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(Hypertension. 1996;27:269-275.)
© 1996 American Heart Association, Inc.

Articles

Protein Kinase C Modulation of Cardiomyocyte Angiotensin II and Vasopressin Receptor Desensitization

Min Zhang; Donald Turnbaugh; Daniel Cofie; Selami Dogan; Hideo Koshida; Robert Fugate; David C. Kem

From the Departments of Medicine and Physiology, Sections of Endocrinology, Metabolism, and Hypertension, University of Oklahoma Health Sciences Center; Department of Veterans Affairs Medical Center; and the W.K. Warren Medical Research Institute, Oklahoma City, Okla.

Correspondence to David C. Kem, MD, University of Oklahoma Health Sciences Center (3SP-511), PO Box 26901, Oklahoma City, OK 73190.

Abstract Angiotensin II (Ang II) and arginine vasopressin (AVP) increased intracellular free Ca²⁺ concentration [Ca²⁺]_i and/or the [Ca²⁺]_i transient 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 produced homologous desensitization to AVP but not heterologous desensitization to Ang II. When the AVP exposure time was increased from 2 to 10 minutes coincident with maximal AVP-mediated PKC activation, heterologous desensitization to Ang II was also observed. Acute activation (15 minutes) of PKC by phorbol 12-myristate 13-acetate (PMA) blocked responsiveness to both Ang II and AVP. When PKC activation was inhibited by 20 hours of prior exposure to PMA, as confirmed by PKC assay, homologous desensitization of Ang II still occurred, confirming an alternative mechanism(s) for homologous desensitization in the cardiomyocytes. In contrast, 20-hour PMA suppression of PKC markedly diminished the ability of the cardiomyocytes to exhibit AVP-mediated heterologous desensitization for Ang II. These data indicate that PKC activation plays a primary role in mediating vasopressin V₁ receptor–induced heterologous desensitization of the Ang II receptor and participates in a hierarchy of two or more kinase systems mediating homologous desensitization of the Ang II receptor in cardiomyocytes.

Key Words: angiotensin II • arginine vasopressin • calcium • protein kinase • phorbol ester • myocardium

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