Norepinephrine-induced diastolic dysfunction with aortic valve opening under calcium-loading in rats

Abstract

Heart failure associated with a high plasma level of norepinephrine (NE) has an extremely poor prognosis with NE being the most powerful predictor of all-cause mortality. An increase in the diastolic intracellular calcium level (Ca2+) occurs in left ventricular dysfunction; however, the cause-and-effect relationships among Ca2+ loading, high plasma NE, and an increase in diastolic ventricular pressure is unclear. Here, we examined the relationship between diastolic dysfunction and NE with and without Ca 2+ loading in rats. Animals were studied in four groups: Ca 2+ loading for 45 min (Ca2+ group), NE alone for 25 min (30 μg/kg/min NE for 25 min; NE group), Ca2+ loading and NE for 25 min after Ca2+ loading (Ca2+-NE group), and a vehicle group. Hemodynamics were examined using a micromanometer-tipped pressure catheter, and diastolic function was studied using Doppler echocardiography. Significantly increased left ventricular end-diastolic pressure (LVEDP) and decreased E and Ea waves and deceleration time (DCT) were found in the Ca 2+-NE group, compared with the Ca2+ and NE groups. There were no changes in left ventricular pressure (LVP) and LV ejection fraction (EF) among the four groups. NE-induced diastolic contracture (NEIDC) with aortic valve opening occurred in the diastole when LVP overshot the aortic pressure after co-administration of NE and Ca2+ after Ca2+ loading, and pulmonary hemorrhage was observed in all animals of the Ca2+-NE group. The results support the suggestion that NE may be an important factor in the development of diastolic dysfunction in ischemic heart disease. © 2006 Wiley-Liss, Inc.