Nitric oxide synthase and guanylate cyclase levels in canine basilar artery after subarachnoid hemorrhage

Kasuya, Hidetoshi; Weir, Bryce; Nakane, Masaki; Pollock, Jennifer S.; Johns, Lydia; Marton, Linda S.; Stefánsson, Kāri

doi:10.3171/jns.1995.82.2.0250

Cited by 90 publications

(38 citation statements)

References 29 publications

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“…eNOS protein expression was unchanged in spastic canine basilar arteries 7 days after SAH. 18 The reduction in eNOS protein observed by Park et al 19 occurred only 20 minutes after SAH, while the 56% reduction in eNOS mRNA reported by Hino et al 20 was not accompanied by a decrease in ipsilateral brain eNOS protein 7 days after SAH. Similarly, our study did not find an effect of SAH on eNOS protein 3 days after SAH.…”

Section: Discussionmentioning

confidence: 85%

Simvastatin Increases Endothelial Nitric Oxide Synthase and Ameliorates Cerebral Vasospasm Resulting From Subarachnoid Hemorrhage

McGirt

Lynch

Parra

et al. 2002

Stroke

227

178

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Background and Purpose-Endothelial nitric oxide synthase (eNOS) activity is decreased after subarachnoid hemorrhage (SAH). Simvastatin increases eNOS activity. We hypothesized that simvastatin would increase eNOS protein and ameliorate SAH-induced cerebral vasospasm. Methods-Mice were treated with subcutaneous simvastatin or vehicle for 14 days and then subjected to endovascular perforation of the right anterior cerebral artery or sham surgery. Three days later, neurological deficits were scored (5 to 27; 27ϭnormal), and middle cerebral artery diameter and eNOS protein were measured. The study was repeated, but simvastatin treatment was started after SAH or sham surgery. Results-In SAH mice, simvastatin pretreatment increased middle cerebral artery diameter (SAH-simvastatinϭ74Ϯ22 m, SAH-vehicleϭ52Ϯ18 m, Pϭ0.03; sham-simvastatinϭ102Ϯ8 m, sham-vehicleϭ105Ϯ6 m). Pretreatment reduced neurological deficits Pϭ0.005;. Simvastatin pretreatment also increased eNOS protein. Simvastatin posttreatment caused a modest increase in middle cerebral artery diameter in SAH mice (SAH-simvastatinϭ56Ϯ12 m, SAH-vehicleϭ45Ϯ4 m, Pϭ0.03; sham-simvastatinϭ92Ϯ13 m, sham-vehicleϭ99Ϯ10 m) and reduced neurological deficits (SAH-simvastatinϭ21Ϯ1, Pϭ0.009). Simvastatin posttreatment did not significantly increase eNOS protein. Conclusions-Simvastatin treatment before or after SAH attenuated cerebral vasospasm and neurological deficits in mice.The mechanism may be attributable in part to eNOS upregulation. Key Words: HMG-CoA reductase inhibitors Ⅲ simvastatin Ⅲ subarachnoid hemorrhage Ⅲ vasospasm Ⅲ mice D elayed cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Current medical treatments fail to consistently prevent or reverse vasospasm. 1 The etiology of vasospasm may result from an imbalance of vasodilation and vasoconstriction. 2 Vascular endothelium regulates smooth muscle tone by generating nitric oxide (NO) 3 and endothelial-derived constriction factors. 4 Disruption of endothelium or its relaxing factors may alter this balance, initiating vasospasm. 5 SAH has been associated with histopathological damage to cerebrovascular endothelium and impaired endothelium-dependent relaxation responses to pharmacological challenge. 1,6 NO depletion accompanies these changes, suggesting that SAH-induced endothelial dysfunction contributes to loss of NO. Furthermore, NO replacement reverses cerebral vasospasm in animal studies. 7 However, it is not clear whether decreased endogenous NO production or increased NO breakdown underlies these changes in NO bioavailability.NO synthase, the primary source of NO in vascular tone regulation, metabolizes L-arginine to NO and citrulline. The endothelial isoform (eNOS) is constitutively expressed in cerebrovascular endothelium. Immunoreactivity for eNOS mRNA and protein has been shown to decrease after SAH. 8 Although the mechanism of eNOS reduction is not known, it likely causes reduction of NO production and disruption of endothelial-depen...

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Section: Discussionmentioning

confidence: 85%

Simvastatin Increases Endothelial Nitric Oxide Synthase and Ameliorates Cerebral Vasospasm Resulting From Subarachnoid Hemorrhage

McGirt

Lynch

Parra

et al. 2002

Stroke

227

178

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“…21,22 Direct NOindependent stimulators of sGC have been developed recently based on the derivative YC-1. 19 The cysteine 238 and cysteine 243 spanning region in the ␣-subunit of the enzyme was identified as part of the target site for BAY 41-2272, in addition to the heme group.…”

