Emergence of a R-Type Ca ²⁺ Channel (Ca _V 2.3) Contributes to Cerebral Artery Constriction After Subarachnoid Hemorrhage

Abstract

Abstract-Cerebral aneurysm rupture and subarachnoid hemorrhage (SAH) inflict disability and death on thousands of individuals each year. In addition to vasospasm in large diameter arteries, enhanced constriction of resistance arteries within the cerebral vasculature may contribute to decreased cerebral blood flow and the development of delayed neurological deficits after SAH. In this study, we provide novel evidence that SAH leads to enhanced Ca 2ϩ entry in myocytes of small diameter cerebral arteries through the emergence of R-type voltage-dependent Ca 2ϩ channels (VDCCs) encoded by the gene Ca V 2.3. Using in vitro diameter measurements and patch clamp electrophysiology, we have found that L-type VDCC antagonists abolish cerebral artery constriction and block VDCC currents in cerebral artery myocytes from healthy animals. However, 5 days after the intracisternal injection of blood into rabbits to mimic SAH, cerebral artery constriction and VDCC currents were enhanced and partially resistant to L-type VDCC blockers. Further, SNX-482, a blocker of R-type Ca 2ϩ channels, reduced constriction and membrane currents in cerebral arteries from SAH animals, but was without effect on cerebral arteries of healthy animals. Consistent with our biophysical and functional data, cerebral arteries from healthy animals were found to express only L-type VDCCs (Ca V 1.2), whereas after SAH, cerebral arteries were found to express both Ca V 1.2 and Ca V 2.3. We propose that R-type VDCCs may contribute to enhanced cerebral artery constriction after SAH and may represent a novel therapeutic target in the treatment of neurological deficits after SAH.

Fundamental increase in pressure-dependent constriction of brain parenchymal arterioles from subarachnoid hemorrhage model rats due to membrane depolarization

“…Previous reports have demonstrated upregulated expression of R-type (Ca V 2.3) and Ttype (Ca V 3.1 and Ca v 3.3) channels in pial cerebral arteries after experimental SAH (30,47,61). In contrast to these findings, we observed no effect on arteriolar [Ca 2ϩ ] i or diameter of the R-type VDCC inhibitor SNX-482 or the T-type VDCC inhibitor mibefradil (after L-type VDCC inhibition) in the present study.…”

Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca 2+ -activated K + (BK) channels

“…For example, pressurized parenchymal arterioles isolated from SAH animals exhibit depolarization of smooth muscle membrane potential and enhanced constriction in vitro (14). Direct vasoconstrictor effects of blood components such as oxyhemoglobin include suppression of smooth muscle K + channels (44)(45)(46), up-regulation of voltagedependent Ca 2+ channels (47) or transient receptor potential channels (48), and scavenging of nitric oxide (49).…”

Reduced Ca2+ Spark Activity after Subarachnoid Hemorrhage Disables BK Channel Control of Cerebral Artery Tone

“…New Zealand White rabbits (males, weighing 3.0 to 3.5 kg; Charles River Laboratories, Saint Constant, Quebec, Canada) were used for a double injection SAH model using surgical procedures described previously (Ishiguro et al, 2002;Ishiguro et al, 2005). In brief, under isoflurane anesthesia, a small midline suboccipital incision was centered over the foramen magnum and neck muscles dissected until the dura was visualized.…”