EFFECT OF YM087, A POTENT NONPEPTIDE VASOPRESSIN ANTAGONIST, ON VASOPRESSIN-INDUCED PROTEIN-SYNTHESIS IN NEONATAL RAT CARDIOMYOCYTE

Objective: Hypertrophy of cardiomyocytes may play an important role in the pathogenesis of cardiac hypertrophy associated with various cardi ovascular diseases such as congestive heart failure. The aim of this s tudy was to investigate whether vasopressin (AVP) induces protein synt hesis in cultured neonatal rat cardiomyocytes through its specific rec eptor and whether YM087, a newly synthesized nonpeptide AVP receptor a ntagonist, inhibits AVP-induced protein synthesis in vitro. Methods: A VP receptors on cardiomyocytes were characterized using the radioligan d [H-3]AVP. The effects of AVP and YM087 on intracellular free calcium concentration ([Ca2+](i)), mitogen-activated protein (MAP) kinase and [H-3]-leucine incorporation were investigated in cultured neonatal ra t cardiomyocytes. Results: In cardiomyocytes, Scatchard analysis showe d a single population of high-affinity binding sites with the expected AVP V-1A receptor subtype profile. YM087 showed high affinity for car diomyocyte V-1A receptors with a K-i value of 0.63 nM. In these same c ells, YM087 potently inhibited AVP-induced increases in [Ca2+](i) and activation of MAP kinase in a concentration-dependent manner. In addit ion; AVP concentration-dependently stimulated the synthesis of protein without changing the rate of DNA synthesis, and YM087 prevented AVP-i nduced protein synthesis in a concentration-dependent manner. Conclusi ons: These results suggest that AVP directly causes protein synthesis and YM087 is a potent inhibitor of AVP-induced protein synthesis of ca rdiomyocytes and thus may have beneficial effects in the development a nd regression of cardiomyocytic hypertrophy. (C) 1998 Elsevier Science B.V.