Study of factors which modify the development of norepinephrine-induced acute renal failure in the dog

Previous studies have demonstrated that the fall in inulin clearance which occurs 3 hours after the intrarenal administration of norepinephrine can be markedly attenuated by the prior adminstration of intrarenal prostaglandin E₂ (PGE). Since in the previous studies PGE led to a marked increase in both renal blood flow and solute excretion, we designed the present series of experiments to investigate whether an increase in renal blood flow, solute excretion, or other factors were responsible for the protective effect in the norepinephrine model. Two renal vasodilators, bradykinin and secretin, were evaluated initially. Bradykinin administration prior to norepinephrine administration had a protective effect similar to that previously found with PGE, whereas secretin did not. Both of these vasodilators increased renal blood flow to the same degree, but only bradykinin increased urine flow and solute excretion. The fall in inulin clearance 3 hours after the administration of norepinephrine was also attenuated by two diuretics (mannitol and furosemide) which tended to increase renal blood flow. In contrast, two natriuretic agents, which are also renal vasoconstrictors (chlorothiazide and benzolamide), had no protective effect. Further, chlorothiazide and benzolamide obviated the protective effect of bradykinin. These studies demonstrate that there are several types of pharmacologic agents which can modify the magnitude of renal functional impairment resulting from extreme renal ischemia. Although the mechanism of the protective effects remain unclear, the findings are compatible with the view that the protective effect noted with PGE, bradykinin, mannitol, and furosemide may be related to an increase in osmolar excretion which occurred with administration of each of these agents. This potentially salutory effect (increased osmolar excretion), however, could be overcome by an agent (e.g., chlorothiazide or benzolamide) which also increased renal resistance prior to the administration of norepinephrine.