Dantrolene improves diastolic property of left ventricle in mineralcorticoid-induced hypertensive rats.

Abstract

Diastolic dysfunction is getting important issue in this era of “heart failure pandemic”. However, there are few options of treatment toward such condition. In this study, we examined whether dantrolene, which is known to stabilize ryanodine receptors, can suppress cardiac hypertrophy and improve HFpEF using a mineral corticoid-induced hypertension rat model. Male Sprague-Dawley rat (8 weeks old) received a uninephrectomy (UNX), a subcutaneous pellet of DOCA (200 mg) implantation and 0.9% NaCl water (UNX+DOCA-salt). UNX and control pellet serves as control (UNX control). Effect of oral administration of 100 mg/kg/day dantrolene in the UNX+DOCA-salt rats were examined (UNX+DOCA-salt+DAN). UNX+DOCA-salt treatment resulted in mild hypertension. Oral dantrolene treated UNX+DOCA-salt rats did not affect blood pressure. Increased lung weight and heart weight in UNX+DOCA-salt were significantly decreased in UNX+DOCA-salt+DAN. Echocardiography revealed almost same fractional shortening of three groups. LV wall thickness was increased and mitral annular early relaxation velocity was decreased in UNX+DOCA-salt compared with UNX control; however, both were significantly improved in UNX+DOCA-salt+DAN. Increased LV fractional fibrosis in UNX+DOCA-salt was significantly improved in UNX+DOCA-salt+DAN. Static compliance of LV was significantly decreased in UNX+DOCA-salt; however, it was significantly improved in UNX+DOCA-salt+DAN. Cardiomyocytes were isolated from heart and then the size of cardiomyocytes, cell shortening, and Ca2+ spark frequency (CaSF) were examined. Increased cell size in UNX+DOCA-salt was significantly decreased in UNX+DOCA-salt+DAN. Increased 80 % recovery time of cell shortening in UNX+DOCA-salt was significantly improved in UNX+DOCA-salt+DAN. SpF in UNX+DOCA-salt was significantly increased, but remained to be normal in UNX+DOCA-salt+DAN. In conclusion, dantrolene improve diastolic property of left ventricle in both terms of myocardial stiffness and relaxation. It could be a new option of treatment for HFpEF.