Inhibitory Effects of K201 on Norepinephrine-induced Diastolic Dysfunction in Rat

Abstract

The pathogenesis of diastolic heart failure remains unclear. Heart failure patients with a high plasma level of norepinephrine (NE) have a poor prognosis, and an increase in the diastolic [Ca2+]i has been shown in left ventricular dysfunction. We investigated whether NE with Ca2+-loading induces diastolic dysfunction (DD) in rats, and examined the effects of K201 (JTV519) and diltiazem in this model. Animals were examined in Ca2+-load for 45 min, NE for 25 min, Ca2+-load and NE for 25 min after Ca2+-load (Ca2+-NE), and vehicle group. The effects of K201 and diltiazem were studied in the Ca2+-NE group. (each group; n = 4-6) Hemodynamics and diastolic function were examined using a micromanometer-tipped pressure catheter and Doppler echocardiography. There were no significant changes in LVP and LV-EF among all groups. In the Ca2+-NE group, a significant increase in LVEDP, and decreased E, Ea and deceleration time (DCT) were found, and NE-induced diastolic contracture (NEIDC) with aortic valve opening occurred in diastole and pulmonary hemorrhage was observed. K201 significantly suppressed the increase in LVEDP and improved Ea and DCT dose-dependently. Diltiazem did not improve DD. NE may be an important factor in development of DD, and K201 may have potential as a cardiac relaxant for treatment of DD.