Effect of YM087, a potent nonpeptide vasopressin antagonist, on vasopressin-induced protein synthesis in neonatal rat cardiomyocyte

• Published in: Cardiovascular research 1998-04, Vol.38 (1), p.198-205
• Main Authors: TAHARA, A, TOMURA, Y, WADA, K.-I, KUSAYAMA, T, TSUKADA, J, ISHII, N, YATSU, T, UCHIDA, W, TANAKA, A
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin - antagonists & inhibitors; Arginine Vasopressin - metabolism; Arginine Vasopressin - pharmacology; Benzazepines - pharmacology; Biological and medical sciences; Calcium - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cardiology. Vascular system; Cells, Cultured; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Leucine - metabolism; Medical sciences; Myocardium - enzymology; Myocardium - metabolism; Piperidines - pharmacology; Protein Biosynthesis; Quinolones - pharmacology; Rats; Rats, Wistar; Receptors, Vasopressin - metabolism; Stimulation, Chemical; Thymidine - metabolism
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/S0008-6363(97)00324-6

Hypertrophy of cardiomyocytes may play an important role in the pathogenesis of cardiac hypertrophy associated with various cardiovascular diseases such as congestive heart failure. The aim of this study was to investigate whether vasopressin (AVP) induces protein synthesis in cultured neonatal rat cardiomyocytes through its specific receptor and whether YM087, a newly synthesized nonpeptide AVP receptor antagonist, inhibits AVP-induced protein synthesis in vitro. AVP receptors on cardiomyocytes were characterized using the radioligand [3H] AVP. The effects of AVP and YM087 on intracellular free calcium concentration ([Ca2+]i), mitogen-activated protein (MAP) kinase and [3H]-leucine incorporation were investigated in cultured neonatal rat cardiomyocytes. In cardiomyocytes, Scatchard analysis showed a single population of high-affinity binding sites with the expected AVP V1A receptor subtype profile. YM087 showed high affinity for cardiomyocyte V1A receptors with a Ki value of 0.63 nM. In these same cells, YM087 potently inhibited AVP-induced increases in [CA2+]I and activation of MAP kinase in a concentration-dependent manner. In addition, AVP concentration-dependently stimulated the synthesis of protein without changing the rate of DNA synthesis, and YM087 prevented AVP-induced protein synthesis in a concentration-dependent manner. These results suggest that AVP directly causes protein synthesis and YM087 is a potent inhibitor of AVP-induced protein synthesis of cardiomyocytes and thus may have beneficial effects in the development and regression of cardiomyocytic hypertrophy.