Abstract
It has been known that various neurohumoral factors play important roles in the regulation of contraction and relaxation in cardiac muscle. Earlier reports suggested that angiotensin II play important roles in the pathogensis of chronic heart failure. However, the roles of endothelin 1 have not been fully clarified. Thus, we investigated the roles of endothelin in excitation-contraction coupling and relaxation in isolated single ventricular myocytes. We focused on the third kinase system: Rho dependent protein kinase (ROCK) in addition to the protein kinase A and C. We isolated single ventricular myocytes from Wister rats and measured intracellular calcium transients and cell contraction simultaneously. When we pretreated cells with PKC inhibitor, exposure to endothelin-1 still produced positive inotropic and lusitrophic effects. These effects were not observed when cells were pretreated with PKC inhibitor and ROCK inhibitor or myosin light chain kinase inihibitor. Effects of myosin light chain phosphatase inhibitor simulated those of endothelin-1. Inhibition of myosin light chain phosphatase accelerated the phosphorylation status of cardiac myosin light chain resulting in positive inotropic action similar to endothelin-1. Our results suggested that endothelin might activate myosin light chain not only via PKC but also via ROCK pathway.
Our working hypothesis is that endothelin 1 may produce positive inotropic effects via ROCK pathway. Thus we try to reveal the role of ROCK pathway in the regulation of contraction and relaxation in cardiac muscle.
