Modulation by angiotensin II of isoproterenol-induced cAMP production in preglomerular microvascular smooth muscle cells from normotensive and genetically hypertensive rats.
The objectives of the present study were to determine whether angiotensin II (Ang II) modifies beta-adrenoceptor-induced cAMP production in preglomerular microvascular smooth muscle cells (PMVSMCs), to determine whether the Ang II/beta-adrenoceptor interaction on cAMP production differs in PMVSMCs from normotensive Wistar-Kyoto (WKY) rats vs. PMVSMCs from spontaneously hypertensive rats (SHR), and to elucidate the mechanism 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 of isoproterenol-induced cAMP was significantly greater in SHR PMVSMCs compared with WKY PMVSMCs. Neither inhibition of calcineurin with FK506, inhibition of calcium-calmodulin with W-7 and calmidazolium, nor inhibition of Gi proteins with pertussis toxin attenuated Ang II enhancement of isoproterenol-induced cAMP in PMVSMCs from either SHR or WKY rats. Moreover, the effect of Ang II on isoproterenol-induced cAMP was not mimicked by alpha-2 adrenoceptor stimulation. In contrast, chelation of intracellular calcium with BAPTA-AM attenuated, increasing intracellular calcium with A23187 augmented, and inhibition of protein kinase C with either calphostin C or chelerythrine chloride abolished Ang II enhancement of isoproterenol-induced cAMP. We conclude that in cultured PMVSMCs Ang II enhances the cAMP response to beta-adrenoceptor agonists 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.
Center for Clinical Pharmacology, Departments of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
R
R
Mokkapatti
S J
SJ
Vyas
G G
GG
Romero
Z
Z
Mi
T
T
Inoue
R K
RK
Dubey
D G
DG
Gillespie
A K
AK
Stout
E K
EK
Jackson
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000502:physiology; D000242:Cyclic AMP / Q000096:biosynthesis*; D019204:GTP-Binding Proteins / Q000502:physiology; D006973:Hypertension / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000098:blood supply*; D008297:Male; D008833:Microcirculation / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D002147:Calmodulin; D000804:Angiotensin II; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D007545:Isoproterenol; D002118:Calcium