Benefit Of Angiotensin-converting Enzyme Inhibitor Therapy Research Articles

Meprin-α in chronic diabetic nephropathy: interaction with the renin-angiotensin axis

Meprin (MEP) A is a metalloendopeptidase that is present in the renal proximal tubule brush-border membrane (BBM) and that colocalizes with angiotensin-converting enzyme (ACE). The MEP beta-chain gene locus on chromosome 18 has been linked to a heightened risk of diabetic nephropathy (DN) in patients with type 2 diabetes. This study evaluated 1) whether MEP-alpha and MEP-beta gene and protein expression are altered in db/db mice before the onset of DN and 2) the role of MEP-alpha in the pathogenesis of DN and the impact of the renin-angiotensin system on this interaction in two experimental models of diabetes. MEP-alpha and MEP-beta gene and protein expression were evaluated in db/db mice, 13-14 wk of age, compared with lean C57BLKS/J littermate animals. A treatment study was then performed in which db/db mice and controls were assigned to one of three groups: control (C) water, no therapy; ACE inhibitor therapy, enalapril (EN)-treated water, 50 mg/l; ANG II receptor type 1 blocker (ARB) therapy, losartan (LOS)-treated water, 500 mg/l. Treatment was started at 8 wk of age and continued for 52 wk. Male Sprague-Dawley rats with diabetes for 52 wk following a single dose of streptozocin (STZ; 60 mg/kg) were also studied. At 13.5 wk of age, MEP-alpha and MEP-beta kidney mRNA abundance and protein expression were significantly lower in db/db mice compared with lean controls, with greater changes in MEP-beta (P < 0.05). In the treatment study, EN ameliorated and LOS exacerbated DN in db/db mice. BBM MEP A enzymatic activity and MEP-alpha protein content were lower in db/db mice vs. control nonobese mice at 52 wk (P < 0.02). EN-treated db/db mice showed increased MEP A activity, MEP-alpha content in BBM, decreased urinary MEP-alpha excretion, and enhanced BBM staining for MEP-alpha protein vs. C and LOS-treated db/db mice. In nonobese mice, EN and LOS treatment had no effect on MEP-alpha expression. In rats with STZ-induced diabetes for 52 wk, urinary MEP-alpha excretion was increased and MEP A activity and MEP-alpha protein content per milligram of BBM protein were decreased compared with age-matched control animals (P < 0.05). These results indicate that db/db mice manifest decreased MEP-alpha and MEP-beta gene and protein expression, before the development of overt kidney disease. Moreover, in db/db mice with DN and rats with STZ-diabetes, there was an inverse relationship between renal MEP-alpha content and the severity of the renal injury. Treatment with an ACE inhibitor was more effective than ARB in ameliorating DN in db/db mice, a change that correlated with alterations in urinary excretion and BBM content of MEP-alpha. MEP-alpha may play a role in the pathogenesis of DN and the benefits of ACE inhibitor therapy on the progression of diabetic kidney disease may be related, in part, to its impact on renal MEP-alpha expression.

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Angiotensin-converting enzyme inhibitors and stroke risk: benefit beyond blood pressure reduction?

Hypertension, a leading cause of morbidity and mortality, accounts for 25-49% of all strokes. Randomized placebo-controlled trials primarily with diuretics and beta-blockers administered in patients with hypertension have demonstrated a 38% reduction in primary stroke. Placebo-controlled trials with angiotensin-converting enzyme (ACE) inhibitors have not been conducted in patients with hypertension. However, in a meta-analysis of four placebo-controlled trials of ACE inhibitors in patients with coronary heart disease and/or diabetes mellitus, the overall risk of primary stroke was significantly reduced. Results of the Heart Outcomes Prevention Evaluation trial, which produced a substantial reduction in stroke with an apparently small reduction in blood pressure, suggest that the benefit of ACE inhibitors may be related to their effects on the renin-angiotensin-aldosterone system more than on blood pressure reduction. In active-control comparisons in patients with hypertension, ACE inhibitors have demonstrated reductions in primary stroke risk similar to reductions with diuretics, beta-blockers, and calcium channel blockers. The data suggest that for primary prevention of stroke antihypertensive therapy should be individualized in patients. Relatively few data are available concerning the benefit of antihypertensive therapy in the secondary prevention of stroke. In patients who had experienced a stroke or transient ischemic attack, therapy with a diuretic or a combination of a diuretic plus an ACE inhibitor could be recommended based on available outcome studies conducted in this patient population. It is premature to conclude that the benefit of ACE inhibitor therapy in primary or secondary prevention of stroke is an effect independent of blood pressure reduction. Hypertension detection, treatment, and control in patients still must be the principal focus of clinicians for both primary and secondary prevention of stroke.

The angiotensin-converting enzyme inhibitor and aspirin interaction in congestive heart failure: fear or reality?

