Modulation by NO of renal myogenic autoregulation: TGF dependency

Blood flow to the kidney is unique in that it is regulated to serve the urine-producing function of the kidney and is far in excess of any conceivable metabolic demand. As renal blood flow (RBF) is so high, and resistance thus so low, the capillaries in the glomerulus are potentially exposed to high transmural pressures. The need to stabilize glomerular capillary pressure plus the need for stable tubular loads to permit regulation of salt excretion has focused attention on the mechanisms by which RBF is stabilized when blood pressure fluctuates. Renal autoregulation, i.e. regulation by the kidney of its own blood flow, effectively stabilizes RBF over a wide range of blood pressure. In turn, autoregulation is the product of two mechanisms: a myogenic mechanism located entirely within the vascular smooth muscle of the preglomerular microcirculation, and tubuloglomerular feedback (TGF) by which information about the distal tubular load is transmitted through the macula densa and the juxtaglomerular apparatus to the afferent arteriole. Both these mechanisms are extensively modulated by a variety of paracrine and endocrine agents. In the 15 years since Tolins et al. (1990) showed that the nitro-arginine derivative Nω-monomethyl-l-arginine (l-NMMA) causes profound renal vasoconstriction, a great number of studies have been performed to characterize and understand the contribution of nitric oxide to the regulation of RBF. These studies have revealed that the renal circulation is perhaps the most sensitive in the body to non-selective inhibition of nitric oxide synthase (NOS) with complete inhibition causing at least a twofold increase in renal vascular resistance that is independent of the pronounced pressor response seen after systemic NOS inhibition. Early studies did not detect any effect of NOS inhibition on renal autoregulation. More recent studies using the classic steady-state, pressure ramp approach have shown that the lower pressure limit of autoregulation is extended to still lower pressures. At the same time, time series analysis has shown distinct augmentation of the myogenic mechanism after non-selective NOS inhibition. These effects have largely been attributed to inhibition of endothelial NOS although the kidney also contains neuronal NOS (nNOS), located largely at and around the macula densa. While selective inhibition of nNOS has been problematic, a number of studies have combined to demonstrate that inhibition of nNOS at the macula densa causes a stronger TGF response (e.g. Ichihara et al. 1998 and other references found in Just & Arendshorst, 2005). In this issue of The Journal of Physiology, Just & Arendshorst (2005) report studies that bear on two aspects of how NO affects renal autoregulation. As non-selective NOS inhibition causes such strong renal vasoconstriction, it is often considered that the enhancement of autoregulation is a consequence of the vasoconstriction. However, blood pressure fluctuates both upward and downward and NOS inhibition improves the stabilization of RBF. The major point made by Just and Arendshorst is the demonstration, which was logically necessary, that non-selective NOS inhibition augments both pressure-induced vasoconstriction and pressure-induced vasodilatation in the kidney. This finding is supported by the demonstration that equivalent vasoconstriction caused by Ang II does not duplicate the autoregulatory result, showing that the vasoconstriction is not sufficient to explain the change in autoregulation. In addition, they show in the same rats that non-selective NOS inhibition does not alter myogenic autoregulation in the hindquarters, indicating regional specificity. The authors further show that the augmentation of renal myogenic autoregulation induced by non-selective NOS inhibition is abrogated in the presence of furosemide. Furosemide of course is a loop diuretic which, at the dose used, blocks NaCl reabsorption from the thick ascending limb and effectively clamps TGF off. The strength of this interaction is somewhat surprising, given that both sources of nitric oxide within the renal cortex were inhibited, only one of which is under TGF control, and that nitric oxide is highly diffusive. However, this is undoubtedly a very interesting result that indicates regulation of the myogenic mechanism by tubular elements. Thus, a control system, TGF, that plays an important role linking renal inputs (RBF and GFR) to output (tightly regulated salt excretion) has now been linked mechanistically to the other autoregulatory system that had been presumed to be independent of tubular function.

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