Oxyhemoglobin (oxyhb) induces R‐type calcium channel expression in cerebral arteries

Abstract

Cerebral vasospasm after subarachnoid hemorrhage (SAH) represents a major cause of mortality and morbidity following aneurysm rupture. Our laboratory has recently shown the emergence of R-type Ca2+ channels is associated with increased cerebral artery constriction in a rabbit SAH model (Ishiguro et al., Cir. Res. 2005). Here, we have examined whether the blood component, oxyhb, can mimic the ability of SAH to induce expression of R-type Ca2+ channels in the cerebral vasculature. Rabbit cerebral arteries were organ cultured for 1–5 days in the presence or absence of oxyhb. In the absence of oxyhb, constriction to 60 mM K+ is completely abolished by diltiazem, a L-type VDCC antagonist. However, following 5days of oxyhb treatment, K+-induced constriction became partially resistant to diltiazem. Further, the combination of SNX-482 (R-type VDCC antagonist) and diltiazem fully dilated oxyhb-exposed arteries. RT-PCR revealed that after 5 days of oxyhb, arteries expressed R-type Ca2+ channels (Cav2.3) in addition to L-type Ca2+ channels (Cav1.2). In contrast, arteries cultured in the absence of oxyhb expressed only L-type Ca2+ channels. These results demonstrate that oxyhb exposure for 5 days induces the expression of Cav2.3 in cerebral arteries. We propose that oxyhb contributes to SAH-induced vasospasm via the emergence of R-type Ca2+ channels in cerebral arteries. Expression of R-type Ca2+ channels may help to explain why L-type antagonists are relatively ineffective at reversing SAH-induced vasospasm. The work was supported by NIH (P20 RR16435, R01 HL078983) and Totman Medical Research Trust.