Exogenous endothelin-1 causes renal vasodilation in the fetal lamb.
OBJECTIVE
Endothelin-1 is known to be a potent vasoconstrictor. We investigated the effects and mechanisms of action of endothelin-1 and its receptors in regulating renal vascular tone in the fetal lamb.


METHODS
We observed the in vivo effects of endothelin-1, an endothelin-b receptor agonist (4-alanine-endothelin-1), endothelin-a receptor antagonists (BQ-610 and BQ-123), and the inhibition of prostaglandin and nitric oxide synthesis on the response of the renal circulation to endothelin-1 in a chronic preparation in third trimester fetal lambs.


RESULTS
After injection of 250 ng./kg. endothelin-1 into the descending aorta proximal to the renal arteries in 8 fetal animals, renal blood flow increased (4.4 +/- 0.7 ml. per minute per kg., p < 0.001 versus vehicle), as did mean arterial blood pressure (3.0 +/- 0.3 mm. Hg,p < 0.001 versus vehicle). Calculated renal vascular resistance decreased (-1.1 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.001 versus vehicle). After injection of 1,725 ng./kg. 4-alanine-endothelin-1 in 5 animals renal blood flow increased (3.8 +/- 0.4 ml. per minute per kg., p < 0.05 versus vehicle) and mean arterial blood pressure was unchanged (1.6 +/- 1.7 mm. Hg). Calculated renal vascular resistance decreased (-0.8 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.05 versus vehicle). After injection of 0.5 mg./kg. BQ-610 in 6 animals renal blood flow increased (2.3 +/- 0.7 ml. per minute per kg., p < 0.05) and mean arterial blood pressure decreased (-2.7 +/- 0.3 mm. Hg, p < 0.05 versus vehicle). Calculated renal vascular resistance decreased but this difference was not statistically significant (-0.7 +/- 0.3 mm. Hg per minute per kg./ml., p < 0.07). A dose of 1 mg./kg. BQ-123 in 2 animals decreased renal vascular resistance markedly. Infusion of a prostaglandin synthesis inhibitor (1 mg./kg. per minute meclofenamic acid) did not alter the decrease in renal vascular resistance after endothelin-1 (-0.7 +/- 0.4 mm. Hg per minute per kg./ml). In contrast, during infusion of a nitric oxide synthesis inhibitor (1.5 mg./kg. per minute N-omega-nitro-L-arginine) endothelin-1 increased renal vascular resistance (1.2 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.001).


CONCLUSIONS
Endothelin-1 is a vasodilator in the fetal renal circulation, which acts primarily via endothelin-b receptors. Ongoing activity of endothelin-a receptors contributes to renal vascular tone in fetal lambs. The vasodilatory effects of endothelin-1 in the fetal lamb renal circulation are mediated via the nitric oxide system and not via prostanoids.
Bogaert
G A
GA
Department of Urology, University of California School of Medicine, San Francisco 94143-0738, USA.
Kogan
B A
BA
Mevorach
R A
RA
Wong
J
J
Gluckman
G R
GR
Fineman
J R
JR
Heymann
M A
MA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D005333:Fetus / Q000187:drug effects*; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000187:drug effects*; D012077:Renal Artery / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects*; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
D016232:Endothelins; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin