Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs

Abstract

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 μg/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 μg/kg) and nitroglycerin (1 to 10 μg/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.