Inhibition of Ca++sparks by oxyhemoglobin in rabbit cerebral arteries

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Abstract
Object. Oxyhemoglobin (HbO(2)) causes cerebral artery constriction and is one component of blood that likely contributes to the pathogenesis of cerebral vasospasm after aneurysm rupture. This study was designed to examine the acute effect of HbO(2) on subcellular Ca++ release events (Ca++ sparks) in cerebral artery myocytes. Calcium sparks provide a tonic hyperpolarizing and relaxing influence to vascular smooth muscle by the activation of plasmalemmal large-conductance Ca++-activated K+ channels. Evidence is provided that HbO(2) may contract cerebral vascular muscle in part by free radical-mediated inhibition of Call sparks. Methods. Calcium sparks were visualized in intact pressurized rabbit cerebral arteries by using laser scanning confocal microscopy and a Ca++ indicator dye. Calcium spark frequency was reduced by approximately 65% after a 15-minute application of HbO(2) (10(-4) M). The HbO(2)-induced decrease in Ca++ spark frequency was prevented by a combination of the free radical scavengers superoxide dismutase and catalase. Isometric force measurements were used to characterize the role of the vascular endothelium and smooth-muscle Ca++ channels in HbO(2)-induced cerebral artery contraction. The HbO(2)-induced contractions were independent of the vascular endothelium, but were abolished by diltiazem, a blocker of L-type voltage-dependent Call channels (VDCCs). Ryanodine, a blocker of ryanodine-sensitive Ca++ release channels located on the sarcoplasmic reticulum, also reduced HbO(2)-induced contractions by approximately 50%. Conclusions. These results support the hypothesis that HbO(2), may contract cerebral artery segments in part by inhibition of Ca++ sparks, leading to decreased large-conductance Ca++-activated K+ channel activity, membrane potential depolarization, and enhanced Ca++ entry through VDCCs.