STIMULATION OF THE P38 MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY IN NEONATAL RAT VENTRICULAR MYOCYTES BY THE G-PROTEIN-COUPLED RECEPTOR AGONISTS, ENDOTHELIN-1 AND PHENYLEPHRINE - A ROLE IN CARDIAC MYOCYTE HYPERTROPHY

We examined the activation of the p38 mitogen-activated protein kinase (p38-MAPK) pathway by the G protein-coupled receptor agonists, endoth elin-l and phenylephrine in primary cultures of cardiac myocytes from neonatal rat hearts. Both agonists increased the phosphorylation (acti vation) of p38-MAPK by similar to 12-fold. A p38-MAPK substrate, MAPK- activated protein kinase 2 (MAPKAPK2), was activated approximately fou rfold and 10 mu M SB203580, a p38-MAPK inhibitor, abolished this activ ation. Phosphorylation of the MAPKAPK2 substrate, heat shock protein 2 5/27, was also increased. Using selective inhibitors, activation of th e p38-MAPK pathway by endothelin-l was shown to involve protein kinase C but not G(i)/G(o) nor the extracellularly responsive kinase (ERK) p athway. SB203580 failed to inhibit the morphological changes associate d with cardiac myocyte hypertrophy induced by endothelin-l or phenylep hrine between 4 and 24 h. However, it decreased the myofibrillar organ ization and cell profile at 48 h. In contrast, inhibition of the ERK c ascade with PD98059 prevented the increase in myofibrillar organizatio n but not cell profile. These data are not consistent with a role for the p38-MAPK pathway in the immediate induction of the morphological c hanges of hypertrophy but suggest that it may be necessary over a long er period to maintain the response.