title: Mechanism of the vascular angiotensin II/alpha2-adrenoceptor interaction.
abstract: alpha(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/alpha(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 microg/kg/min; alpha(2)-adrenoceptor agonist]. Intrarenal infusions of U-73122 [1-[6-[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]-hexyl]-1H-pyrrole-2,5-dione; 3 microg/min; PLC inhibitor], GF109203X [bisindolylmaleimide I; 10 microg/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 microg/min; c-src inhibitor], and wortmannin (1 microg/min; PI3K inhibitor) abolished the angiotensin II/alpha(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 microM) potentiated these responses (to 36 +/- 4, 67 +/- 7, and 135 +/- 17 mm Hg, respectively). This angiotensin II/alpha(2)-adrenoceptor interaction was abolished by U-73122 (10 microM), GF109203X (3 microM), CGP77675 (5 microM), and wortmannin (0.2 microM). Preglomerular microvascular smooth muscle cells expressed phospholipase (PLC)-beta(2), PLC-beta(3), c-src, phospho(tyrosine 416)-c-src, and PI3K. In these cells, angiotensin II (0.1 microM) and UK-14,304 (1 microM) 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 microM) and GF109203X (3 microM). In conclusion, the PLC/PKC/c-src/PI3K pathway may contribute importantly to the interaction between alpha(2)-adrenoceptors and angiotensin II on renal vascular resistance.
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmacology, University of Pittsburgh School of Medicine, PA 15219-3130, USA. edj@pitt.edu
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.forename: Liping
authors.initials: L
authors.lastname: Gao
authors.forename: Chongxue
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000068438:Brimonidine Tartrate; D000081247:CSK Tyrosine-Protein Kinase; D007527:Isoenzymes / Q000502:physiology; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D054799:Phospholipase C beta; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000502:physiology; D010738:Type C Phospholipases / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects*; D019061:src-Family Kinases
chemical_list: D000804:Angiotensin II; D000068438:Brimonidine Tartrate; D000081247:CSK Tyrosine-Protein Kinase; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D054799:Phospholipase C beta; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D010738:Type C Phospholipases; D019061:src-Family Kinases