Obligatory Role for Endogenous Endothelin in Mediating the Hypertrophic Effects of Phenylephrine and Angiotensin II in Neonatal Rat Ventricular Myocytes:Evidence for Two Distinct Mechanisms for Endothelin Regulation

摘要

Various G_q protein-coupled receptor agonists such as the alpha_1 adrenoceptor agonist phenylephrine,angiotensin II,and endothe-lin-1 are potent hypertrophic factors.There is evidence of potential cross talk between these agents,particularly in terms of endothe-lin-1 as playing a central role in mediating the actions of other hypertrophic factors.Using cultured rat neonatal ventricular myo-cytes,we assessed the potential cross talk between these factors and sought to examine the potential underlying mechanisms.Twenty-four-hour exposure to either agent produced significant hypertrophy as determined by cell size and molecular markers.Although the hypertrophic effects of phenylephrine and angiotensin II were expectedly prevented by alpha_1 and AT_1,receptor antagonists,respectively,these effects were also blocked by the ET_A receptor antagonist BQ123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)] but not by the ET_B antagonist BQ788 N-cis-2,6-dimethylpiperidi-nocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl- D-norleucine).Both phenylephrine and angiotensin II significantly increased protein expression of both endothelin receptor subtypes.Both phenylephrine and angiotensin II produced significant activation of p38 as well as extracellular signal-regulated protein kinase and c-Jun NH_2-terminal kinase,although this was unaffected by endothelin receptor blockade.Further studies revealed that the effects of phenylephrine and angiotensin II were mediated by stimulated endothelin-1 production occurring via two separate mechanisms:angiotensin II by increasing the levels of the endothelin-1 precursor prepro endothelin-1 and phenylephrine by up-regulating endothelin-converting enzyme 1.Our results indicate that the endothelin-1 system plays an obligatory role in the hypertrophic response to both phenylephrine and angiotensin II in cultured myocytes through a mechanism independent of mitogen-activated protein kinase activation.