MODULATION BY ANGIOTENSIN-II OF ISOPROTERENOL-INDUCED CAMP PRODUCTIONIN PREGLOMERULAR MICROVASCULAR SMOOTH-MUSCLE CELLS FROM NORMOTENSIVE AND GENETICALLY HYPERTENSIVE RATS

The objectives of the present study were to determine whether angioten sin II (Ang II) modifies beta-adrenoceptor-induced cAMP production in preglomerular microvascular smooth muscle cells (PMVSMCs), to determin e whether the Ang II/beta-adrenoceptor interaction on cAMP production differs in PMVSMCs from normotensive Wistar-Kyoto (WKY) rats vs. PMVSM Cs from spontaneously hypertensive rats (SHR), and to elucidate the me chanism of Ang II/beta-adrenoceptor interactions on cAMP production in PMVSMCs. In cultured PMVSMCs, isoproterenol increased cAMP levels and this effect was markedly enhanced by Ang II. The Ang II enhancement o f isoproterenol-induced cAMP was significantly greater in SHR PMVSMCs compared with WKY PMVSMCs. Neither inhibition of calcineurin with FK50 6, inhibition of calcium-calmodulin with W-7 and calmidazolium, nor in hibition of Gi proteins with pertussis toxin attenuated Ang II enhance ment of isoproterenol-induced cAMP in PMVSMCs from either SHR or WKY r ats. Moreover, the effect of Ang II on isoproterenol-induced cAMP was not mimicked by alpha-2 adrenoceptor stimulation. in contrast, chelati on of intracellular calcium with BAPTA-AM attenuated, increasing intra cellular calcium with A23187 augmented, and inhibition of protein kina se C with either calphostin C or chelerythrine chloride abolished Ang II enhancement of isoproterenol-induced cAMP. We conclude that in cult ured PMVSMCs Ang II enhances the cAMP response to beta-adrenoceptor ag onists via a mechanism that involves coincident activation of adenylyl cyclase by stimulatory G proteins and protein kinase C. Thus, protein kinase C-mediated activation of adenylyl cyclase may attenuate Ang II -induced vasoconstriction in the renal microcirculation by raising the intracellular levels of cAMP, and this mechanism may be augmented in genetic hypertension.