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CELLULAR AND MOLECULAR

AT₂ Receptors Attenuate AT₁ Receptor-Induced Phospholipase D Activation in Vascular Smooth Muscle Cells

Department of Pharmacology (B.T.A., G.G.R., E.K.J.) and Center for Clinical Pharmacology (B.T.A., E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Previous studies indicate that angiotensin (AT)₁ receptor-induced activation of phospholipase D (PLD) may importantly contribute to vascular hypertrophy, injury, and contraction. However, the role of AT₂ receptors in regulating AT₁ receptor-induced PLD activation is unknown. In this study, we identified angiotensin II receptors on cultured preglomerular vascular smooth muscle cells (PGSMCs) from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) by reverse transcription-polymerase chain reaction (RT-PCR) and binding assays and examined their functional effects on angiotensin II-mediated PLD activity. Both RT-PCR and binding indicated that cultured SHR and WKY PGSMCs expressed AT₁ and AT₂ receptors, and the combined total of AT₁ and AT₂ receptors was similar between the strains. However, the number of AT₁ and AT₂ receptors differed between SHR and WKY PGSMCs in so much as the ratio of AT₁ to AT₂ receptors was approximately 1 to 1 and 3 to 1 in WKY and SHR PGSMCs, respectively. As previously reported, angiotensin II more potently activated PLD in SHR PGSMCs (SHR EC₅₀ = 4 nM; WKY EC₅₀ = 47 nM). Addition of an AT₂ receptor-specific antagonist or agonist shifted the angiotensin II-mediated PLD concentration-response curve of WKY PGSMCs in a manner consistent with AT₂ receptors producing an inhibitory signal. In contrast, in SHR little change was observed. Our findings indicate that the ratio of AT₁ to AT₂ receptors in vascular smooth muscle cells may be a determinant of the net effects of angiotensin II on PLD activity due to AT₂-dependent inhibition of AT₁-mediated PLD activity. Furthermore, cultured WKY PGSMCs provide an excellent model system to study endogenous AT₂ receptor signal transduction.

Address correspondence to: Dr. Edwin K. Jackson, The Center for Clinical Pharmacology, 623 Scaife Hall, University of Pittsburgh School of Medicine, 3550 Terrace St., Pittsburgh, PA 15261. E-mail: edj{at}pitt.edu

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