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

最近的研究表明，在慢性肾功能衰竭的动物模型中，醛固酮(ALDO)会加速高血压、蛋白尿和肾小球硬化。尽管其潜在的机制尚未明确，但Aldo可能通过升高肾血管阻力(RVR)和肾小球毛细血管压(P&lt；GC&gt；)来发挥这些有害的肾脏效应。为了测试这种可能性，我们检查了该操作。Aldo对控制肾小球血流动力学的关键血管段--兔体外微灌流的传入小动脉(Af-)和传出小动脉(EF-ART)的作用。在EF-ART中，ALDO引起双侧小动脉呈剂量依赖性收缩，其敏感性更高。这些收缩在10分钟内观察到。在任一小动脉上，Aldo的血管收缩作用不受盐皮质激素受体拮抗剂螺内酯的影响，而是被膜不通透性白蛋白偶联的Aldo所复制，这表明Aldo的血管收缩作用是非基因组的。放线菌素D和放线菌亚胺对Aldo诱导的小动脉收缩都没有作用，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)均可抑制Aldo对Af-ARCH的收缩作用，而L和T型钙通道阻断剂伊福地平均可抑制其收缩作用，但硝苯地平无此作用。此外，阻断血管内皮细胞或抑制NO合成可显著增强Af-Art的血管收缩作用，表明内皮来源的NO可调节Aldo的血管收缩作用。这些结果表明，在Af-ART和EF-ART中，Aldo分别通过L或T型电压依赖性钙通道动员钙，从而引起非基因组血管收缩。这些对肾小球微循环的收缩作用可能通过升高P&lt；GC&GT；和RVR而在肾脏疾病的病理生理和进展中发挥重要作用，尤其是在内皮功能受损的情况下。

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.