Chronic infusion of bradykinin delays the progression of heart failure and preserves vascular endothelium-mediated vasodilation in conscious dogs

Background - This study examined the effects of chronic bradykinin infusion on hemodynamics and myocardial and endothelial functions during the development of heart failure. Methods and Results - Sixteen instrumented dogs were randomized to receive through the left atria either vehicle or bradykinin (1 mug/min) during ventricular pacing (250 bpm, 5 weeks). Hemodynamic and left ventricular (LV) parameters and the vasodilator responses to intravenous acetylcholine (0.3 to 3 mug/kg) and nitroglycerin (1 to 10 mug/kg) were examined in the control and after 3 and 5 weeks of pacing. The expression of endothelial NOS in femoral, carotid, and renal arteries was determined by Western blot analysis. After 3 weeks of pacing, changes in LV diastolic and systolic parameters were significantly lower in bradykinin-treated than vehicle-treated dogs ( LV end-diastolic pressure, + 10 +/- 3 versus + 19 +/- 2 mm Hg; time constant of LV isovolumic relaxation, + 11 +/- 2 versus + 17 +/- 1 ms; LV wall thickening, - 33 +/- 18% versus - 75 +/- 9%; and cardiac output, - 16 +/- 6% versus - 32 +/- 6%; all P < 0.05). Compared with vehicle-treated dogs, bradykinin-treated dogs had a reduced rightward shift of the diastolic LV pressure-diameter relation and a reduced diastolic LV wall stress. Similar trends were observed after 5 weeks. The vasodilator response to nitroglycerin was preserved in both groups. The response to acetylcholine was blunted in vehicle-treated but preserved in bradykinin-treated dogs. Vascular endothelial NOS expression decreased in vehicle-treated but was preserved in bradykinin-treated dogs. Conclusions - In conscious dogs, chronic bradykinin infusion delays the heart failure progression by preserving LV diastolic and systolic functions and by preserving vascular endothelial function.