Oxyhemoglobin-Induced Expression of R-Type Ca Channels in Cerebral Arteries

Background and Purpose—Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a major contributor to mortality and morbidity after aneurysm rupture. Recently, R-type voltage-dependent Ca channel (VDCC) expression has been associated with increased cerebral artery constriction in a rabbit model of SAH. The goal of the present study was to examine whether the blood component oxyhemoglobin (oxyHb) can mimic the ability of SAH to cause R-type VDCC expression in the cerebral vasculature. Methods—Rabbit cerebral arteries were organ cultured in serum-free media for up to 5 days in the presence or absence of purified oxyHb (10 mol/L). Diameter changes in response to diltiazem, (L-type VDCC antagonist) and SNX-482 (R-type VDCC antagonist) were recorded at day 1, 3, or 5 in arteries constricted by elevated extracellular potassium. RT-PCR was performed on RNA extracted from arteries cultured for 5 days ( oxyHb) to assess VDCC expression. Results—After 5 days, oxyHb-treated arteries were less sensitive and partially resistant to diltiazem compared to similar arteries organ cultured in the absence of oxyHb. Further, SNX-482 dilated arteries organ cultured for 5 days in the presence, but not in the absence, of oxyHb. RT-PCR revealed that oxyHb treated arteries expressed R-type VDCCs (CaV 2.3) in addition to L-type VDCCs (CaV 1.2), whereas untreated arteries expressed only CaV 1.2. Conclusions—These results demonstrate that oxyhemoglobin exposure for 5 days induces the expression of CaV 2.3 in cerebral arteries. We propose that oxyhemoglobin contributes to enhanced cerebral artery constriction after SAH via the emergence of R-type VDCCs. (Stroke. 2008;39:2122-2128.)