NITRIC-OXIDE, ATRIAL-NATRIURETIC-PEPTIDE, AND CYCLIC-GMP INHIBIT THE GROWTH-PROMOTING EFFECTS OF NOREPINEPHRINE IN CARDIAC MYOCYTES AND FIBROBLASTS

This study tested the hypothesis that nitric oxide (NO) and atrial nat riuretic peptide (ANP) can attenuate the effects of adrenergic agonist s on the growth of cardiac myocytes and fibroblasts. in ventricular ce lls cultured from neonatal rat heart, ANP and the NO donor S-nitroso-N -acetyl-D,L-penicillamine (SNAP) caused concentration-dependent decrea ses in the norepinephrine (NE)-stimulated incorporation of [H-3]leucin e in myocytes and [H-3]thymidine in fibroblasts. In myocytes, the NO s ynthase inhibitor N-G-monomethyl-L-arginine potentiated NE-stimulated [H-3]leucine incorporation. In both fell types, ANP and SNAP increased intracellular cGMP levels, and their growth-suppressing effects were mimicked by the cGMP analogue 8-bromo-cGMP. Furthermore, in myocytes, 8-bromo-cGMP attenuated the alpha(1)-adrenergic receptor-stimulated in creases in c-fos. Likewise, ANP and 8-bromo-cGMP attenuated the alpha( 1)-adrenergic receptor-stimulated increase in prepro-ANP mRNA and the alpha(1)-adrenergic receptor-stimulated decrease in sarcoplasmic retic ulum calcium ATPase mRNA. The L-type Ca2+ channel blockers verapamil a nd nifedipine inhibited NE-stimulated incorporation of [H-3]leucine in myocytes and [3(H)]thymidine in fibroblasts, and these effects were n ot additive with those of ANP, SNAP, or 8-bromo-cGMP. In myocytes, the Ca2+ channel agonist BAY K8644 caused an increase in [H-3]leucine inc orporation which was inhibited by ANP, These findings indicate that NO and ANP can attenuate the effects of NE on the growth of cardiac myoc ytes and fibroblasts, most Likely by a cGMP-mediated inhibition of-NE- stimulated Ca2+ influx.