PROTEIN-KINASE-C MODULATION OF CARDIOMYOCYTE ANGIOTENSIN-II AND VASOPRESSIN RECEPTOR DESENSITIZATION

Angiotensin II (Ang II) and arginine vasopressin (AVP) increased intra cellular free Ca2+ concentration [Ca2+](i) and/or the [Ca2+](i) transi ent rate (CaTR) in cultured neonatal rat cardiomyocytes. These agents increased membrane-bound protein kinase C (PKC) with peak activity at 5 and 10 minutes, respectively. Two-minute exposure to Ang II produced homologous desensitization to a repeated stimulation with Ang II and heterologous desensitization to AVP. Two-minute exposure to AVP also p roduced homologous desensitization to AVP but not heterologous desensi tization to Ang II. When the AVP exposure time was increased from 2 to 10 minutes coincident with maximal AVP-mediated PKC activation, heter ologous desensitization to Ang II was also observed. Acute activation (15 minutes) of PKC by phorbol 12-myristate 13-acetate (PMA) blocked r esponsiveness to both Ang II and AVP. When PKC activation was inhibite d by 20 hours of prior exposure to PMA, as confirmed by PKC assay, hom ologous desensitization of Ang II still occurred, confirming an altern ative mechanism(s) for homologous desensitization in the cardiomyocyte s. In contrast, 20-hour PMA suppression of PKC markedly diminished the ability of the cardiomyocytes to exhibit AVP-mediated heterologous de sensitization for Ang II. These data indicate that PKC activation play s a primary role in mediating vasopressin V-l receptor-induced heterol ogous desensitization of the Ang II receptor and participates in a hie rarchy of two or more kinase systems mediating homologous desensitizat ion of the Ang II receptor in cardiomyocytes.