Stabilizing Ryanodine Receptor with Chronic Dantrolene Treatment Does not Affect Hypertension, but Attenuates Atrial Fibrillation Inducibility under Sympathetic Stimulation in Spontaneously Hypertensive Rats

Abstract

IntroductionRyanodine receptor (RyR) dysfunction in skeletal muscle (RyR1) is linked to malignant hyperthermia, and in cardiac muscle (RyR2) is associated with cardiac arrhythmias and heart failure. We hypothesized that RyR dysfunction in vascular smooth muscle (RyR 1,2 and 3) could increase vascular resistance and blood pressure by increasing intracellular calcium level. RyR dysfunction may also contribute to increased atrial fibrillation (AF) in hypertension. Thus, stabilizing RyR function with chronic dantrolene treatment may attenuate hypertension development and AF inducibility in spontaneously hypertensive rats (SHR).MethodsMale SHR (16 week‐old) were randomized into vehicle‐ (n=10) and dantrolene‐treated (10mg/kg/d, n=10) groups for 4‐weeks. Male Wistar Kyoto (WKY, n=10) rats served as controls. Tail‐cuff blood pressures were recorded before treatment, and at 1‐week, 3‐week during the treatment period. At the end of the 4‐week treatment period, direct blood pressure, echocardiography and hemodynamics were recorded. Atrial fibrillation inducibility tests were performed at baseline and under sympathetic stimulation (SS) with isoproterenol infusion.ResultsCompared with WKY rats, SHR rats had significantly higher blood pressure throughout the experimental period and at the end of 4‐week treatment the systolic blood pressure (SBP) was 212±9mmHg in SHR versus 122±15mmHg in WKY (P<0.001). Dantrolene treatment in SHR had no effect on blood pressure level (208±16 mmHg in dantrolene versus 212±9mmHg in vehicle, P>0.05). AF inducibility was not significantly different between WKY and SHR rats at baseline. However, under SS AF inducibility was significantly increased in SHR compared with WKY rats (58±28% in SHR versus 20±23% in WKY, P<0.01) and dantrolene treatment attenuated AF inducibility under SS in SHR (58±28% in SHR‐vehicle versus 27±21% in SHR‐dantrolene group, P<0.05). Dantrolene treatment also reduced AF duration (0.8±1.4s in dantrolene group versus 10.0±15.0s in vehicle group, P<0.05).Conclusions: Stabilizing RyR with dantrolene treatment did not affect hypertension development in SHR rats, indicating RyR dysfunction does not play an important role in mediating hypertension development in this animal model. SHR rats did not show increased AF inducibility compared with WKY rats at baseline; however, under SS, SHR rats had increased vulnerability to AF induction which was attenuated with dantrolene treatment, indicating that enhanced SS‐induced RyR dysfunction in SHR may be responsible for enhanced AF inducibility in hypertension.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.