Significant reduction of vascular reactivity with dantrolene and nimodipine in diabetic rats: a potential approach to cerebral vasospasm management in diabetes.

BACKGROUND: Diabetics have a higher risk of developing cerebral vasospasms (CVSPs) than non-diabetics. Current therapies are ineffective in reducing CVSPs, but a a combination of dantrolene and nimodipine may be a viable treatment. Considering the potentially harmful secondary effects of dantrolene, however, we evaluated the efficacy of 10 μM dantrolene compared to 50 μM dantrolene alone or in combination with 50 nM nimodipine. METHODS: Dose-response curves for the phenylephrine (PHE)-induced contraction and acetylcholine (ACh)-induced relaxation were performed on aortic rings from diabetic and non-diabetic rats, before and after a 30-min incubation period with dantrolene (50 μM and 10 μM), alone or in combination with 50 nM nimodipine. RESULTS: 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. Furthermore, 50 μM dantrolene reduced PHE-induced contraction by about 80% in both diabetic and controls when combined with nimodipine (N = 9, P < 0.05). The combination of 10 μM dantrolene and 50 nM nimodipine, however, was ineffective. Only 50 μM dantrolene improved endothelial dysfunction. CONCLUSIONS: Improved endothelial-dependent relaxation and reduced vascular contractility with dantrolene are dose dependent. Thus, although dantrolene appears to be a promising alternative for the treatment of CVSPs when added to conventional therapies, careful titration should be performed to achieve a significant reduction in vascular hyperreactivity. Moreover, if our findings with rats are applicable to humans, the combined use of dantrolene and nimodipine at optimal doses may reduce CVSPs, especially in the diabetic population.