Diabetics have a higher risk of developing cerebral vasospasms (CVSP) than nondiabetics. The addition of the ryanodine receptor (RyR) blocker dantrolene to standard therapies reduces vasospasms in nondiabetics. Whether diabetics with CVSP also benefit from this drug, however, is unknown. We evaluated the effects of a 30 min incubation with dantrolene (50 μM), nimodipine (50 nM), and both drugs in combination, on phenylephrine- (PHE-) induced contraction and on acetylcholine- (ACh-) induced relaxation in aortic rings from streptozotocin (STZ) diabetic rats. Age-matched, nondiabetic rats served as controls. The oxidative stress markers malondialdehyde (MDA) and 4-hydroxyalkenal (4-HAE) were also evaluated in the presence and absence of dantrolene and nimodipine. The combination of these two drugs acted synergistically to reduce the PHE-induced contraction by 80% in both diabetics and controls. In contrast, it increased the Emax value for ACh-induced relaxation (from 56.46 ± 5.14% to 96.21 ± 7.50%; n = 6, P < 0.05), and it decreased MDA + 4-HAE values in diabetic rats only. These results suggest that the combination of dantrolene and nimodipine benefits both diabetics and nondiabetics by decreasing arterial tone synergistically.

Background: Diabetics have a higher risk of developing cerebral vasospasms (CVSPs) than nondiabetics. Current therapies are ineffective in reducing CVSPs, but a viable treatment may be a combination of dantrolene and nimodipine. 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 nondiabetic rats, before and after a 30-minute 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 hyper-reactivity. 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.Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1

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Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose–response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 μM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (Emax), but 50 μM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC50 values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.

A cerebral vasospasm (CVSP) is a potent vasoconstriction of the cerebral vasculature, and the primary cause of morbidity and mortality following a hemorrhagic stroke. The middle cerebral artery (MCA) is one of the most common vessels affected by CVSPs. Experimental evidence shows that concomitant administration of dantrolene (a ryanodine receptor blocker) and nimodipine (a Ca+2 channel blocker) has synergistic effects in reducing vasospasms in aortic rings from Sprague Dawley rats. To determine if the effects observed in the systemic vasculature extend to the cerebral circulation, we investigated the effect of intravenous administration of dantrolene (2.5 mg/kg) and nimodipine (1 mg/kg and 2 mg/kg) on MCA blood flow velocity (BFV). Using a PeriFlux 5000 Laser Doppler System, we measured BFV before and after administration of the drugs 7 days after induction of cerebral vasospasms in Sprague Dawley rats. A reduction in blood flow velocity indicates that vascular reactivity decreases and blood perfusion increases. Mean blood pressure (MBP) and heart rate (HR) were also measured. Individual administration of these drugs resulted in similar reductions in BFV (34% with dantrolene, n=6, p<0.05; 32% with nimodipine 2 mg/kg, n=6, p<0.05). Moreover, dantrolene combined with 1mg/kg of nimodipine decreased BFW by 48% (from 435.70 ± 21.50 to 284.30 ± 26.10 perfusion units, n=6, p<0.05). Similarly, dantrolene combined with 2 mg/kg of nimodipine, reduced BFW by 54% (from 536.00 ± 32.60 to 367.80 ± 40.90 perfusion units, n=6, p<0.05). Although when combined with 2 mg/kg of nimodipine, dantrolene significantly increases HR, the combination of dantrolene and 1mg/kg of nimodipine, did not alter MBP or HR. Thus, our results indicate that concurrent administration of 2.5 mg/kg dantrolene and 1 mg/kg nimodipine significantly reduce BFV in the MCA without altering systemic hemodynamic parameters. By reducing vascular reactivity synergistically, these drugs may improve cerebral blood perfusion. Therefore, adding dantrolene to current standard pharmacological therapies with calcium channel blockers (CCB) may allow a dosage reduction of CCB and minimize the systemic secondary effects of these drugs. Furthermore, if our findings with rats are applicable to humans, the combined use of dantrolene and nimodipine at optimal doses may be effective in reducing CVSPs.