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Renal medullary ET_B receptors produce diuresis and natriuresis via NOS1

Vascular Biology Center, Medical College of Georgia, Augusta, Georgia

Submitted 4 December 2007 ; accepted in final form 20 February 2008

Endothelin-1 (ET-1) plays an important role in the regulation of salt and water excretion in the kidney. Considerable in vitro evidence suggests that the renal medullary ET_B receptor mediates ET-1-induced inhibition of electrolyte reabsorption by stimulating nitric oxide (NO) production. The present study was conducted to test the hypothesis that NO synthase 1 (NOS1) and protein kinase G (PKG) mediate the diuretic and natriuretic effects of ET_B receptor stimulation in vivo. Infusion of the ET_B receptor agonist sarafotoxin S6c (S6c: 0.45 µg·kg^–1·h^–1) in the renal medulla of anesthetized, male Sprague-Dawley rats markedly increased the urine flow (UV) and urinary sodium excretion (UNaV) by 67 and 120%, respectively. This was associated with an increase in medullary cGMP content but did not affect blood pressure. In addition, S6c-induced diuretic and natriuretic responses were absent in ET_B receptor-deficient rats. Coinfusion of N^G-propyl-L-arginine (10 µg·kg^–1·h^–1), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-Br-PET-cGMPS (10 µg·kg^–1·h^–1) or RQIKIWFQNRRMKWKK-LRK₅H-amide (18 µg·kg^–1·h^–1), a PKG inhibitor, also inhibited S6c-induced increases in UV and UNaV. These results demonstrate that renal medullary ET_B receptor activation induces diuretic and natriuretic responses through a NOS1, cGMP, and PKG pathway.

sodium excretion; nitric oxide synthase 1; guanosine 3',5'-cyclic monophosphate; protein kinase G