Synergistic Effects of Dantrolene and Nimodipine on the Phenylephrine-Induced Contraction and ACh-Induced Relaxation in Aortic Rings from Diabetic Rats

Abstract

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.

The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats

“…The reduction of contractility is dose-dependent. Previously, we reported that these two drugs, when combined, improve endothelial-dependent relaxation and reduce PHE-induced contraction in diabetic rats 16 , 17 . The findings of the current study are relevant to SAH patients because bleeding is associated with higher release of 5-HT, which is an important contributor to the etiology of CVSP 26 .…”

“…These treatments, however, do not effectively block the neurological deterioration observed after CVSPs 26 . The addition of dantrolene to standard therapies may improve neurological outcomes in diabetic patients because of their dual effect in reducing vascular contractility and improving endothelial- dependent relaxation throughout reduction of the lipid peroxidation markers MDA and 4-HAE in diabetic rats 16 . Thus, by acting additionally as an antioxidant agent, dantrolene may contribute to reduced neuroinflammation, which plays an important role in the pathogenesis of SAH, and improve stroke manifestations in diabetics.…”

“…The effects of 10 µM and 50 µM dantrolene, 50 nM nimodipine, and these two drugs in combination, on the 5-HT-induced contraction were evaluated following the protocols previously described by our laboratory 16 , 17 . Cumulative concentration–response curves were generated by adding 5-HT (0.1 nM to 100.0 μM) to the aortic rings before and after incubation with the drugs.…”

“…Previous studies of diabetic and non-diabetic rats in our laboratory indicated that concomitant administration of dantrolene and the CCB nimodipine significantly lessens vascular tone by reducing phenylephrine (PHE)-induced contraction of aortic rings 16 , 17 . The effects of this drug combination on the 5-HT-induced vascular response in diabetics, however, remain unknown.…”

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

“…The three subtypes of the RyR family (RyR1, RyR2, and RyR3) are present in the VSM of the thoracic aorta [16], the mesenteric arteries [14], the large cerebral arteries [17], and the cerebral microcirculation [4]. Dantrolene effectively blocks all the RyR subtypes [18,19], reduces malondialdehyde (MDA) levels [20,21], and provides neuroprotection by increasing the antioxidant defenses in spinal cord-injured rats [22]. Moreover, concomitant administration of dantrolene and nimodipine significantly decreases serotonin-induced contraction in isolated basilar and femoral arteries of rats [23], which suggests that the combined use of these drugs reduces the incidence and severity of CVSPs by simultaneously blocking Ca +2 entry through the L-type VDCC and Ca +2 release by RyR from the SR.…”