Impaired Endothelium-Dependent Regulation of Ventricular Relaxation in Pressure-Overload Cardiac Hypertrophy

Abstract

Background —Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation and may benefit diastolic function. Left ventricular hypertrophy (LVH) is characterized by abnormal myocardial relaxation and endothelial dysfunction. We investigated endothelium-dependent regulation of LV relaxation in moderate pressure-overload LVH induced by aortic banding in guinea pigs. Methods and Results —Isolated ejecting hearts of banded or sham-operated animals (shams) were studied. The specific agonists for endothelial release of NO, bradykinin (10 nmol/L), and substance P (100 nmol/L) both induced earlier onset of LV relaxation in shams (time to LV dP/dt min [tdP/dt min ], −13.4±3.0 and −10.4±2.5 ms, respectively) without altering peak LV pressure or LV dP/dt max . Neither agent altered tdP/dt min in banded animals. The ACE inhibitor captopril (1 μmol/L) also selectively reduced tdP/dt min in shams via a bradykinin/NO-dependent mechanism but had no effect in banded animals. An exogenous NO donor, sodium nitroprusside (0.1 μmol/L), selectively reduced tdP/dt min to a similar extent in both shams and banded animals. Endothelial-type NO synthase (eNOS) protein expression in whole LV homogenate was unaltered in banded animals. Conclusions —Endothelium-dependent enhancement of LV relaxation is impaired in moderate pressure-overload LVH, despite a preserved response to exogenous NO. This is not accounted for by altered eNOS expression. These abnormalities may contribute to diastolic dysfunction in LVH.