Aldosterone nongenomically worsens ischemia via protein kinase C-dependent pathways in hypoperfused canine hearts
Aldosterone nongenomically worsens ischemia via protein kinase C-dependent pathways in hypoperfused canine hearts
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DOI：
10.1161/01.hyp.0000171184.84077.80
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发表时间：
2005-07-01
期刊：
影响因子：
8.3
通讯作者：
Kitakaze, M
中科院分区：
文献类型：
--
作者：
Fujita, M;Minamino, T;Kitakaze, M
醛固酮独立于矿物皮质激素受体（MRs）对血管张力的快速非基因组作用是不同的。到目前为止，醛固酮对体内缺血性心脏冠状动脉血管张力和心功能的快速非基因组作用尚未得到充分的估计。此外，尽管醛固酮可以调节蛋白激酶C （PKC）的活性，但PKC是否参与醛固酮对缺血心脏的非基因组作用还没有明确的共识。在开胸犬中，选择性地将醛固酮输注到左冠状动脉前降支（LAD）以剂量依赖的方式减少非缺血心脏的冠状动脉血流量（CBF）。此外，在CBF下降至基线的33%的缺血状态下，冠状动脉内给予醛固酮（0.1 nmol/L）可迅速降低CBF (37.4 +/- 3.8 ~ 19.3 +/- 5.2 mL/100 g/min, P < 0.05)，同时降低分数缩短（FS） （8.4 +/- 0.7 ~ 5.4 +/- 0.4%, P < 0.05）和乳酸提取率（LER） （-31.7 +/- 2.9 ~ -41.4 +/- 3.7%, P < 0.05）。灌注牛血清白蛋白结合醛固酮可重现CBF的减少。值得注意的是，这些醛固酮引起的心肌收缩和代谢功能的恶化被PKC抑制剂GF109203X（而非螺内酯）联合施用所减弱。此外，醛固酮激活了血管PKC。这些结果表明，醛固酮非基因组性地通过pkc依赖性途径可能通过膜受体诱导血管收缩，从而导致缺血心脏收缩和代谢功能的恶化。血浆或心脏醛固酮水平升高可能通过其非基因组效应对缺血性心脏病有害。
Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors ( MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C ( PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery ( LAD) reduced coronary blood flow ( CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone ( 0.1 nmol/L) rapidly decreased CBF ( 37.4 +/- 3.8 to 19.3 +/- 5.2 mL/100 g/min; P < 0.05), along with decreases in fractional shortening ( FS) ( 8.4 +/- 0.7 to 5.4 +/- 0.4%; P < 0.05) and lactate extraction rate ( LER) ( -31.7 +/- 2.9 to -41.4 +/- 3.7%; P < 0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKC-dependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects.