血管紧张素II/α2-肾上腺素能受体相互作用的机制。
Mechanism of the vascular angiotensin II/alpha2-adrenoceptor interaction.
作者信息
Jackson Edwin K, Gao Liping, Zhu Chongxue
机构信息
Center for Clinical Pharmacology, Department of Pharmacology, University of Pittsburgh School of Medicine, PA 15219-3130, USA.
出版信息
J Pharmacol Exp Ther. 2005 Sep;314(3):1109-16. doi: 10.1124/jpet.105.086074. Epub 2005 May 18.
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.
α₂肾上腺素能受体增强血管对血管紧张素II的反应。本研究的目的是检验以下假设：磷脂酶C（PLC）/蛋白激酶C（PKC）/c-src/磷脂酰肌醇3激酶（PI3K）途径参与血管紧张素II/α₂肾上腺素能受体相互作用。在大鼠体内，肾内输注血管紧张素II（10 ng/kg/min）使肾血管阻力增加5.8±0.5个单位，而UK-14,304 [5-溴-N-（4,5-二氢-1H-咪唑-2-基）-6-喹喔啉胺；3 μg/kg/min；α₂肾上腺素能受体激动剂]可使该反应增强（p<0.05）至9.1±1.2个单位。肾内输注U-73122 [1-[6-[[（17β）-3-甲氧基雌甾-1,3,5（10）-三烯-17-基]氨基]-己基]-1H-吡咯-2,5-二酮；3 μg/min；PLC抑制剂]、GF109203X [双吲哚基马来酰亚胺I；10 μg/min；PKC抑制剂]、CGP77675 [1-（2-{4-[4-氨基-5-（3-甲氧基苯基）吡咯并[2,3-d]嘧啶-7-基]苯基}乙基）哌啶-4-醇；5 μg/min；c-src抑制剂]和渥曼青霉素（1 μg/min；PI3K抑制剂）可消除血管紧张素II/α₂肾上腺素能受体相互作用。在离体灌注大鼠肾脏中，血管紧张素II（0.3、1和3 nM）分别使灌注压升高（15±8、39±4和93±9 mmHg），UK-14,304（1 μM）增强了这些反应（分别至36±4、67±7和135±17 mmHg）。U-73122（10 μM）、GF109203X（3 μM）、CGP77675（5 μM）和渥曼青霉素（0.2 μM）可消除这种血管紧张素II/α₂肾上腺素能受体相互作用。球前微血管平滑肌细胞表达磷脂酶（PLC）-β₂、PLC-β₃、c-src、磷酸化（酪氨酸416）-c-src和PI3K。在这些细胞中，血管紧张素II（0.1 μM）和UK-14,304（1 μM）本身不会增加磷酸化c-src；然而，血管紧张素II与UK-14,304联合使用可使磷酸化c-src增加一倍，且U-73122（10 μM）和GF109203X（3 μM）可消除这种相互作用。总之，PLC/PKC/c-src/PI3K途径可能在α₂肾上腺素能受体与血管紧张素II对肾血管阻力的相互作用中起重要作用。
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