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

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 Ca²⁺loading in rats. Animals were studied in four groups: Ca²⁺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 Ca²⁺‐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. Drug Dev. Res. 67:511–518, 2006. © 2006 Wiley‐Liss, Inc.