Attenuation of changes in G_i‐proteins and adenylyl cyclase in heart failure by an ACE inhibitor, imidapril

Abstract

Cardiac dysfunction in animals with congestive heart failure due to myocardial infarction (MI) is known to be associated with a wide variety of defects in receptor and post-receptor mechanisms. Since the heart function have been shown to be improved by treatment with different angiotensin converting enzyme (ACE) inhibitors, we examined the effects of imidapril, an ACE inhibitor, on changes in post-receptor mechanisms involving adenylyl cyclase (AC) and G proteins in the failing heart. Heart failure in rats was induced by occluding the coronary artery and 3 weeks later the animals were treated daily with 1 mg/kg (orally) imidapril for 5 weeks. The animals were assessed for their left ventricular function and crude membranes were isolated from the viable left ventricle and examined for AC activities as well as G-protein activities and expression. Animals with heart failure exhibited depressions in ventricular function and AC activities in the absence or presence of forskolin, NaF and Gpp(NH)p. The AC activity in the presence of pertussis toxin was increased whereas that in the presence of cholera toxin was decreased in the failing heart. Protein contents and mRNA levels for G i -proteins were increased whereas those for G s -proteins were unaltered in the infarcted heart. All these changes due to MI were prevented by imidapril treatment. The results indicate that the depressed cardiac function in the failing heart may partly be due to the direct effects of changes in AC and G i proteins.

Role of angiotensin II in the development of subcellular remodeling in heart failure

“…In this regard, various ACE inhibitors such as captopril, benazepril, enalapril, ramipril, perindopril, imidapril and trandolapril [110][111][112][113][114][115], and different AT1R antagonists including losartan, valsartan, irbesartan, candesartan cilexetil, telmisartan and eprosartan [116][117][118][119][120][121][122] have been reported to prevent alterations in the failing heart at subcellular and molecular levels and improve heart function in heart failure. It should also be mentioned that ANG II blockade has been shown to attenuate changes in collagen expression, β-adrenoceptor signal transduction system and ATP-induced increase in [Ca 2+ ] i in the failing heart [123][124][125][126]. These observations support the view that the activation of RAS and elevated plasma levels of ANG II play an important role in the pathogenesis of cardiac dysfunction and subcellular abnormalities in heart failure.…”

The influence of diabetes on cardiac β-adrenoceptor subtypes

“…As a matter of fact, in chronic human heart failure and in many animal models of the syndrome, b-adrenoceptor function has been demonstrated to be limited by several molecular mechanisms [21]. These include a decrease in the expression and coupling of the b 1 -adrenoceptors [22], a decrease in the coupling of b 2 -adrenoceptors [22,23], an increase in the expression of the inhibitory G protein (G i ) [24,25], an increase in the expression of the G protein-coupled receptor kinases (GRKs) [24], and a decrease in the expression or function of adenylyl cyclase [26]. Since diabetes frequently leads to cardiac pump failure, further leading to congestive heart failure, the changes in cardiac b-adrenoceptor expression and/or function might be comparable with those of the heart in diabetes.…”

Signal Transduction in the Cardiovascular System in Health and Disease

“…Since the activation of RAS was seen before any change in the heart or plasma upon inducing PO (Akers et al 2000), it appears that the activation of RAS plays a dominant role in changing the sensitivity of failing hearts to β-adrenergic stimulation. Also, we have demonstrated that downregulation of the β-AR G-protein AC system in the LV from the failing heart due to myocardial infarction is attenuated by blockade of the RAS (Sethi et al 2003). In addition, we have shown that treatment of the infarcted animals with propionyl L-carnitine, a metabolic therapy, not only improved cardiac function but also attenuated defects in the β-adrenergic mechanisms (Sethi et al 2004).…”