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Protein kinase C-dependent prostaglandin production mediates angiotensin II-induced atrial-natriuretic peptide release.

ABSTRACT: The respective roles of protein kinase C (PKC) and endogenous prostaglandin formation in angiotensin II (Ang II)-induced myocardial secretion of atrial natriuretic peptide (ANP) was studied in cultured, spontaneously beating, neonatal-rat cardiomyocytes. Incubation of cardiomyocytes with 0.1 microM Ang II led to a rapid but transient increase in particulate-bound PKC activity, a response accompanied by marked increases in cellular 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) generation and ANP secretion. A role for PKC in Ang II-induced 6-oxo-PGF1 alpha formation and ANP secretion was apparent, insofar as both responses were suppressed in the presence of the PKC inhibitors staurosporine (1 microM) and CGP 41251 (1 microM), as well as in cells in which PKC had been previously down-regulated by pretreatment with phorbol diester. Furthermore, Ang II-induced 6-oxo-PGF1 alpha production was found to be strongly correlated with Ang II-induced ANP release (r = 0.87, P < 0.001, n = 6), indicating a role for prostacyclin (PGI2) in Ang II-induced ANP secretion in these cells. This hypothesis was confirmed by finding that both Ang II-induced 6-oxo-PGF1 alpha production and ANP release were abolished in the presence of the respective phospholipase A2 and cyclo-oxygenase inhibitors quinacrine (10 microM) and indomethacin (10 microM), whereas exogenously applied PGI2 (1 microM) and prostaglandin E2 (0.1 microM) mimicked Ang II-induced ANP secretion in this system. Taken together, these results suggest that Ang II induces ANP secretion in spontaneously beating rat cardiomyocytes via a PKC-dependent autocrine pathway involving a cyclo-oxygenase product and a yet-to-be-identified myocardial prostanoid receptor.

SUBMITTER: Church DJ

PROVIDER: S-EPMC1137961 | biostudies-other | 1994 Mar

REPOSITORIES: biostudies-other

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Project description:The role of endogenous prostaglandin production in phorbol diester-induced myocardial atrial natriuretic peptide (ANP) secretion was investigated in cultured spontaneously beating ventricular rat cardiomyocytes. Incubation of cells with 4 beta-phorbol 12-myristate 13-acetate (PMA; 0.1 microM) led to a rapid response in ANP release, a response accompanied by increases in cellular prostacyclin (PGI2) production, cyclic AMP (cAMP) formation and spontaneous contraction frequency. Although PMA-induced ANP secretion exhibited the pharmacological profile of a protein kinase C (PKC)-mediated event, the response was abolished in the presence of the cyclo-oxygenase inhibitors indomethacin (10 microM) and diclofenac (1 microM), indicating that endogenous prostaglandin production is responsible for PMA-induced ANP secretion in this system. Confirming this, PMA-induced ANP secretion was strongly correlated with endogenous formation of 6-oxo-prostaglandin F1 alpha (r = 0.93, P < 0.0005, n = 11), and exogenously applied PGI2, prostaglandin E2 (PGE2) or prostaglandin F2 alpha (PGF2 alpha) elicited simultaneous increases in cAMP formation, contraction frequency and ANP secretion in these cells. Furthermore, PMA-induced cAMP formation was abolished in the presence of either diclofenac or indomethacin, whereas the cAMP-elevating agent forskolin (0.1 microM) mimicked the secretory and chronotropic effect of PMA in these cells. A role for cAMP in PMA-induced ANP secretion was also apparent insofar as PMA-induced ANP release was substantially decreased in the presence of the Rp-diastereomer of 3',5'-cyclic adenosine monophosphorothioate (Rp-cAMPS; 10 microM), whereas the cAMP-mimetic agent dibutyryl cAMP (10 microM) provoked a rapid increase in ANP secretion in this system. Finally, the Ca(2+)-channel antagonist nifedipine (0.1 microM) severely decreased PGI2-, PGE2- and PMA-induced ANP secretion without affecting PGF2 alpha-induced peptide release, suggesting that PGI2 and/or PGE2, but not PGF2 alpha, are the prostanoids involved in PMA-induced ANP release. Taken together, these results suggest that PKC activation induces ANP secretion in spontaneously beating rat ventricular cardiomyocytes via an autocrine pathway involving increased PGI2 and/or PGE2 formation, a response leading to the activation of a myocardial adenylate cyclase and, subsequently, to that of a nifedipine-sensitive Ca2+ channel.

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Protein kinase C-dependent prostaglandin production mediates angiotensin II-induced atrial-natriuretic peptide release.

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