Reduction of Vascular Reactivity with Dantrolene in Type 1 Diabetic Rats is Dose‐dependent

Diabetics have a greater predisposition for developing cerebral vasospasms (CVSPs) than nondiabetics, even when under glycemic control. The etiology of CVSPs is associated with increased vascular tone, secondary to augmented intracellular Ca +2 in vascular smooth muscle. Current pharmacological treatments are ineffective in reducing CVSPs. The combination of the ryanodine receptor blocker dantrolene (50 μM) and the Ca +2 channel blocker nimodipine significantly decreases vascular reactivity in streptozotocin (STZ)‐induced diabetic rats. In order to determine if the beneficial effects observed at 50 μM are also maintained at a much lower concentration with less potentially harmful secondary effects, we evaluated the vascular effects of 10 μM dantrolene, alone and in combination with 50 nM nimodipine. Dose‐response curves for the phenylephrine (PHE)‐induced contraction (0.1 nM to 10 μM) and acetylcholine (ACh)‐induced relaxation (1 nM to 10 μM) were performed on aortic rings from STZ‐diabetic rats, both before and after a 30‐minute incubation period with dantrolene alone or in combination with nimodipine. Whereas 50 μM dantrolene reduced PHE‐induced contraction by 47% in diabetic rats and 29% in controls, 10 μM dantrolene failed to reduce this parameter in either group. Moreover, 50 μM dantrolene reduced PHE‐induced contraction by about 80% in both diabetic and controls when combined with nimodipine. The combination of 10 μM dantrolene and nimodipine, however, does not increase the reduction of 35% in diabetic rats and 47% in controls obtained with nimodipine alone. In addition, only 50 μM dantrolene increased ACh‐induced relaxation by 50% (N=9, P<0.05) in diabetic rats. These results suggest that both, improved endothelial‐dependent relaxation and reduced vascular contraction with dantrolene are dosedependent. Thus, careful titration should be performed in order to achieve a significant reduction in hyper‐reactivity in both diabetics and nondiabetics. Support or Funding Information This work was supported by Grants from the National Institute of Health (MBRS‐RISE Grant R25GM061838), the NIMHD‐RCMI Program (Grant G12‐MD007600), and the Anesthesiology Department of the University of Puerto Rico‐School of Medicine. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .