Voltage-Gated K⁺ Channel Dysfunction in Myocytes from a Dog Model of Subarachnoid Hemorrhage

Abstract

Delayed cerebral vasospasm after subarachnoid hemorrhage is primarily due to sustained contraction of arterial smooth muscle cells. Its pathogenesis remains unclear. The degree of arterial constriction is regulated by membrane potential that in turn is determined predominately by K+ conductance (GK). Here, we identified the main voltage-gated K+ (Kv) channels contributing to outward delayed rectifier currents in dog basilar artery smooth muscle as Kv2 class through a combination of electrophysiological and pharmacological methods. Kv2 current density was nearly halved in vasospastic myocytes after subarachnoid hemorrhage (SAH) in dogs, and Kv2.1 and Kv2.2 were downregulated in vasospastic myocytes when examined by quantitative mRNA, Western blotting, and immunohistochemistry. Vasospastic myocytes were depolarized and had a smaller contribution of GK toward maintenance of their membrane potential. Pharmacological block of Kv current in control myocytes mimicked the depolarization observed in vasospastic arteries. The degree of membrane depolarization was found to be compatible with the amount of vasoconstriction observed after SAH. We conclude that Kv2 dysfunction after SAH contributes to the pathogenesis of delayed cerebral vasospasm. This may confer a novel target for treatment of delayed cerebral vasospasm.

Temporal profile of potassium channel dysfunction in cerebrovascular smooth muscle after experimental subarachnoid haemorrhage

“…For example, inwardly rectifying K + channels were increased during vasospasm after SAH, suggesting one possible mechanism for such reversal [20]. Another is that the decrease in K V channel function does not cause vasospasm, although function studies suggested that this is not the case [6]. Also, studies reported that vasospasm in rabbits was decreased with K + channel agonists [9;10;23].…”

“…We previously characterized K V current (IK V ) from dog basilar artery and validated protocols to characterize these currents [6]. The same protocols were used in the present study.…”

“…We reported that the function of voltage-gated K + (K V ) channels was significantly decreased during vasospasm 7 days after SAH in dogs [6]. Arterial diameter is regulated by smooth muscle membrane potential that controls influx of external Ca 2+ through voltage-gated Ca 2+ channels [19].…”

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

“…For example, using rabbit pial arteries, our laboratory has shown (28,35) that acute exposure of vascular smooth muscle to the blood component oxyhemoglobin can cause internalization of K V 1.5 via a mechanism involving protein tyrosine kinase activation. Others have additionally demonstrated that mRNA and protein levels of K V 2.2 channels were decreased in basilar arteries from a canine SAH model (31). Further studies are required to determine whether K V channel suppression or additional mechanisms contribute to enhanced pressure-dependent depolarization of parenchymal arteriolar myocytes in SAH animals.…”

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

“…Membrane potential depolarization caused by a decrease in Ca 2+ spark-induced transient BK currents would be predicted to cause an increase in the open-state probability of VDCCs and combined with enhanced VDCC expression would increase global cytosolic Ca 2+ leading to enhanced contraction of cerebral artery myocytes. Additional mechanisms such as decreased voltage-dependent potassium (K V ) channel expression (Jahromi et al, 2008a) and activity (Ishiguro et al, 2006;Koide et al, 2007;Quan and Sobey, 2000) and increased protein kinase C activity (Nishizawa et al, 2000) are also likely to contribute to enhanced cerebral artery constriction after SAH.…”