INTERACTIONS OF THE KALLIKREIN-KININ AND RENIN-ANGIOTENSIN SYSTEMS INEXPERIMENTAL DIABETES

The kallikrein-kinin system (KKS) has been postulated to play a role i n modulation of hemodynamic function in diabetes and to contribute to the hemodynamic effects of angiotensin-converting enzyme inhibition (C EI). To further explore the KKS and its interactions with the renin-an giotensin system (RAS), studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic rats. In protocol 1, con trol and diabetic rats were studied before and after administration of one of two dissimilar B-2 kinin receptor antagonists (BK2As), or vehi cle. At a low dose (0.5 mu g . kg(-1) . min(-1)), the first generation antagonist D-Arg,[Hyp(3),Thi(5,8),D-Phe(7)]-bradykinin significantly reduced the glomerular filtration rate (GFR) and renal plasma flow rat e in diabetic rats, despite variable effectiveness in blocking the hyp otensive response to injected bradykinin. However, a similar hemodynam ic effect occurred in nondiabetic rats, suggesting that the observed e ffect was not specific to diabetes. Higher doses (20 mu g bolus, then 1 mu g . kg(-1) . g min(-1) infusion) did not affect hemodynamics in e ither group, perhaps because of partial agonist effect. The second BK( 2)A tested was the newer compound, icatibant (Hoe 140; D-Arg,[Hyp(3),T hi(5),D-Tic(7),Oic(8)]-bradykinin). Hoe 140 consistently blocked the v asodepressor action of injected bradykinin, but had no effect on syste mic or renal hemodynamics in either control or diabetic rats. In proto col 2, control and diabetic rats were pretreated with the CEI ramipril for 1-2 weeks, after which renal function was studied before and afte r Hoe 140 (0.1 mg s.c. and i.v.) or vehicle. CEI lowered blood pressur e in both groups. Hoe 140 did not affect renal function in control rat s, but in diabetic rats pretreated with ramipril, it induced a modest but significant decline in GFR. Ramipril induced the predicted changes in the systemic and intrarenal RAS, while acute BK(2)A had no consist ent effect on RAS parameters. These studies suggest that the endogenou s KKS has only a minor role in modulation of renal hemodynamics in the euvolemic diabetic rat, in the absence of KKS stimulation by CEI. How ever, angiotensin-converting enzyme is also kininase II, which serves to increase endogenous kinin activity. The increased kinin activity re sulting from CEI treatment may participate, to a modest degree, in hem odynamic regulation of the diabetic kidney.