Role of Extracellular Ca 2+ in Subarachnoid Hemorrhage−Induced Spasm of the Rabbit Basilar Artery

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Abstract
Background and Purpose The role of extracellular Ca 2+ in the maintenance of chronic vasospasm after subarachnoid hemorrhage (SAH) is largely unknown. Indeed, studies thus far have been limited to demonstrations that L-type Ca 2+ −channel antagonists were unable to reverse the spasm. This study tested whether SAH-induced vasospasm is maintained, at least in part, through the influx of extracellular Ca 2+ and whether the influx of extracellular Ca 2+ occurs through L-type Ca 2+ channels and possibly, in addition, through store operated channels (SOCs). Furthermore, as there is considerable evidence in the literature to suggest that the spasm is mediated through endothelin-1 (ET-1) release, we tested whether the Ca 2+ dependency of the spasm was consistent with the mediation of the spasm by ET-1. Methods Chronic spasm of the basilar artery was induced in a double SAH rabbit model. Relaxation of SAH-, ET-1−, serotonin-, and KCl-constricted basilar artery in response to Ca 2+ -free solution, verapamil, and Ni 2+ was measured in situ with the use of a cranial window. Results SAH induced 23% constriction of the basilar artery. Ca 2+ -free solution and 1 μmol/L verapamil reversed the constriction of SAH vessels by 60% and 17%, respectively. In contrast, control vessels challenged with 40 to 50 mmol/L KCl, which induced 34% constriction, relaxed in response to Ca 2+ -free solution and verapamil by 98% and 89%, respectively. In SAH vessels, verapamil followed by 0.1 mmol/L Ni 2+ , which is known to block SOCs, induced a combined relaxation of 67%. Control vessels challenged with 3 nmol/L ET-1, which induced a magnitude of constriction similar to that of SAH (29%), relaxed in response to Ca 2+ -free solution, verapamil, and verapamil plus Ni 2+ by 69%, 20%, and 50%, respectively ( P >.05 versus respective values in SAH vessels). In contrast, control vessels challenged with 2 to 8 μmol/L serotonin, which induced a magnitude of constriction similar to those of SAH and ET-1 (22%), completely relaxed in response to Ca 2+ -free solution and verapamil. Conclusions These results demonstrate that the maintenance of chronic spasm in the two-hemorrhage rabbit model after SAH is due to smooth muscle cell contractile mechanisms partly dependent on the influx of extracellular Ca 2+ . The influx of extracellular Ca 2+ results from the opening of L-type Ca 2+ channels and an additional channel or channels. We speculate that the L-type Ca 2+ channel−independent influx of extracellular Ca 2+ results from the opening of SOCs. The Ca 2+ -dependent characteristics of the spasm likely reflect the mediation of the spasm by ET-1.