Unequal effects of renin-angiotensin system inhibitors in acute cardiac dysfunction induced by isoproterenol

Abstract

Several clinical trials have demonstrated that angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 receptor blocker (ARB) are equally effective in the treatment of chronic heart failure. However, this has not been confirmed for acute cardiac dysfunction. We examined whether ACEI or ARB prevents isoproterenol-induced acute left ventricular (LV) dysfunction in dogs. LV dysfunction induced by a large dose of isoproterenol (1 microg.kg(-1).min(-1), 3-h infusion) was compared in dogs treated with ACEI (temocaprilat) or ARB (olmesartan). Atrial pacing induced a constant heart rate and use of adjustable aortic banding provided a nearly constant afterload. LV systolic function (LV dP/dt, fractional shortening, and ejection fraction) and diastolic function (tau and LV end-diastolic pressure) were significantly deteriorated after isoproterenol infusion. The LV dysfunction was almost totally prevented by ARB but was only partially prevented by ACEI. The partial effect of ACEI was complemented by cotreatment with HOE-140, a bradykinin B2 receptor antagonist. At baseline, the response to low doses of isoproterenol was significantly attenuated by ACEI but not by ARB, and the ACEI-induced attenuation was totally abolished by cotreatment with HOE-140. The response to isoproterenol was significantly attenuated after 3 h of excess isoproterenol loading, and it was almost completely preserved by ARB but not by ACEI. In conclusion, acute LV dysfunction and beta-adrenergic desensitization induced by excess isoproterenol administration were almost totally prevented by ARB but only partially prevented by ACEI. These differences were attributable at least in part to bradykinin pathways activated by ACEI administration in acute LV dysfunction.

Valsartan, an Angiotensin II Receptor Blocker, Attenuates Cardiac Dysfunction and Oxidative Stress in Isoproterenol-Induced Cardiotoxicity

“…The pharmacological mechanism is that ARBs have direct effect via dilatation of arteries and veins and thereby results in reduction in preload and afterload and hence subsequent decrease in LVEDP [1,5,8]. In corroboration with our findings Ohta et al have also demonstrated that ARBs restored cardiac dysfunction induced by ISO [22]. Lipid peroxidation plays an important role in the pathogenesis of MI.…”

“…Furthermore, ARBs also inhibit cardiac and vascular remodeling associated with chronic hypertension and MI thereby suggesting a protective role in myocardial injury [7,8]. In consonance with our findings various experimental studies have also reported beneficial effects of AT1 antagonists in myocardial infarction in rats [21][22][23]. However, no significant alterations were observed in heart rate, among all groups.…”

Magnesium attenuates isoproterenol-induced acute cardiac dysfunction and β-adrenergic desensitization

“…The ISO loading dose was determined from both a preliminary study and previous study using the same experimental model (31). As the maximal dose, one which did not induce crucial hemodynamic deterioration or fatal arrhythmias during more than 4 h of experiments, 1 g ⅐ kg Ϫ1 ⅐ min Ϫ1 of ISO was selected.…”

“…To achieve this goal, we used an ISO-induced cardiac dysfunction and ␤-adrenergic desensitization dog model (31).…”

Missing Links: Mechanisms of Protean Agonism: Fig. 1.

“…In 1983, however, one did not know about the five different dopamine receptor subtypes, so re-examination of this question with receptor-knockout models and/or improved pharmacological agents may be worthwhile. In addition, the role of G␣ selectivity in the novel pharmacology of aripiprazole (Ohta et al, 2004) will be of interest to study. Second, distinct effector mechanisms have been proposed for G i and G o signaling, activation of G protein-coupled inwardly rectifying potassium channel currents, and inhibition of voltage-gated Ca 2ϩ channels (Sowell et al, 1997;Valenzuela et al, 1997).…”