alpha(1)-Adrenoceptor-G(q)-RhoA signaling is upregulated to increase myofibrillar Ca2+ sensitivity in failing hearts

alpha (1)-Adrenergic stimulation, coupled to G(q), has been shown to promot e heart failure. However, the role of alpha (1)-adrenergic signaling in the regulation of myocardial contractility in failing myocardium is still poor ly understood. To investigate this, we observed 1) the effect of phenylephr ine on myofibrillar Ca2+ sensitivity in alpha -toxin-skinned cardiomyocytes , and 2) protein expression of G(q), RhoA, and myosin light chain phosphory lation using tachypacing-induced canine failing hearts. Phenylephrine signi ficantly increased myofibrillar Ca2+ sensitivity in failing but not in norm al cardiomyocytes. Whereas Y-27632 (Rho kinase inhibitor) blocked the pheny lephrine-induced Ca2+ sensitization in the failing myocytes, calphostin C ( protein kinase C inhibitor) had no effect on Ca2+ sensitization. The protei n expression of G alpha (q) and RhoA and the phosphorylation level of regul atory myosin light chain significantly increased in the failing myocardium. Our results suggest that alpha (1)-adrenoceptor-G(q) signaling is upregula ted in the failing myocardium to increase the myofibrillar Ca2+ sensitivity mainly through the RhoA-Rho kinase pathway rather than through the protein kinase C pathway.