Infusion of a variety of agonists (bradykinin, angiotensin II, arachidonic acid and ATP) into rabbit kidneys perfused after 3 days of ureteral obstruction led to the release of a substance which contracts the rabbit aorta. The contralateral (nonobstructed) kidney and the normal kidney did not release rabbit aorta contracting substance with doses of bradykinin up to 1000 ng, but high doses of arachidonic acid (AA) and ATP cause the release of detectable levels of rabbit aorta contracting substance. The rabbit aorta contracting substance appearing in the renal venous effluent after drug treatment was labile and disappeared with a t.5 of 37 sec at 37°C suggesting that the labile constrictor was thromboxane A2 (TxA2). Cortical and medullary microsomal fractions obtained from hydronephrotic kidneys were incubated with the endoperoxide prostaglandin (PG) H2 at 0°C for 2 min and generated a potent labile t.5 of 40 sec at 37°C) contractile substance. The enzymatic generation of the contractile substance was inhibited by imidazole, a specific inhibitor of thromboxane synthetase. Radiochemical identification of the contractile substance was studied by incubating microsomes (37°C) from cortex or medulla of ureter-obstructed kidneys with [14C]AA. The primary products formed after incubation (25 min) of renal medullary microsomes with [14C]AA were PGE2 (25% of [14C]AA converted) and thromboxane B2 (TxB2, 8%) and 7.5% PGE2 and 5.0% TxB2 from the cortex. The radioactive TxB2 zone was abolished when the incubations were carried out in the presence of 5 mM imidazole. Microsomes prepared from the cortex and medulla of the contralateral kidney possessed comparable rates of synthesis of PGE2, but formed no TxB2. Thus, TxA2 biosynthesis in cortex and medulla is unmasked by ureteral obstruction and this temporal appearance of cortical biosynthesis of thromboxane A2 may be important to the alteration of renal blood flow occurring in chronic ureteral obstruction.
|Number of pages
|Journal of Pharmacology and Experimental Therapeutics
|Published - Jan 1 1978