Thromboxane synthetase inhibition improves function of hydronephrotic rat kidneys.
Twenty-four hours of complete unilateral ureteral obstruction (UUO) produces intense renal vasconstriction in the rat even after release of obstruction. In the ex vivo perfused hydronephrotic rabbit kidney, bradykinin stimulates increased production of the vasoconstrictor autocoid thromboxane. In the present study, we measured basal and bradykinin-stimulated thromboxane and prostaglandin E2 production by UUO and contralateral rat kidneys perfused ex vivo. Furthermore, we evaluated thromboxane synthetase inhibition by imidazole and by two of its substituted derivatives, UK 37248 and UK 38485, in vitro. We compared these in vitro findings with in vivo measurements of renal hemodynamics and excretory function before and after the intrarenal artery administration of thromboxane synthetase inhibitors. Both basal and bradykinin-stimulated thromboxane and prostaglandin E2 production were significantly increased in hydronephrotic kidneys. Imidazole and its substituted congeners were effective inhibitors of bradykinin-stimulated thromboxane B2 production in vitro. However, the substituted imidazoles were more potent, more efficacious, and more selective for thromboxane synthetase inhibition than the parent compound. In vivo, administration of imidazole into the renal artery of the UUO kidney improved function slightly, whereas administration of UK 37248 or UK 38485 doubled renal blood flow and excretory function but did not restore them to normal. We conclude that the hydronephrotic rat kidney produces increased amounts of the vasoconstrictor eicosanoid thromboxane and that thromboxane is an important mediator of vasoconstriction in this model of disease.
Klotman
P E
PE
Smith
S R
SR
Volpp
B D
BD
Coffman
T M
TM
Yarger
W E
WE
D000818:Animals; D015232:Dinoprostone; D004305:Dose-Response Relationship, Drug; D006869:Hydronephrosis / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology; D008689:Methacrylates / Q000494:pharmacology; D011458:Prostaglandins E / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014517:Ureteral Obstruction / Q000201:enzymology
D007093:Imidazoles; D008689:Methacrylates; D011458:Prostaglandins E; C029166:dazoxiben; C039242:dazmegrel; D013929:Thromboxane B2; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; C029899:imidazole; D013930:Thromboxane-A Synthase; D015232:Dinoprostone