The role of endothelin and nitric oxide in modulation of normal and spastic cerebral vascular tone in the dog

Hirose, Hiroyasu; Ide, Katsuhisa; Sasaki, Tatsuya; Takahashi, Rena; Kobayashi, Masahiko; Ikemoto, Fumihiko; Yano, Mitsuo; Nishikibe, Masaru

doi:10.1016/0014-2999(95)00070-2

Cited by 63 publications

(28 citation statements)

References 32 publications

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“…Part of this effect may relate to the ability of hemoglobin to bind the vasodilator nitric oxide, but oxyhemoglobin also produces free radicals, which could induce vasospasm by means of several mechanisms. The demonstration of the effectiveness of endothelin antagonists 36 and nitric oxide donors 37,38 in the management of vasospasm after experimental SAH holds further promise in the treatment of the condition. Furthermore, activation of the renin-angiotensin system seems to be of importance in the SAH condition, although no firm relationship could be found with regard to vasospasm and ECG changes in a small patient study.…”

Section: Discussionmentioning

confidence: 99%

Increased Sympathetic Nervous Activity in Patients With Nontraumatic Subarachnoid Hemorrhage

Naredi

Lambert

Edén

et al. 2000

Stroke

309

186

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Background and Purpose-Activation of the sympathetic nervous system, which leads to elevation of circulating catecholamines, is implicated in the genesis of cerebral vasospasm and cardiac aberrations after subarachnoid hemorrhage. To this juncture, sympathetic nervous testing has relied on indirect methods only. Methods-We used an isotope dilution technique to estimate the magnitude and time course of sympathoadrenal activation in 18 subarachnoid patients. Results-Compared with 2 different control groups, the patients with subarachnoid hemorrhage exhibited an approximately 3-fold increase in total-body norepinephrine spillover into plasma within 48 hours after insult (3.2Ϯ0.3 and 4.2Ϯ0.7 versus 10.2Ϯ1.4 nmol/L; PϽ0.05 versus both). This sympathetic activation persisted throughout the 7-to 10-day examination period and was normalized at the 6-month follow-up visit. Conclusions-The present study has established that massive sympathetic nervous activation occurs in patients after subarachnoid hemorrhage. This overactivation may relate to the well-known cardiac complications described in subarachnoid hemorrhage. (Stroke. 2000;31:901-906.)

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Section: Discussionmentioning

confidence: 99%

Increased Sympathetic Nervous Activity in Patients With Nontraumatic Subarachnoid Hemorrhage

Naredi

Lambert

Edén

et al. 2000

Stroke

309

186

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“…It has been reported that forearm blood flow increases in humans 18 and dog cerebral arteries dilate 19 after ET-1 receptor blockade. Our results demonstrate that the constitutive release of endotheliumderived ET-1 affects smooth muscle cell sensitivity in vitro and facilitates PE-induced contraction of isolated rat MCA; in the presence of BQ123 or bosentan, contractile responses to the ␣ 1 -adrenergic receptor agonist were shifted to the right without change in maximum responses (Fig 2A, Table 2).…”

Section: Vascular Reactivity To ␣ 1 -Adrenergic Agonist and Etmentioning

confidence: 99%

Endothelin-1 Regulates Tone of Isolated Small Arteries in the Rat

1998

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Abstract-Chronic elevation of plasma endothelin-1 (ET-1) levels has been reported in several pathological conditions. To investigate the consequences of increased circulating ET-1 on vascular responsiveness, Sprague-Dawley rats (nϭ16) were chronically instrumented with a minipump delivering ET-1 at a constant dose for 7 days. Plasma ET-1 levels were more than doubled in treated (0.98Ϯ0.09 pmol/L; PϽ.05) versus untreated sham-operated rats (0.43Ϯ0.04 pmol/L), whereas systolic arterial blood pressure increased (139Ϯ5 versus 128Ϯ4 mm Hg in untreated rats; PϽ.05). After rats were killed, segments of middle cerebral (MCA) and mesenteric (MES) arteries were mounted on an isometric myograph. ET-induced contraction was shifted to the right in ET-1-treated animals and not modified by BQ123 (an ET A receptor antagonist); bosentan (ET A/B receptor antagonist) prevented ET-1-induced contraction in both groups. After inhibition of nitric oxide synthase with N -nitro-L-arginine (L-NNA), both phenylephrine and oxymetazoline (an ␣ 2 -adrenoceptor agonist) induced MCA contraction. The sensitivity to phenylephrine was decreased in ET-1-treated compared with control rats (PϽ.05). Sensitivity to phenylephrine-induced contraction was decreased by BQ123 in control rats only. In contrast, L-NNA revealed greater oxymetazoline-induced contractions in treated compared with control MCA rings (PϽ.05); this potentiation was blunted by bosentan but unaffected by BQ123. Removal of the endothelium revealed a direct constrictor effect of oxymetazoline that was insensitive to L-NNA alone or combined with bosentan; however, oxymetazoline induced significantly lower constriction in treated rat MCA segments. Responses to oxymetazoline were also blunted in treated compared with untreated denuded MES arteries. In conclusion, chronic elevated plasmatic ET-1 decreases smooth muscle cell sensitivity to contractile agonists both in MCA and MES rings. In cerebral vessels, endothelial ␣ 2 -adrenoceptor-dependent stimulation induced greater contractile responses in treated rats which were sensitive to bosentan, suggesting that oxymetazoline stimulates ET-1 release from the endothelium. This may represent a compensatory mechanism for the loss of smooth muscle sensitivity. (Hypertension. 1998;31:1035-1041.)

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“…In addition to this indirect evidence, more direct demonstrations have been made in various animal models of cerebral vasospasm using endothelin receptor antagonists. In dogs (mostly double-hemorrhage model), cerebral vasospasm was effectively ameliorated by the following treatments: intracisternal administration of FR139317 (211) or phosphoramidon (212), continuous intrathecal infusion of BQ-123 (209,213), intracisternal administration of SB 209670 (214) or intravenous administration of bosentan (215). With respect to the pathogenesis of cerebral vasospasm, the attractively straightforward "endothelin hypothesis" appears to be supported by several different lines of experimental data, and suggests that an abluminal clot may stimulate endothelial cells in a cerebral artery to produce endothPlin-1…”

Section: V-4 Brain Injury and Cerebral Vasospasmmentioning

confidence: 99%

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Goto

Hama

Kasuya

1996

Japanese Journal of Pharmacology

159

108

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ABSTRACT-Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelia converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may

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The role of endothelin and nitric oxide in modulation of normal and spastic cerebral vascular tone in the dog

Cited by 63 publications

References 32 publications

Increased Sympathetic Nervous Activity in Patients With Nontraumatic Subarachnoid Hemorrhage

Increased Sympathetic Nervous Activity in Patients With Nontraumatic Subarachnoid Hemorrhage

Endothelin-1 Regulates Tone of Isolated Small Arteries in the Rat

Molecular Pharmacology and Pathophysiological Significance of Endothelin

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