Effects of thromboxane synthetase inhibitor (RS-5186) on experimentally-induced cerebral vasospasm

Takeuchi, Hirochika; Tanabe, Michiharu; Okamoto, Hisayo; Yamazaki, Mitsuo

doi:10.1080/01616412.1999.11740967

Cited by 20 publications

(14 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, by increasing levels of TxA 2 synthase, testosterone may enhance cerebrovascular constriction by a number of agents. Increased levels of TxA 2 in cerebral arteries also would increase the risk of thrombosis, vasospasm (39), and ischemic injury (20). The impact of cerebrovascular TxA 2 is highly relevant during pathophysiological conditions such as endothelial dysfunction (3,4,22,41), cerebral vasomotion (22,39), oxidative stress (4,19), hypoxia (38), and stroke (20).…”

Section: Discussionmentioning

confidence: 99%

“…The supernatant was discarded, and pellets were resuspended in cold PBS. The mixture was layered over a 15% dextran solution (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) and separated by centrifugation (1,300 g for 30 -40 min at 4°C), and the pellet containing blood vessels was collected and washed with ice-cold PBS over a nylon mesh (50 m). Next, vessels were collected from the mesh using fine tip forceps and transferred to a small glass homogenizer containing lysis buffer (4°C).…”

Section: Western Blot Analysismentioning

confidence: 99%

See 1 more Smart Citation

Testosterone treatment increases thromboxane function in rat cerebral arteries

Gonzales¹,

Ghaffari²,

Duckles³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

We previously showed that testosterone, administered in vivo, increases the tone of cerebral arteries. A possible underlying mechanism is increased vasoconstriction through the thromboxane A2 (TxA2) pathway. Therefore, we investigated the effect of chronic testosterone treatment (4 wk) on TxA2 synthase levels and the contribution of TxA2 to vascular tone in rat middle cerebral arteries (MCAs). Using immunofluorescence and confocal microscopy, we demonstrated that TxA2 synthase is present in MCA segments in both smooth muscle and endothelial layers. Using Western blot analysis, we found that TxA 2 synthase protein levels are higher in cerebral vessel homogenates from testosteronetreated orchiectomized (ORXϩT) rats compared with orchiectomized (ORX) control animals. Functional consequences of changes in cerebrovascular TxA2 synthase were determined using cannulated, pressurized MCA segments in vitro. Constrictor responses to the TxA2 mimetic U-46619 were not different between the ORXϩT and ORX groups. However, dilator responses to either the selective TxA 2 synthase inhibitor furegrelate or the TxA2-endoperoxide receptor (TP) antagonist SQ-29548 were greater in the ORXϩT compared with ORX group. In endothelium-denuded arteries, the dilation to furegrelate was attenuated in both the ORX and ORXϩT groups, and the difference between the groups was abolished. These data suggest that chronic testosterone treatment enhances TxA 2-mediated tone in rat cerebral arteries by increasing endothelial TxA 2 synthesis without altering the TP receptors mediating constriction. The effect of in vivo testosterone on cerebrovascular TxA 2 synthase, observed here after chronic hormone administration, may contribute to the risk of vasospasm and thrombosis related to cerebrovascular disease. thromboxane synthase; cerebral circulation; vascular smooth muscle; endothelium ALTHOUGH THE RISK for cardiovascular disease and stroke is higher in males, the influence of testosterone on vascular function is not well understood (25). This lack of information also fuels concerns about the vascular impact of testosterone therapy for elderly men (33) and postmenopausal women (28) as well as the use of anabolic androgens in young athletes, both male and female (30). Androgens appear to influence a variety of cardiovascular risk factors including lipid profile, platelet aggregation, blood pressure, and vascular reactivity (1,25,31,44). Data on vascular reactivity, however, are limited and often conflicting. For example, acute exposure of arteries to testosterone has been found to cause either vasodilation or vasoconstriction (6,7,25,40,43), whereas chronic testosterone exposure in vivo results in increased vascular tone (13)(14)(15)31). A better understanding of how testosterone modulates vascular function is needed to explain these observations. In the cerebral circulation, the critical vascular bed in stroke, arterial tone is elevated after in vivo treatment with testosterone (14, 15, 31). Using rat middle cerebral arteries (MCAs), we demonstrated th...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