Angiotensin-converting enzyme (ACE) inhibitors have become the cornerstone of therapy for congestive heart failure (CHF). Because ischemic heart disease is the most common cause of CHF, aspirin is frequently given concomitantly with ACE inhibitors in patients with CHF. Increased bradykinin levels, with the consequent enhanced synthesis of vasodilatory prostaglandins, appear to mediate a significant benefit of ACE inhibitor therapy in these patients. In contrast, aspirin inhibits cyclooxygenase, and thereby suppresses prostaglandin production. Thus, these counteracting effects on prostaglandins may result in antagonism between ACE inhibitor and aspirin therapy in heart failure patients. Several early reports questioned the safety of aspirin in CHF, and the potential antagonistic interaction between ACE inhibitors and aspirin in patients with heart failure has become the focus of both increasing research and intense debate. This article briefly highlights the theoretic considerations underlying this interaction, and reviews the available evidence for such an interaction from clinical trials.

Effects of angiotensin-converting enzyme inhibitors and digoxin on health outcomes of very old patients with heart failure. SAGE Study Group. Systematic Assessment of Geriatric drug use via Epidemiology.

Randomized trials have shown that angiotensin-converting enzyme (ACE) inhibitors reduce mortality and morbidity, and improve symptoms and exercise tolerance in selected patients with congestive heart failure (CHF). There is, however, no evidence on the effectiveness of ACE inhibitors in the typical, very old and frail patients with CHF. To compare the effects of ACE inhibitors and digoxin on 1-year mortality, morbidity, and physical function among patients aged 85 years. We conducted a retrospective cohort study using the SAGE database, a long-term care database linking patient information with drug utilization data. Among 64637 patients with CHF admitted to all nursing homes in 5 states between 1992 and 1995, we identified 19492 patients taking either an ACE inhibitor (n = 4911) or digoxin (n = 14890). Record of date of death was derived from Medicare enrollment files, and we used the part A Medicare files to identify hospital admissions and discharge diagnoses. As a measure of physical function, we used a scale for activities of daily living performance. The effect of ACE inhibitors was estimated using Cox proportional hazards models with digoxin users as the reference group. The overall mortality rate among ACE inhibitor recipients was more than 10% less than that of digoxin users (relative rate, 0.89; 95% confidence interval, 0.83-0.95). Mortality was equally reduced regardless of concomitant cardiovascular conditions and baseline physical function. Treatment with ACE inhibitors was associated with a tendency toward reduced hospital admissions that was more evident among patients with greater functional impairment. The adjusted relative rate for hospitalization for any reason was 0.96 (95% confidence interval, 0.91-1.01). The rate of functional decline was greatly reduced among ACE inhibitor recipients (relative rate, 0.74; 95% confidence interval, 0.69-0.80), and this effect was consistent and independent of background comorbidity and baseline physical function. These data suggest that survival and functional benefits of ACE inhibitor therapy extend to patients with CHF 85 years and older, and mostly women, both systematically underrepresented in randomized trials. Alternatively, digoxin has a detrimental effect in this population.

Who should be treated with angiotensin-converting enzyme inhibitors after myocardial infarction?

Angiotensin-converting enzyme (ACE) inhibitors are now established drugs in the treatment of hypertension and heart failure. However, their use in patients after a myocardial infarction has occurred remains controversial. The major clinical question regarding ACE inhibitors is whether they should be given to all patients immediately after thrombolysis or whether their use should be restricted to a particular subgroup. This question has now been addressed in several large-scale trials of mortality after myocardial infarction, and no important new information seems likely to emerge on the issue. Clinicians must therefore decide what their practice will be on the basis of data that are currently available. The authors of the recently published Gruppo italiano per lo Studio delta Sopravvlvenza nell' infarcto Miocardico (GISSI-3) and Fourth International Study of Infarct Survival (ISIS-4) mega-trials advocate a policy of widespread and early use of ACE inhibitors in all patients after myocardial infarction occurs. However, the small mortality benefit observed from use of ACE inhibitors in these studies lacks certainly and may prove difficult to reproduce in the general population of patients who have had an infarct outside the setting of a trial. Although patients were essentially not selected apart from the exclusion of those with marked hypotension, the low 6-month and 1-year mortality figures indicate "selection" compared with the typical population of patients who have had a myocardial infarction. Furthermore, a significant long-term mortality benefit was not observed with the short-term (4- to 6-week) use of ACE inhibitors in these trials. In contrast, in the Survival and Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE), and Trandopril Cardiac Evaluation (TRACE) trials, where evidence of impairment of ventricular function was used to select patients, both a marked and certain benefit regarding mortality was apparent from long-term prescription of these drugs. Importantly, the marked benefit observed in these selected patients may have been "diluted out" in the larger scale trials of unselected patients where the majority may have gained little and some may have been harmed by treatment or its withdrawal. In most of the large mortality trials the rationale for use of ACE inhibitors after myocardial infarction was stated to be their likely beneficial effect on "remodeling" of the heart after "Infarct expansion." Because adverse remodeling occurs in only a proportion of patients after a heart attack, the benefits of ACE inhibitor therapy might be predicted to be largely limited to this group, which would favor a selective policy. However, strong claims have been made that ACE inhibitors have other important actions, including prevention of myocardial infarction. If this is confirmed in a number of ongoing large-scale trials. then an even ore widespread use of these agents can be expected.