Objective Delayed cerebral vasospasm has long been recognized as an important cause of poor outcome after an otherwise successful treatment of a ruptured intracranial aneurysm, but it remains a pathophysiological enigma despite intensive research for more than half a century. Method Summarized in this review are highlights of research from North America, Europe and Asia reflecting recent advances in the understanding of delayed ischemic deficit. Result It will focus on current accepted mechanisms and on new frontiers in vasospasm research. Conclusion A key issue is the recognition of events other than arterial narrowing such as early brain injury and cortical spreading depression and of their contribution to overall mortality and morbidity.

Local calcium transients ('Ca2+ sparks') are thought to be elementary Ca2+ signals in heart, skeletal and smooth muscle cells. Ca2+ sparks result from the opening of a single, or the coordinated opening of many, tightly clustered ryanodine receptor (RyR) channels in the sarcoplasmic reticulum (SR). In arterial smooth muscle, Ca2+ sparks appear to be involved in opposing the tonic contraction of the blood vessel. Intravascular pressure causes a graded membrane potential depolarization to approximately -40 mV, an elevation of arterial wall [Ca2+]i and contraction ('myogenic tone') of arteries. Ca2+ sparks activate calcium-sensitive K+ (KCa) channels in the sarcolemmal membrane to cause membrane hyperpolarization, which opposes the pressure induced depolarization. Thus, inhibition of Ca2+ sparks by ryanodine, or of KCa channels by iberiotoxin, leads to membrane depolarization, activation of L-type voltage-gated Ca2+ channels, and vasoconstriction. Conversely, activation of Ca2+ sparks can lead to vasodilation through activation of KCa channels. Our recent work is aimed at studying the properties and roles of Ca2+ sparks in the regulation of arterial smooth muscle function. The modulation of Ca2+ spark frequency and amplitude by membrane potential, cyclic nucleotides and protein kinase C will be explored. The role of local Ca2+ entry through voltage-dependent Ca2+ channels in the regulation of Ca2+ spark properties will also be examined. Finally, using functional evidence from cardiac myocytes, and histological evidence from smooth muscle, we shall explore whether Ca2+ channels, RyR channels, and KCa channels function as a coupled unit, through Ca2+ and voltage, to regulate arterial smooth muscle membrane potential and vascular tone.

The molecular bases of inwardly rectifying K(+) (Kir) currents and K(+)-induced dilations were examined in cerebral arteries of mice that lack the Kir2.1 and Kir2.2 genes. The complete absence of the open reading frame in animals homozygous for the targeted allele was confirmed. Kir2.1(-/-) animals die 8 to 12 hours after birth, apparently due to a complete cleft of the secondary palate. In contrast, Kir2.2(-/-) animals are viable and fertile. Kir currents were observed in cerebral artery myocytes isolated from control neonatal animals but were absent in myocytes from Kir2.1(-/-) animals. Voltage-dependent K(+) currents were similar in cells from neonatal control and Kir2.1(-/-) animals. An increase in the extracellular K(+) concentration from 6 to 15 mmol/L caused Ba(2+)-sensitive dilations in pressurized cerebral arteries from control and Kir2.2 mice. In contrast, arteries from Kir2.1(-/-) animals did not dilate when the extracellular K(+) concentration was increased to 15 mmol/L. In summary, Kir2.1 gene expression in arterial smooth muscle is required for Kir currents and K(+)-induced dilations in cerebral arteries.

