Acute angiotensin-converting enzyme inhibition evokes bradykinin-induced sympathetic activation in diabetic rats

Abstract

We have previously shown that acute intravenous injection of the angiotensin-converting enzyme (ACE) inhibitor enalapril in diabetic rats evokes a baroreflex-independent sympathoexcitatory effect that does not occur with angiotensin receptor blockade alone. As ACE inhibition also blocks bradykinin degradation, we sought to determine whether bradykinin mediated this effect. Experiments were performed in conscious male Sprague-Dawley rats, chronically instrumented to measure mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), 2 wk after streptozotocin (55 mg/kg iv, diabetic, n = 11) or citrate vehicle (normal, n = 10). Enalapril (2.5 mg/kg iv) decreased MAP in normal rats (-15 +/- 3 mmHg), while a smaller response (-4 +/- 1 mmHg) occurred in diabetic rats. Despite these different depressor responses to enalapril, HR (+44 +/- 8 vs. +26 +/- 7 bpm) and RSNA (+90 +/- 21 vs +71 +/- 8% baseline) increased similarly between the groups (P > or = 0.22 for both). Pretreatment with the bradykinin B2 receptor antagonist Hoe 140 (10 microg/kg bolus followed by 0.8.mug(-1)kg.min(-1) infusion) attenuated the decrease in MAP observed with enalapril in normal rats but had no effect in diabetic rats. Moreover, the normal group had smaller HR and RSNA responses (HR: +13 +/- 8 bpm; RSNA: +32 +/- 13% baseline) that were abolished in the diabetic group (HR: -4 +/- 5 bpm; RSNA: -5 +/- 9% baseline; P < 0.05 vs. preenalapril values). Additionally, bradykinin (20 microg/kg iv) evoked a larger, more prolonged sympathoexcitatory effect in diabetic compared with normal rats that was further potentiated after treatment with enalapril. We conclude that enhanced bradykinin signaling mediates the baroreflex-independent sympathoexcitatory effect of enalapril in diabetic rats.

Fig. 1

Time course of the change in mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) from baseline to either enalapril alone (•) or enalapril following pretreatment with the bradykinin B₂ receptor antagonist Hoe 140 (○) in normal (n = 7) and diabetic rats (n = 6); enalapril was injected at time 0. *P < 0.05 vs. enalapril alone.

Fig. 2

Time course of absolute MAP, HR, and RSNA responses to bradykinin alone (injected at time 0; left) or to bradykinin following pretreatment with enalapril (right) in normal (•, n = 9) and diabetic (○, n = 9) rats. *P < 0.05 vs. normal.

Fig. 3

The differences in the area under the curves (from Fig. 2) between bradykinin alone and bradykinin with enalapril in normal (■) and diabetic (□) groups for MAP, HR, and RSNA between 30 and 120 s after bradykinin. *P < 0.05 vs. normal.