Chronic Dantrolene Treatment Does not Affect Hypertension, but Attenuates Sympathetic Stimulation Enhanced Atrial Fibrillation Inducibility in SHR

BACKGROUND: Ryanodine receptor (RyR) dysfunction in skeletal muscle (RyR1) leads to malignant hyperthermia, and in cardiac muscle (RyR2) triggers cardiac arrhythmias. We hypothesized that RyR dysfunction in vascular smooth muscle could increase vascular resistance and hypertension, and may contribute to increased atrial fibrillation (AF) in hypertension. Thus, stabilizing RyR function with chronic dantrolene treatment may attenuate hypertension and AF inducibility in spontaneously hypertensive rats (SHR). METHODS: Male SHR (16 weeks-old) were randomized into vehicle- (n=10) and dantrolene-treated (10mg/kg/d, n=10) groups for 4-weeks. Wistar Kyoto (WKY, n=11) rats served as controls. Blood pressures (BP) were monitored before and during the 4-week treatment. After 4- week treatment, direct BP, echocardiography and hemodynamics were recorded. AF inducibility tests were performed in vivo at baseline and repeated under sympathetic stimulation (SS). RESULTS: Compared with WKY, SHR had significantly higher BP throughout the experimental period. Dantrolene treatment had no effect on BP levels in SHR (final systolic BP 212+/-9mmHg in vehicle group versus 208+/-16 mmHg in dantrolene group, p>0.05). AF inducibility was very low and not significantly different between 5-month old WKY and SHR at baseline. However, under SS, AF inducibility and duration were significantly increased in SHR (20% in WKY versus 60% in SHR-vehicle, p<0.05). Dantrolene treatment significantly attenuated AF inducibility under SS in SHR (60% in vehicle versus 20% in dantrolene, p<0.05). CONCLUSIONS: Stabilizing RyR with chronic dantrolene treatment does not affect hypertension development in SHR. SHR has increased vulnerability to AF induction under SS, which can be attenuated with dantrolene treatment.