During their reproductive years, women have a much lower incidence of coronary heart disease compared with men of similar age. Estrogen appears to be largely responsible for this decrease in cardiovascular mortality in women. In the present study, isolated pressurized coronary arteries from rats were used to assess the role of gender and circulating estrogen on coronary vascular function. Pressure-induced constrictions ("myogenic tone") were greater (approximately 2-fold) in isolated coronary arteries from estrogen-deficient male or ovariectomized (OVX) rats compared with similar arteries obtained from female rats or OVX rats receiving physiological levels of estrogen replacement (OVX+E group). These differences in coronary artery diameter were abolished by removal of the vascular endothelium or chemical inhibition of NO synthase. The anti-estrogen, tamoxifen, increased pressure-induced constrictions of coronary arteries from female and OVX+E rats. Dilations of pressurized coronary arteries from female and OVX animals to sodium nitroprusside, a nitrovasodilator that generates NO, were reduced by > 50% by iberiotoxin (IBTX), an inhibitor of Ca(2+)-dependent K+ (KCa) channels. Sodium nitroprusside (10 mumol/L) hyperpolarized coronary arteries by 13 +/- 2 mV, an effect that was greatly diminished (approximately 80%) by IBTX. Coronary arteries isolated from female rats produced greater constrictions in response to IBTX and KT 5823, an inhibitor of cGMP-dependent protein kinase, compared with coronary arteries from OVX rats. cGMP-dependent protein kinase increased the activity of KCa channels 16.5 +/- 5-fold in excised membrane patches from smooth muscle cells enzymatically isolated from these small coronary arteries. We propose that physiological levels of circulating 17 beta-estradiol elevate basal NO release from the endothelial cells, which increases the diameter of pressurized coronary arteries. Further, our results suggest that part of the effect of this NO is through activation of KCa channels in the smooth muscle cells of the coronary arteries.

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We used patch clamp to study whole‐cell K+ currents activated by calcitonin gene‐related peptide (CGRP) in smooth muscle cells freshly dissociated from pig coronary arteries. CGRP (50 nm) activated an inward current at −60 mV in symmetrical 140 mm K+ that was blocked by glibenclamide (10 μm), an inhibitor of ATP‐sensitive potassium (KATP) channels. CGRP‐induced currents were larger in cells dialysed with 0.1 mm ATP than with 3.0 mm ATP. Forskolin (10 μm) activated a glibenclamide‐sensitive current, as did intracellular dialysis with cAMP (100 μm). The catalytic subunit of cAMP‐dependent protein kinase (protein kinase A, PKA), added to the pipette solution, activated equivalent currents in five out of twelve cells. CGRP‐induced currents were reduced by the PKA inhibitors adenosine 3′,5′‐cyclic monophosphorothioate, RP‐isomer, triethylammonium salt (Rp‐cAMPS; 100 μm) and N‐[2‐((p‐bromocinnamyl)amino)ethyl]‐5‐isoquinolinesulphonamide dihydrochloride (H‐89; 1 μm), and abolished by inclusion of a PKA inhibitor peptide in the pipette solution. The β‐adrenergic agonist isoprenaline (10 μm) also activated a glibenclamide‐sensitive K+ current. CGRP‐induced currents were unaffected by the inhibitor of cGMP‐dependent protein kinase (PKG) KT5823 (1 μm). Sodium nitroprusside (10 μm) did not activate a glibenclamide‐sensitive current in cells held at −60 mV, but did activate an outward current at +60 mV that was abolished by KT5823, or by 100 nm iberiotoxin (an inhibitor of BKCa channels). Our findings suggest that CGRP activates coronary KATP channels through a pathway that involves adenylyl cyclase and PKA, but not PKG.

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...

The cellular events that cause ischemic neurological damage following aneurysmal subarachnoid hemorrhage (SAH) have remained elusive. We report that subarachnoid blood profoundly impacts communication within the neurovascular unit-neurons, astrocytes, and arterioles-causing inversion of neurovascular coupling. Elevation of astrocytic endfoot Ca 2+ to ∼400 nM by neuronal stimulation or to ∼300 nM by Ca 2+ uncaging dilated parenchymal arterioles in control brain slices but caused vasoconstriction in post-SAH brain slices. Inhibition of K + efflux via astrocytic endfoot large-conductance Ca 2+ -activated K + (BK) channels prevented both neurally evoked vasodilation (control) and vasoconstriction (SAH