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

Abstract

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...

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

“…In humans, ischemic neurological deficits frequently occur several days after cerebral aneurysm rupture and SAH. To mimic aneurysmal SAH, we surgically injected whole autologous arterial blood through the cisterna magna into the subarachnoid space of anesthetized rats (14). Sham-operated animals received injections of artificial cerebral spinal fluid (aCSF) rather than blood.…”

“…The exact cause of these infarcts and their relationship to impaired neurovascular coupling remains to be determined. Conversion of the neurovascular response from vasodilation to vasoconstriction may act in concert with other actions of SAH, such as direct constrictor effects on parenchymal arterioles (14), microthrombi formation (12), and cortical spreading depolarization (7,25), to compromise cortical blood flow. For example, pressurized parenchymal arterioles isolated from SAH animals exhibit depolarization of smooth muscle membrane potential and enhanced constriction in vitro (14).…”

“…Conversion of the neurovascular response from vasodilation to vasoconstriction may act in concert with other actions of SAH, such as direct constrictor effects on parenchymal arterioles (14), microthrombi formation (12), and cortical spreading depolarization (7,25), to compromise cortical blood flow. 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).…”

“…All experiments used male Sprague-Dawley rats (10-12 wk of age) and were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (62) and followed protocols approved by the Institutional Animal Use and Care Committee of the University of Vermont. Aneurysmal SAH was mimicked by injecting autologous, unheparinized arterial blood (500 μL) into the cisterna magna of anesthetized animals using a surgical approach (14). Twenty-four hours later, animals received a second intracisternal injection of blood.…”

“…Additional mechanisms that may contribute to SAH-induced DINDs include early brain injury, inflammation, cortical spreading depression, and focal cortical infarcts arising from perfusion deficiencies within the microcirculation (5,6,10,11). Perfusion deficiencies reflecting restricted blood flow through intracerebral (parenchymal) arterioles could result from microthrombi formation (12), vasoconstriction caused by extravascular blood or blood breakdown products (13,14), or impaired neurovascular coupling (15).…”