Abstract

Endothelin (ET) and angiotensin mediate glomerular responses to systemic nitric oxide (NO) inhibition. Acute systemic NO synthase (NOS) inhibition in the rat causes marked increases in both preglomerular (RA) and efferent arteriolar (RE) resistances and a fall in the glomerular capillary ultrafiltration coefficient (Kf). In contrast, local intrarenal NOS inhibition increases RA, but has no effect on RE while producing a similar Kf lowering effect as seen with systemic NOS inhibition. These studies were designed to assess whether the increase in RE during systemic NOS inhibition is mediated by endogenous ET and whether angiotensin II (Ang II) also contributes. Micropuncture measurements were made before and during acute systemic NOS inhibition with N-monomethyl L-arginine (NMA) alone, NMA + the nonpeptide ETA and ETB receptor antagonist, bosentan, NMA + the Ang II type 1 receptor blocker, losartan, and NMA during combined bosentan and losartan. The falls in single nephron glomerular filtration rate (SNGFR) and glomerular plasma flow seen with systemic NOS inhibition were prevented by concomitant administration of bosentan and losartan alone and in combination. The increases in systemic blood pressure (BP), glomerular BP (PGC), RA, and RE and the reduction in Kf seen with systemic NOS inhibition were attenuated by either bosentan or losartan. An attenuation in the elevation in total renal vascular resistance seen with systemic NOS inhibition was also observed with bosentan. Combined ET and Ang II type 1 blockade completely prevented the increase in systemic BP, PGC, and RE and the fall in Kf with systemic NOS inhibition, leaving only a very attenuated rise in RA. These findings suggest that endogenous ET and Ang II partially mediate the glomerular hemodynamic responses (including the increased RE) to acute systemic NOS inhibition. The actions of ET and Ang II are mainly additive, and almost all of the vasoconstrictor responses to acute NOS inhibition are prevented when both vasoconstrictor systems are blocked.

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