α1-AR-induced positive inotropic response in heart is dependent on myosin light chain phosphorylation

Abstract

The possible involvement of different kinases in the α1-adrenoreceptor (AR)-mediated positive inotropic effect (PIE) was investigated in rat papillary muscle and compared with β-AR-, endothelin receptor- and phorbol ester-induced changes in contractility. The α1-AR-induced PIE was not reduced by the inhibitors of protein kinase C (PKC), MAPK (ERK and p38), phosphatidyl inositol 3-kinase, or calmodulin kinase II. However, PKC inhibition attenuated the effect of phorbol 12-myristate 13-acetate (PMA) on contractility. α1-AR-induced PIE was reduced by ∼90% during inhibition of myosin light chain kinase (MLCK) by 1-(5-chloronaphthalene-1-sulfonyl)1 H-hexahydro-1,4-diazepine (ML-9). Endothelin-induced PIE was also reduced by ML-9, but ML-9 had no effect on β-AR-induced PIE. The Rho kinase inhibitor Y-27632 also reduced the α1-AR-induced PIE. The α1-AR-induced PIE in muscle strips from explanted failing human hearts was also sensitive to MLCK inhibition. α1-AR induced a modest increase in 32P incorporation into myosin light chain in isolated rat cardiomyocytes. This effect was eliminated by ML-9. The PIE of α1-AR stimulation seems to be dependent on MLCK phosphorylation.