VASCULAR REACTIVITY TO ANGIOTENSIN-II IN BLOOD-PERFUSED KIDNEYS OF HYPERTENSIVE DIABETIC RATS

The present study examined vascular reactivity to angiotensin II in bl ood-perfused kidneys of diabetic normotensive Wistar-Kyoto (WKY) and d iabetic spontaneously hypertensive rats (SHR). In addition, the effect of the angiotensin AT(1) receptor antagonist, CV-11974 iphenyl-4-yl]m ethyl]-1H-benzimidazole-7-carboxylic acid), on angiotensin II response s was examined. Dose-response curves to angiotensin II(0.1-30 mu g/kg, i.a.) were obtained in kidneys of control- and diabetic-WKY rats and -SHR rats, either in the absence or presence of CV-11974 (3 mu g/kg, i .v.). In all four treatment groups, angiotensin II produced dose-depen dent increases in renal perfusion pressure with the order of reactivit y: control-SHR > control-WKY = diabetic-SHR > diabetic-WKY. In the pre sence of CV-11974 (3 mu g/kg, i.v.), dose-response curves to angiotens in II were significantly inhibited in kidneys of control-SHR and WKY r ats. However, CV-11974 (3 mu g/kg, i.v.) had no significant effect on angiotensin II responses in kidneys of diabetic-SHR or -WKY rats. Thes e results suggest that diabetes in normotensive rats is associated wit h impaired renal responsiveness to angiotensin II, while hypertension augments renal responsiveness to angiotensin II. However, the combinat ion of diabetes and hypertension has largely offset the opposite effec ts on angiotensin II responses seen separately. Importantly, the lack of effect of CV-11974 in diabetic rats, with or without hypertension, has been identified, While the reasons for these alterations have yet to be determined, they may involve changes in angiotensin II receptor mechanisms (e.g. density and/or affinity).