Section: Discussionmentioning

confidence: 99%

Vasorelaxing Effect of BAY 41-2272 in Rat Basilar Artery

et al. 2006

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Abstract-Decreases in intrinsic NO cause cerebral vasospasms because of the dysregulation of cGMP formation by NO-mediated pathways. Because 5-cyclopropyl-2-{1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl}pyrimidin-4-ylamine (BAY 41-2272) is a potent soluble guanylyl cyclase (sGC) stimulator in an NO-independent manner, this study aimed to investigate the mechanisms underlying the relaxant effects of BAY 41-2272 in the rat basilar artery. Key Words: nitric oxide Ⅲ cyclic GMP Ⅲ nitric oxide synthase N itric oxide (NO) derived from perivascular nerve fibers and endothelial cells acts as vasodilator for the smooth muscle in the wall of cerebral arteries and, hence, plays an essential role in the regulation of cerebral blood flow under physiological and pathological conditions. 1-3 Physiologically, NO is produced by NO synthase (NOS) present in the endothelium (eNOS) and nerves (nNOS) to maintain a basal cerebrovasodilator tone. Conversely, inhibitors of NOS constrict cerebral arteries in vitro 4,5 and decrease cerebral blood flow in vivo. 6,7 NO promotes relaxation of the vascular smooth muscle of cerebral arteries through stimulation of soluble guanylyl cyclase (sGC). 8 -10 The binding of NO to the heme portion of the enzyme results in cGMP accumulation, which causes smooth muscle relaxation via different mechanisms, including activation of K ϩ channels, desensitization of the contractile proteins, and reduction in intracellular Ca 2ϩ concentration. 11 Impairment of NO-mediated vasodilation accounts for the pathogenesis of cerebral vasospasm. 12,13 Indeed, an inappropriate activation of sGC has been linked to various pathological conditions affecting the cardiovascular system. 14 Although the administration of NO donors to rats with stroke causes brain cGMP levels to increase, induces cell genesis, and improves functional recovery, 15 there are certain disadvantages with NO donor-based therapies, such as the unpredictable pharmacokinetics of NO, development of tolerance, and peroxinitrite formation that can lead to protein S-nitrosylation, as well as tyrosine nitration. 16 -18 Therefore, compounds that activate sGC in an NO-independent manner represent a promising therapeutic strategy.The non-NO-based pyrazolopyridine 5-cyclopropyl-2-{1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl}pyrimidin-4-ylamine (BAY 41-2272) represents a new therapeutic principle that directly stimulates sGC and increases the sensitivity of the enzyme to NO. 19 This is the primary mechanism through which BAY 41-2272 produces antiplatelet activity, strong decreases in blood pressure, and vasorelaxation. 19,20 This study was designed to identify the mechanisms involved in the relaxations of rat basilar artery induced by BAY 41-2272. We also sought to test the hypothesis that direct stimulation of sGC by BAY 41-2272 relaxes this vessel in a synergistic fashion with endogenous NO.

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“…At 7 days post-SAH in the rat, a significant decrease in NOS-3 mRNA (-56%) was found (122), although another group found a non-significant decrease (-22%) in NOS-3 protein, but a substantial fall in soluble cyclic guanylate cyclase (123). In the rat femoral artery model, perivascular blood clot induced biphasic changes in NOS-3 protein levels; i.e., increase at 3 days and decrease (-39%) at 7 days (124).…”

Section: Nos Expression /Activity After Sahmentioning

confidence: 99%

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

Sercombe

Dinh

Gomis

2002

Japanese Journal of Pharmacology

184

140

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ABSTRACT-Aneurysmal subarachnoid hemorrhage frequently results in complications including intracranial hypertension, rebleeding and vasospasm. The extravasated blood is responsible for a cascade of reactions involving release of various vasoactive and pro-inflammatory factors (several of which are purported to induce vasospasm) from blood and vascular components in the subarachnoid space. The authors review the available evidence linking these factors to the development of inflammatory lesions of the cerebral vasculature, emphasizing: 1) neurogenic inflammation due to massive release of sensory nerve neuropeptides; 2) hemoglobin from lysed erythrocytes, which creates functional lesions of endothelial and smooth muscle cells; 3) activity, expression and metabolites of lipoxygenases cyclooxygenases and nitric oxide synthases; 4) the possible role of endothelin-1 as a pro-inflammatory agent; 5) serotonin, histamine and bradykinin which are especially involved in blood-brain barrier disruption; 6) the prothrombotic and pro-inflammatory action of complement and thrombin towards endothelium; 7) the multiple actions of activated platelets, including platelet-derived growth factor production; 8) the presence of perivascular and intramural macrophages and granulocytes and their interaction with adhesion molecules; 9) the evolution, origins, and effects of pro-inflammatory cytokines, especially IL-1, TNF-a and IL-6. Human and animal studies on the use of anti-inflammatory agents in subarachnoid hemorrhage include superoxide and other radical scavengers, lipid peroxidation inhibitors, iron chelators, NSAIDs, glucocorticoids, and serine protease inhibitors. Many animal studies claim reduced vasospasm, but these effects are not always confirmed in human trials, where symptomatic vasospasm and outcome are the major endpoints. Despite recent work on penetrating vessel constriction, there is a paucity of studies on inflammatory markers in the microcirculation.

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Nitric oxide synthase and guanylate cyclase levels in canine basilar artery after subarachnoid hemorrhage

Cited by 90 publications

References 29 publications

Simvastatin Increases Endothelial Nitric Oxide Synthase and Ameliorates Cerebral Vasospasm Resulting From Subarachnoid Hemorrhage

Simvastatin Increases Endothelial Nitric Oxide Synthase and Ameliorates Cerebral Vasospasm Resulting From Subarachnoid Hemorrhage

Vasorelaxing Effect of BAY 41-2272 in Rat Basilar Artery

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

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