Changes in  -adrenoceptors in heart failure due to myocardial infarction are attenuated by blockade of renin–angiotensin system

Abstract

Earlier studies have revealed an improvement of cardiac function in animals with congestive heart failure (CHF) due to myocardial infarction (MI) by treatment with angiotensin converting enzyme (ACE) inhibitors. Since heart failure is also associated with attenuated responses to catecholamines, we examined the effects of imidapril, an ACE inhibitor, on the beta-adrenoceptor (beta-AR) signal transduction in the failing heart. Heart failure in rats was induced by occluding the coronary artery, and 3 weeks later the animals were treated with g/(kg x day) (orally) imidapril for 4 weeks. The animals were assessed for their left ventricular function and inotropic responses to isoproterenol. Cardiomyocytes and crude membranes were isolated from the non-ischemic viable left ventricle and examined for the intracellular concentration of Ca2+ [Ca2+]i and beta-ARs as well as adenylyl cyclase (AC) activity, respectively. Animals with heart failure exhibited depressions in ventricular function and positive inotropic response to isoproterenol as well as isoproterenol-induced increase in [Ca2+]i in cardiomyocytes; these changes were attenuated by imidapril treatment. Both beta1-AR receptor density and isoproterenol-stimulated AC activity were decreased in the failing heart and these alterations were prevented by imidapril treatment. Alterations in cardiac function, positive inotropic effect of isoproterenol, beta1-AR density and isoproterenol-stimulated AC activity in the failing heart were also attenuated by treatment with another ACE inhibitor, enalapril and an angiotensin II receptor antagonist, losartan. The results indicate that imidapril not only attenuates cardiac dysfunction but also prevents changes in beta-AR signal transduction in CHF due to MI. These beneficial effects are similar to those of enalapril or losartan and thus appear to be due to blockade of the renin-angiotensin system.

Defective calcium handling in cardiomyocytes isolated from hearts subjected to ischemia-reperfusion

“…Because such an augmentation of the KClinduced increase in [Ca 2ϩ ] i by Iso was prevented by propranolol, a ␤-adrenoceptor blocker, it is evident that the Isoinduced increase in [Ca 2ϩ ] i is mediated through activation of ␤ 1 -adrenoceptors in cardiomyocytes. These results are consistent with earlier observations showing an increase in [Ca 2ϩ ] i by Iso in KCl-depolarized as well as electrically stimulated cardiomyocytes (37,40). The data described here show that the Iso-induced increase in [Ca 2ϩ ] i in KCl-depolarized cells is attenuated in I/R hearts.…”

“…Accordingly, we investigated in detail the Ca 2ϩ handling abilities of nondepolarized and depolarized cardiomyocytes isolated from hearts subjected to different periods of ischemia and reperfusion to test whether changes in [Ca 2ϩ ] i in cardiomyocytes are related to reversible and irreversible phases of I/R injury. Because catecholamines are known to cause an increase in [Ca 2ϩ ] i (37), the effect of isoproterenol (Iso), a ␤ 1 -adrenoceptor agonist (30), on intracellular Ca 2ϩ handling was studied in depolarized cardiomyocytes. In view of the important role of oxidative stress in inducing I/R injury, experiments were carried out to examine whether I/R-induced Ca 2ϩ handling abnormalities in cardiomyocytes are mediated through the generation of oxyradicals.…”

Gαq-mediated Activation of GRK2 by Mechanical Stretch in Cardiac Myocytes

“…Furthermore, a decrease in GRK mRNA expression is seen in HF patients after chronic administration of an angiotensin converting enzyme inhibitor (41). In addition, angiotensin converting enzyme inhibition has been shown to increase ␤ 1 -AR density in patients with HF (42). Inhibition of G q -mediated activation of PKC and subsequent up-regulation of GRK2 activity may play an important role in the efficacy of angiotensin-converting enzyme inhibitors in patients with HF.…”

Role of Subcellular Remodeling in Cardiac Dysfunction due to Congestive Heart Failure

“…While the significance of cardiac remodeling in CHF still remains to be elucidated, it is apparent that the cardiac subcellular organelles need to be selectively treated and appropriate therapy needs to be designed. It is therefore of greatest importance to acquire the underlying mechanisms involved as we are challenged to study the prevention of structural modification in the myocardium as well as changes in subcellular organelles using diverse approaches and experimental methodologies for inducing CHF [103][104][105] . In addition, it will be essential to carry out experiments showing the reversal of subcellular remodeling using a wide variety of pharmacological and surgical interventions.…”