Testosterone treatment increases thromboxane function in rat cerebral arteries

Gonzales¹,

Ghaffari²,

Duckles³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Enhanced turnover of fatty acids and increased formation of vasoconstrictor metabolites of arachidonic acid (AA) have also been observed after SAH (10,12). Previous reports that inhibitors of thromboxane synthesis ameliorate the fall in cerebral blood flow after SAH support a role for metabolites of AA in this response (24,42).…”

mentioning

confidence: 97%

20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat

Kehl¹,

Cambj-Sapunar²,

Maier³

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

man. 20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat. Am J Physiol Heart Circ Physiol 282: H1556-H1565, 2002. First published December 6, 2001 10.1152/ajpheart.00924.2001.-This study examined the effects of blocking the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) on the acute fall in cerebral blood flow after subarachnoid hemorrhage (SAH) in the rat. In vehicle-treated rats, regional cerebral blood flow (rCBF) measured with laser-Doppler flowmetry fell by 30% 10 min after the injection of 0.3 ml of arterial blood into the cisterna magna, and it remained at this level for 2 h. Pretreatment with inhibitors of the formation of 20-HETE, 17-octadecynoic acid (17-ODYA; 1.5 nmol intrathecally) and N-hydroxy-NЈ-(4-butyl-2-methylphenyl)formamidine (HET0016; 10 mg/kg iv), reduced the initial fall in rCBF by 40%, and rCBF fully recovered 1 h after induction of SAH. The concentration of 20-HETE in the cerebrospinal fluid rose from 12 Ϯ 2 to 199 Ϯ 17 ng/ml after SAH in vehicle-treated rats. 20-HETE levels averaged only 15 Ϯ 11 and 39 Ϯ 13 ng/ml in rats pretreated with 17-ODYA or HET0016, respectively. HET0016 selectively inhibited the formation of 20-HETE in rat renal microsomes with an IC50 of Ͻ15 nM and human recombinant CYP4A11, CYP4F2, and CYP4F3 enzymes with an IC50 of 42, 125, and 100 nM, respectively. These results indicate that 20-HETE contributes to the acute fall in rCBF after SAH in rats.

show abstract

“…Subarachnoid hemorrhage and traumatic brain injury are often associated with instability of the cerebrovascular tone, which may initiate diffuse angiospastic reactions. 12 The loss of endothelial NO formation, [13][14][15] increased thromboxane levels, 16 and the action of different vasoconstrictor metabolites, especially nucleotides, 17,18 are all capable of producing long-lasting vasospasm experimentally. The change of these parameters can be observed in patients with subarachnoid hemorrhage or clinical vasospasm; however, therapeutic approaches are of limited success, partly because the mechanism of the development of vasospasm is still not well characterized.…”

mentioning

confidence: 99%

NO Synthase Blockade Induces Chaotic Cerebral Vasomotion via Activation of Thromboxane Receptors

Lacza¹,

Hermán²,

Görlach³

et al. 2001

Stroke

View full text Add to dashboard Cite

Background and Purpose-Instability of the vascular tone (vasomotion) develops in several cerebrovascular diseases associated with endothelial dysfunction. The aim of the present study was to characterize cerebral vasomotion induced by diminished NO production with quantitative evaluation and chaos analysis. We tested the hypothesis that activation of thromboxane receptors mediates chaotic vasomotion after NO synthase (NOS) inhibition. Methods-Measurements of vascular tension were carried out in isolated rat middle cerebral arteries. The extent of vasomotion was characterized by tension instability, whereas vasomotion complexity was assessed by chaos analysis. Results-Blocking the basal NO release by N -nitro-L-arginine (L-NA) induced vasomotion, which was further enhanced and became irregular after UTP administration. The NO donor sodium nitroprusside was able to reverse this effect, and stable steady-state conditions reappeared. The guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) or coapplication of ODQ and L-NA had an effect identical to that of L-NA alone. Vasoconstriction by K ϩ failed to induce vasomotion in intact vessels or in the presence of L-NA or ODQ. The thromboxane receptor antagonist ICI 192605 dose-dependently attenuated the vasomotion induced by L-NA and UTP, and the thromboxane-receptor agonist U-46619 induced significant vasomotion in intact vessels. Conclusions-The lack of NO in cerebral vessels provokes vulnerability to chaotic vasomotion, which can be triggered by the administration of UTP, whereas excess NO reverses it to stable conditions. The vasomotion after blockade of the NO-cGMP pathway is mediated by activation of thromboxane receptors.

show abstract

Effects of thromboxane synthetase inhibitor (RS-5186) on experimentally-induced cerebral vasospasm

Cited by 20 publications

References 0 publications

Testosterone treatment increases thromboxane function in rat cerebral arteries

Testosterone treatment increases thromboxane function in rat cerebral arteries

20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat

NO Synthase Blockade Induces Chaotic Cerebral Vasomotion via Activation of Thromboxane Receptors

Contact Info

Product

Resources

About