Dantrolene Significantly Improves Cerebral Blood Flow In Diabetic Rats With Cerebral Vasospasms

Abstract

Cerebral vasospasm (CVSP) is a potent vasoconstriction of the cerebral vasculature, and the primary cause of morbidity and mortality following a hemorrhagic stroke. Diabetics have a greater predisposition for developing CVSPs than nondiabetics, even when under glycemic control. 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) synergistically reduces vasospasms in aortic rings from streptozotocin (STZ)‐induced diabetic rats. To determine if the effects observed in the systemic vasculature extend to the cerebral circulation, we investigated the effects of intravenous administration of dantrolene (2.5 mg/kg) and nimodipine (1 mg/kg and 2 mg/kg) on MCA blood flow velocity (BFV) seven days after the induction of CVSP in diabetic rats. Vasospasms were induced by bathing the external surface of the left common carotid artery with autologous whole blood. BFV was measured with a PeriFlux 5000 Laser Doppler System before, and sixty minutes after administering the drugs. Morphometric evaluations of the common carotid arteries were also performed to assess vascular alterations secondary to the induction of vasospasms. BFV was reduced by 30% with dantrolene alone (from 495.90 ±21.38 to 345.50±31.46 perfusion units, n=6, p≤0.05), however, nimodipine alone (1mg/kg or 2 mg/kg) did not affect this variable. The combination of dantrolene with 1 mg/kg nimodipine decreased BFV by 22% (from 518.90±31.49 to 405.50±23.84 perfusion units, n=7, p≤0.05), while a 32% reduction was obtained with the combination of dantrolene and 2 mg/kg nimodipine (from 504.60±15.38 to 344.90±36.98 perfusion units, n=6, p≤0.05). Furthermore, seven days after the induction of vasospasms, the lumen area of the left common carotid artery decreased, whereas media thickness and the wall‐to‐lumen ratio increased when compared to contralateral controls. The latter findings suggest that a period of seven days after the induction of vasospasms, was sufficient to cause vascular remodeling. Thus, our results indicate that, in diabetic rats, 2.5 mg/kg dantrolene alone was as effective as the combination of dantrolene and the highest dose of nimodipine in reducing BFV in the MCA. Therefore, dantrolene may provide a promising alternative therapy for the treatment of CVSP in the diabetic population.