Physiological and pathophysiological significance of vascular action of aldosterone on the glomerular microcirculation.

最近的研究表明，醛固酮（Aldo）在慢性肾衰竭动物模型中加速高血压、蛋白尿和肾小球硬化。虽然潜在的机制尚不清楚，但Aldo可能通过提高肾血管阻力（RVR）和肾小球毛细血管压力（P_<GC>）来发挥这些有害的肾脏作用。为了测试这种可能性，我们检查了这个动作。体外微灌注兔传入（Af-）和传出小动脉（Ef-Arts）是控制肾小球血流动力学的关键血管段。阿尔多引起两种小动脉的剂量依赖性收缩，在Ef-Arts中具有较高的敏感性。这些收缩在10分钟内观察到。在这两种小动脉中，Aldo的血管收缩作用不受矿物皮质激素受体拮抗剂螺内酯的影响，而是由膜不渗透白蛋白偶联的Aldo复制，这表明血管收缩作用是非基因组性的。放线菌素D和环己亚胺对两种小动脉的醛诱导收缩均无影响，这一发现进一步支持了这一观点。硝苯地平（L型钙通道阻滞剂）均能抑制Aldo对Af-Arts的血管收缩作用，而埃非尼地平（L型和t型钙通道阻滞剂）均能抑制Aldo对Af-Arts的血管收缩作用，而硝苯地平则不能。此外，破坏内皮细胞或一氧化氮合成抑制显著增强了Af-Arts的血管收缩，表明内皮来源的一氧化氮调节了Aldo的血管收缩作用。这些结果表明，Aldo分别通过Af-或Af- arts中的L型或t型电压依赖性钙通道，通过钙动员引起非基因组性血管收缩。这些血管收缩对肾小球微循环的作用可能通过升高P_<GC>和RVR在肾脏疾病的病理生理和进展中起重要作用，特别是当内皮功能受损时。

Recent studies provide evidence that aldosterone (Aldo) accelerates hypertension, proteinuria and glomerulosclerosis in animal models of chronic renal failure. Although the underlying mechanisms are not well defined, Aldo may exert these deleterious renal effects by elevating renal vascular resistance (RVR) and glomerular capillary pressure (P_<GC>). To test this possibility, we examined the action. of Aldo on the in vitro microperfused rabbit afferent (Af-) and efferent arterioles (Ef-Arts), crucial vascular segments to the control of glomerular hemodynamics. Aldo caused dose-dependent constriction in both arterioles with a higher sensitivity in Ef-Arts. These constrictions were observed within 10 minutes. In either arteriole, vasoconstrictor action of Aldo was not affected by a mineralocorticoid receptor antagonist spironolactone and was reproduced by membrane-impermeable albumin-conjugated Aldo, suggesting that the vasoconstrictor actions are nongenomic. This notion was further supported by the finding that neither actinomycin D nor cycloheximide had effect on Aldo-induced constriction in either arteriole. The vasoconstrictor action of Aldo on Af-Arts was inhibited by both nifedipine (L-type calcium channel blocker), whereas that on Ef-Arts was inhibited by efonidipine (both L- and T-type calcium channel blocker) but not nifedipine. In addition, disrupting the endothelium or NO synthesis inhibition significantly augmented the vasoconstriction in Af-Arts, demonstrating that endothelium-derived NO modulates vasoconstrictor actions of Aldo. These results demonstrate that Aldo causes nongenomic vasoconstriction via calcium mobilization thorough L- or T-type voltage-dependent calcium channels in Af- or Ef-Arts, respectively. These vasoconstrictor actions on the glomerular microcirculation may play an important role in the pathophysiology and progression of renal diseases by elevating P_<GC> and RVR especially when endothelium functions are impaired.