Vol. 288, Issue 3, 1229-1234, March 1999

Angiotensin Receptor Subtype 1 Mediates Angiotensin II Enhancement of Isoproterenol-Induced Cyclic AMP Production in Preglomerular Microvascular Smooth Muscle Cells¹

Tomoo Inoue, Zaichuan Mi, Delbert G. Gillespie, Raghvendra K. Dubey and Edwin K. Jackson

Center for Clinical Pharmacology, Departments of Pharmacology (E.K.J.) and Medicine (R.K.D., D.G.G., E.K.J., T.I., Z.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

In a previous study, we found that angiotensin (Ang) II enhances -adrenoceptor-induced cAMP production in cultured preglomerular microvascular smooth muscle cells (PMVSMCs) obtained from spontaneously hypertensive rats. The purpose of the present investigation was to identify the Ang receptor subtypes that mediate this effect. In our first study, we compared the ability of Ang II, Ang III, Ang (3-8), and Ang (1-7) to increase cAMP production in isoproterenol (1 µM)-treated PMVSMCs. Each peptide was tested at 0.1, 1, 10, 100, and 1000 nM. Both Ang II and Ang III increased intracellular (EC₅₀s, 1 and 11 nM, respectively) and extracellular (EC₅₀s, 2 and 14 nM, respectively) cAMP levels in a concentration-dependent fashion. In contrast, Ang (3-8) and Ang (1-7) did not enhance either intracellular or extracellular cAMP levels at any concentration tested. In our second study, we examined the ability of L 158809 [a selective Ang receptor subtype 1 (AT₁) receptor antagonist] to inhibit Ang II (100 nM) and Ang III (100 nM) enhancement of isoproterenol (1 µM)-induced cAMP production in PMVSMCs. L 158809 (10 nM) abolished or nearly abolished (p < .001) Ang II and Ang III enhancement of isoproterenol-induced intracellular and extracellular cAMP levels. In contrast, PD 123319 (300 nM; a selective AT₂ receptor antagonist) did not significantly alter Ang II enhancement of isoproterenol-induced intracellular or extracellular cAMP levels. We conclude that AT₁ receptors, but not AT₂, Ang (3-8), nor Ang (1-7) receptors mediate Ang II and Ang III enhancement of -adrenoceptor-induced cAMP production in cultured PMVSMCs.