1. Eleven healthy, unanaesthetized sheep were given either a single intravenous bolus infusion of U63,577A (Upjohn), a selective thromboxane synthetase inhibitor, at a dose of 30 mg/kg (group 1, n = 6), or vehicle alone (group 2, n = 5). Animals were maintained in metabolic cages during the study, and received 150 ml of water/h and 7.5 mmol of sodium/h as Ringers lactate by intravenous infusion for 24 h before and during the study. During two 1 h control urine collections via bladder catheter, urine volume and sodium excretion closely paralleled these infusion rates.
2. In the first hour after injection of U63,577A, there were significant two- to three-fold increases in urine volume, urinary sodium excretion and fractional sodium excretion, compared with the control collections. During the subsequent 4 h, urine volume, urinary sodium excretion, and fractional sodium excretion fell to values significantly lower than in the control period. Creatinine clearance was reduced 1, 2 and 4 h post injection and returned to control values at 5 h. Urinary excretion of thromboxane B2 was significantly reduced compared with control values during the 5 h after injection of U63,577A. Excretion of 6-keto-prostaglandin F1α did not change. Plasma renin activity was significantly increased 1, 3 and 5 h after injection of U63,577A. Vehicle controls showed no change in any of the above parameters.
3. The results indicate that in healthy conscious sheep, sodium and water replete, U63,577A has a transient but significant diuretic and natriuretic effect, followed by sodium and water retention and increased plasma renin activity. The results may reflect an antidiuretic/antinatriuretic effect of thromboxane A2, or possibly diversion of cyclic endoperoxides into formation of vasodilator/natriuretic prostaglandins. These effects might be exaggerated and/or modified in conditions where arachidonic acid metabolism is stimulated.