Renal medullary [ET.sub.B] receptors produce diuresis and natriuresis via NOS1

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.sub.B] receptor mediates ET-l-induced inhibition of electrolyte reabsorption by stimulating nitric oxide (NO) production. The present study was conducted to test the hypothesis that NO synthase 1 (NOS 1) and protein kinase G (PKG) mediate the diuretic and natriuretic effects of [ET.sub.B] receptor stimulation in vivo. Infusion of the [ET.sub.B] receptor agonist sarafotoxin $6c ($6c: 0.45 [micro] g*[kg.sup.-1]* [h.sup.-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.sub.B] receptor-deficient rats. Coinfusion of [N.sup.G]-propyl-L-arginine (10 [micro]g*[kg.sup.-1]*[h.sup.-1]), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-Br-PET-cGMPS (10 [micro]g* [kg.sup.-1]*[h.sup.-1]) or [RQIKIWFQNRRMKWKKLRK.sub.5]H-amide (18 [micro]g*[kg.sup.-1]*[h.sup.-1]), a PKG inhibitor, also inhibited S6c-induced increases in UV and UNaV. These results demonstrate that renal medullary [ET.sub.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