Cytochrome P-450 metabolites in endothelin-stimulated cardiac hormone secretion

Department of Physiology and Biophysics and the University of South Florida, Cardiac Hormone Center, Tampa, Florida 33612 Submitted 22 August 2003 ; accepted in final form 6 January 2004 We examined the role of cytochrome P -450-arachidonate (CYP450-AA) metabolites in endothelin-1 (ET-1)-stimulated atrial natriuretic peptide (ANP) and pro-ANP-(1-30) secretion from the heart. 17-Octadecynoic acid (17-ODYA, 10 -5 M) significantly inhibited ANP secretion stimulated by ET-1 (10 -8 M) in the isolated perfused rat atria and inhibited pro-ANP-(1-30) secretion stimulated by ET-1 (10 -8 M) or 20-hydroxyeicosatetraenoic acid in cultured neonatal rat ventricular myocytes (NRVM). In NRVM, 17-ODYA significantly ( P < 0.05) increased secretion of cAMP but had no significant effect on the secretion of cGMP from NRVM. Staurosporine, an inhibitor of protein kinase C, completely blocked the inhibitory action of 17-ODYA, whereas a protein kinase A inhibitor, H-89 (5 x 10 -5 M), did not significantly attenuate the effects of 17-ODYA. The results show that the inhibitory action of 17-ODYA on ET-1-augmented ANP secretion is mediated through cAMP and suggest that CYP450-AA may play an important role in ET-1-induced cardiac hormone secretion. endothelin-1; 20-hydroxyeicosatetraenoic acid; 17-octadecynoic acid; nitric oxide; protein kinase A; protein kinase C; atrial natriuretic peptide; pro-ANP-(1-30); cardiac hypertrophy Address for reprint requests and other correspondence: J. R. Dietz, Dept. of Physiology and Biophysics, Univ. of South Florida, College of Medicine, Box 8, Tampa, FL 33612 (E-mail: jdietz{at}hsc.usf.edu ).