in insulin-dependent diabetes mellitus (IDDM) or non—insulin-dependent diabetes mellitus (NIDDM) patients. In rats with experimental or spontaneous diabetes, ACE inhibitors also reduce proteinuria and limit glomerular as well as tubulointerstitial damage, independent of their effects on systemic arterial pressure. How ACE inhibitors limit renal injury in diabetes is not entirely clear, but hemodynamic and nonhemodynamic mechanisms may be involved. Increasing evidence suggests that the intrarenal renin-angiotensin system (RAS) may be altered or activated in the diabetic kidney. Such activation may be specifically inhibited by ACE inhibitors and may explain the superiority of this class of agents over other antihypertensive agents in reducing proteinuria and slowing the progression of diabetic nephropathy.

Role of angiotensin-converting enzyme inhibition in reversal of endothelial dysfunction in coronary artery disease

Angiotensin-converting enzyme (ACE) inhibitors have shown unexpected benefits in the prevention of ischemic events in patients with hypertension and congestive heart failure. In addition to these clinical observations, there is a growing body of knowledge about the molecular and cellular effects of ACE inhibitors. For example, ACE inhibition prevents stimulation of smooth muscle cell angiotensin II receptors, thereby blocking both contractile and proliferative actions. Angiotensin II blockade also diminishes the production of superoxide anion, which inactivates ambient nitric oxide. ACE inhibition of kininase II inhibits the breakdown of bradykinin, a direct stimulant of nitric oxide release from the intact endothelial cell. Thus, at the cellular level within the vasculature, ACE inhibition shifts the balance of ongoing mechanisms in favor of those promoting vasodilatory, antiaggregatory, antithrombotic, and antiproliferative effects. These effects underlie the potential benefits of ACE inhibition in the therapy of ischemia and atherosclerosis. Some data is available in humans to show that these effects can be sustained for months, thereby maintaining improved endothelial function and, presumably, allowing the initiation of steps that might alter the progression of atherosclerosis. Definitive information is not yet available in humans to show that ACE inhibition clearly alters the progression of atherosclerosis or diminishes coronary events in uncomplicated coronary disease. This promising area of investigation is, however, the subject of multiple clinical trials, which should provide clarification of this important question in coming years.

Clinical background to the use of ACE inhibitor therapy after myocardial infarction.

The rationale for using angiotensin converting enzyme (ACE) inhibitor therapy after acute myocardial infarction has been largely founded on observations made in experimental situations, and in humans before the routine introduction of reperfusion therapies. An important area of ongoing debate therefore continues to be the role of ACE inhibition as an early adjunct to attempts to achieve and maintain patency of infarct-related coronary arteries. Data from clinical trials indicate a substantial survival benefit in patients with impaired ventricular function, but provide little support for the routine treatment of the remaining majority of patients. An important issue in determining whether these agents should be used in a more general and long-term secondary prevention role, is their potential ability to prevent subsequent reinfarction. However, such a strategy is unlikely to be enhanced by either immediate initiation of treatment or withdrawal after just 1 month of therapy.

The use of angiotensin-converting enzyme inhibitors after acute myocardial infarction.

During and immediately after myocardial infarction (MI), many interrelated and complex processes manifest the body's attempt to minimize damage and compensate for lost cardiac function. Although these compensatory responses may provide some short-term restoration of function, their long-term consequences actually may increase morbidity and mortality. Several agents have established roles in the treatment of these patients, whereas others, including the angiotensin-converting enzyme (ACE) inhibitors, have yet to be investigated thoroughly. Results of two trials investigating the role of ACE inhibition after MI seem to provide sufficient data to warrant the use of these drugs in certain patient populations. These results are promising, but further investigation is necessary to answer key questions arising from these trials.

Mechanisms in heart failure and the role of angiotensin-converting enzyme inhibition

The four major diagnostic criteria for the syndrome of congestive heart failure are left ventricular dysfunction, exercise intolerance, pulmonary congestion or edema and ventricular arrhythmias. Activation of norepinephrine, angiotensin II, vasopressin and atrial natriuretic peptide may be a key factor in the vasoconstriction and increased impedance to left ventricular ejection in heart failure. Interventions that interfere with these vasoconstrictor mechanisms should have a salutary effect on left ventricular performance. Treatment with angiotensin-converting enzyme (ACE) inhibitors, α-adrenoceptor blockers and vasopressin antagonists has resulted in hemodynamic benefits, but it has been more difficult to demonstrate long-term clinical effectiveness. Reductions in mortality have been demonstrated in patients with heart failure treated with vasodilators and ACE inhibitors. Improvement in the quality of life and prolongation of life are the only two appropriate goals in the management of heart failure. Further understanding of the role of angiotensin II and its interference by ACE inhibition in the tissue processes of heart failure is needed.

Failure of captopril to prevent nitrate tolerance in congestive heart failure secondary to coronary artery disease

The possible role of angiotensin-converting enzyme inhibition in preventing or minimizing tolerance to intravenous nitroglycerin in severe congestive heart failure (CHF) was studied by quantitating the degree of tolerance in 12 patients receiving nitroglycerin (group 1) and in 9 patients (group 2) receiving nitroglycerin and concurrent treatment with captopril (60 ± 29 mg/day). At peak effect, nitroglycerin produced almost identical hemodynamic changes in both groups, with significant decreases in right atrial and pulmonary arterial wedge pressure, systolic blood pressure and systemic and pulmonary vascular resistances. Cardiac index increased. The extent of nitrate tolerance was calculated for each hemodynamic parameter as the percentage loss of the peak effect achieved by the drug. At 24 hours, 98 ± 80% of the benefit achieved with respect to right atrial pressure was lost in group 1 and 61 ± 74% in group 2 (group 1 vs 2, difference not significant). For pulmonary arterial wedge pressure, 51 ± 31% (group 1) and 85 ± 53% (group 2) (difference not significant) of the effect was lost, and for cardiac index, 53 ± 58% (group 1) and 54 ± 44% (group 2) (difference not significant). Tolerance was also almost identical regarding systolic blood pressure and systemic and pulmonary vascular resistance. Thus, the extent of tolerance to high-dose intravenous nitroglycerin in CHF was unaltered by administration of captopril, indicating that in clinical dosage, counter-regulatory neurohumoral mechanisms involving the renin-angiotensin system appear to be unimportant in its development.