Nystoriak MA, O'Connor KP, Sonkusare SK, Brayden JE, Nelson MT, Wellman GC. Fundamental increase in pressure-dependent constriction of brain parenchymal arterioles from subarachnoid hemorrhage model rats due to membrane depolarization. Am J Physiol Heart Circ Physiol 300: H803-H812, 2011. First published December 10, 2010 doi:10.1152 doi:10. /ajpheart.00760.2010 arterioles are morphologically and physiologically unique compared with pial arteries and arterioles. The ability of subarachnoid hemorrhage (SAH) to induce vasospasm in large-diameter pial arteries has been extensively studied, although the contribution of this phenomenon to patient outcome is controversial. Currently, little is known regarding the impact of SAH on parenchymal arterioles, which are critical for regulation of local and global cerebral blood flow. Here diameter, smooth muscle intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i), and membrane potential measurements were used to assess the function of intact brain parenchymal arterioles isolated from unoperated (control), sham-operated, and SAH model rats. At low intravascular pressure (5 mmHg), membrane potential and [Ca 2ϩ ]i were not different in arterioles from control, sham-operated, and SAH animals. However, raising intravascular pressure caused significantly greater membrane potential depolarization, elevation in [Ca 2ϩ ]i, and constriction in SAH arterioles. This SAH-induced increase in [Ca 2ϩ ]i and tone occurred in the absence of the vascular endothelium and was abolished by the L-type voltage-dependent calcium channel (VDCC) inhibitor nimodipine. Arteriolar [Ca 2ϩ ]i and tone were not different between groups when smooth muscle membrane potential was adjusted to the same value. Protein and mRNA levels of the L-type VDCC CaV1.2 were similar in parenchymal arterioles isolated from control and SAH animals, suggesting that SAH did not cause VDCC upregulation. We conclude that enhanced parenchymal arteriolar tone after SAH is driven by smooth muscle membrane potential depolarization, leading to increased L-type VDCC-mediated Ca 2ϩ influx.voltage-dependent calcium channels; vascular smooth muscle; cerebral blood flow; endothelium; ion channels CEREBRAL BLOOD FLOW IS REGULATED by the diameter of resistance arteries and arterioles both on the surface of the brain and within the brain parenchyma. Parenchymal arterioles, unlike pial arteries and arterioles, lack extrinsic innervation and are encased by astrocytic processes ("endfeet") (17, 27). The close association of this microvasculature with astrocytic endfeet is essential for functional hyperemia, whereby focal increases in neuronal activity are coupled to vasodilation of nearby arterioles and increased blood flow (6,14,27,45). In addition to their role in neurovascular coupling, parenchymal arterioles also contribute significantly to autoregulation of global cerebral blood flow and account for ϳ40% of total cerebral vascular resistance (12 (1,13,19,32,44). Recent work has established that pressuredependent constriction, or myogeni...

Intracellular Ca2+ release events ('Ca 2+ sparks') and transient activation of large-conductance Ca 2+ -activated potassium (BK) channels represent an important vasodilator pathway in the cerebral vasculature. Considering the frequent occurrence of cerebral artery constriction after subarachnoid hemorrhage (SAH), our objective was to determine whether Ca 2+ spark and BK channel activity were reduced in cerebral artery myocytes from SAH model rabbits. Using laser scanning confocal microscopy, we observed B50% reduction in Ca 2+ spark activity, reflecting a decrease in the number of functional Ca 2+ spark discharge sites. Patch-clamp electrophysiology showed a similar reduction in Ca 2+ spark-induced transient BK currents, without change in BK channel density or single-channel properties. Consistent with a reduction in active Ca 2+ spark sites, quantitative real-time PCR and western blotting revealed decreased expression of ryanodine receptor type 2 (RyR-2) and increased expression of the RyR-2-stabilizing protein, FKBP12.6, in the cerebral arteries from SAH animals. Furthermore, inhibitors of Ca 2+ sparks (ryanodine) or BK channels (paxilline) constricted arteries from control, but not from SAH animals. This study shows that SAH-induced decreased subcellular Ca 2+ signaling events disable BK channel activity, leading to cerebral artery constriction. This phenomenon may contribute to decreased cerebral blood flow and poor outcome after aneurysmal SAH. Keywords: cerebral aneurysm; FKBP12.6; potassium channels; ryanodine receptors; vascular smooth muscle; vasospasm IntroductionCerebral aneurysm rupture and the ensuing subarachnoid hemorrhage (SAH) has an enormous impact on individuals and society, with 30-day mortality rates approaching 50% and the majority of survivors left with moderate-to-severe disability (Hop et al, 1997). For decades, 'angiographically defined' cerebral vasospasm of conduit arteries ( > 1 mm in diameter) has been considered to be the major contributor to death and disability in SAH patients surviving the initial intracranial bleed. However, recent evidence indicates that factors other than large-artery vasospasm contribute to SAH-induced pathologies (Macdonald et al, 2007). Additional factors contributing to the deleterious consequences of aneurysmal SAH may include global transient ischemia, early brain injury, disruption of the bloodbrain barrier, and activation of inflammatory pathways (Ostrowski et al, 2006;Prunell et al, 2005). It has now been realized that SAH may also impact small-diameter arteries and arterioles, i.e., those involved in the autoregulation of cerebral blood flow (Hattingen et al, 2008;Ishiguro et al, 2002;Ohkuma et al, 2000).In resistance arteries from healthy animals, vasoconstrictor stimuli such as physiologic increases in intravascular pressure lead to smooth muscle membrane potential depolarization, increased voltage-dependent Ca 2+ channel (VDCC) activity, and elevated global cytosolic calcium (Knot and Nelson, 1998 , the NIH (R01 HL078983, R01 HL078983-05S1, R01 ...

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