K201 improves norepinephrine -induced diastolic dysfunction with preserved ejection fraction

Heart failure with preserved ejection fraction differs from systolic heart failure in pathogenesis, underlying disease, and prognosis; however, the onset mechanism of this type of heart failure remains unknown and there is no proven therapy. Recently, we showed that norepinephrine (NE) under Ca2+ loading induces severe diastolic dysfunction without a significant change in the left ventricular ejection fraction (LVEF), that is, increased left ventricular end-diastolic pressure (LVEDP), norepinephrine-induced diastolic contracture (NEIDC), and diastolic opening of the aortic valve. In this study, the effects of two benzothiazepine derivatives, K201 (JTV519) and diltiazem, on diastolic dysfunction were examined using this model. K201 significantly suppressed the increase in LVEDP, reduced the incidence of NEIDC, and significantly improved the Ea wave and DCT in a dose-dependent manner, as well as reducing pulmonary hemorrhage. In contrast, diltiazem did not improve diastolic dysfunction and the mortality in the diltiazem group was 57%, compared to 0% in the K201 group. These results suggest that reduction of intracellular Ca2+ alone does not inhibit diastolic heart failure; in contrast, blocking of α-adrenoceptors and regulation of proteins such as troponin I via protein kinase C are required for treatment of diastolic heart failure. These results also suggest that K201 may be an agent for treatment of diastolic heart failure. Drug Dev. Res. 67:852–861, 2006. © 2007 Wiley-Liss, Inc.