Renal medullary ETB 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(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 microg x kg(-1) x 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 microg x kg(-1) x h(-1)), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-Br-PET-cGMPS (10 microg x kg(-1) x h(-1)) or RQIKIWFQNRRMKWKK-LRK(5)H-amide (18 microg x kg(-1) x 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.
Nakano
Daisuke
D
Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912, USA.
Pollock
Jennifer S
JS
Pollock
David M
DM
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004231:Diuresis / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007679:Kidney Medulla / Q000187:drug effects / Q000502:physiology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000187:drug effects / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000652:urine; D014563:Urodynamics / Q000187:drug effects; D014757:Viper Venoms / Q000494:pharmacology*; D014867:Water / Q000378:metabolism
D004791:Enzyme Inhibitors; D044023:Receptor, Endothelin B; D014757:Viper Venoms; C057354:sarafotoxins s6; D014867:Water; D012964:Sodium; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester