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CARDIOVASCULAR

Mechanism of the Vascular Angiotensin II/₂-Adrenoceptor Interaction

Center for Clinical Pharmacology, Departments of Pharmacology (E.K.J.) and Medicine (E.K.J., L.G., C.Z.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

₂-Adrenoceptors potentiate vascular responses to angiotensin II. The goal of this study was to test the hypothesis that the phospholipase C (PLC)/protein kinase C (PKC)/c-src/phosphatidylinositol 3-kinase (PI3K) pathway contributes to the vascular angiotensin II/₂-adrenoceptor interaction. In rats in vivo, intrarenal infusions of angiotensin II (10 ng/kg/min) increased renal vascular resistance by 5.8 ± 0.5 units, and this response was enhanced (p < 0.05) to 9.1 ± 1.2 units by UK-14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine; 3 µg/kg/min; ₂-adrenoceptor agonist]. Intrarenal infusions of U-73122 [1-[6-[[(17)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]-hexyl]-1H-pyrrole-2,5-dione; 3 µg/min; PLC inhibitor], GF109203X [bisindolylmaleimide I; 10 µg/min; PKC inhibitor], CGP77675[1-(2-{4-[4-amino-5-(3-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]phenyl}ethyl)piperidin-4-ol; 5 µg/min; c-src inhibitor], and wortmannin (1 µg/min; PI3K inhibitor) abolished the angiotensin II/₂-adrenoceptor interaction. In isolated perfused rat kidneys, angiotensin II (0.3, 1, and 3 nM) increased perfusion pressure (by 15 ± 8, 39 ± 4, and 93 ± 9 mm Hg, respectively), and UK-14,304 (1 µM) potentiated these responses (to 36 ± 4, 67 ± 7, and 135 ± 17 mm Hg, respectively). This angiotensin II/₂-adrenoceptor interaction was abolished by U-73122 (10 µM), GF109203X (3 µM), CGP77675(5 µM), and wortmannin (0.2 µM). Preglomerular microvascular smooth muscle cells expressed phospholipase (PLC)-₂, PLC-₃, c-src, phospho(tyrosine 416)-c-src, and PI3K. In these cells, angiotensin II (0.1 µM) and UK-14,304 (1 µM) per se did not increase phospho-c-src; however, the combination of angiotensin II plus UK-14,304 doubled phospho-c-src, and this interaction was abolished by U-73122 (10 µM) and GF109203X (3 µM). In conclusion, the PLC/PKC/c-src/PI3K pathway may contribute importantly to the interaction between ₂-adrenoceptors and angiotensin II on renal vascular resistance.

Address correspondence to: Dr. Edwin K. Jackson, Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, 100 Technology Dr., Suite 450, Pittsburgh, PA 15219-3130. E-mail: edj{at}pitt.edu

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