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

Lacza, Zsombor; Hermán, Péter; Görlach, Christoph; Hortobágyi, Tibor; Sándor, Péter; Wahl, Michael; Benyó, Zoltán

doi:10.1161/hs1101.098526

Cited by 38 publications

(35 citation statements)

References 41 publications

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“…Our data agree with earlier reports of TxA 2 activity in cerebral arteries (3,22,23,36,41). We demonstrated functional consequences of vascular TxA 2 production using isolated, pressurized segments of MCAs that were pretreated with the NO synthase inhibitor L-NAME.…”

Section: Discussionsupporting

confidence: 93%

“…Similar to Benyo et al (3), we used NO synthase inhibition to preconstrict the arteries and enhance the relatively weak dilator responses to furegrelate and SQ-29548. Many studies suggest that NO modulates vascular prostanoid production (3,22,38,42), which may explain why block of NO synthesis allowed us to study the contribution of TxA 2 to basal tone. Similarly, inhibition of NO production was found to enhance the prostacyclin prostanoid pathway in cerebral blood vessels (24).…”

Section: Discussionmentioning

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

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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...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

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

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“…This was attributed to loss of endothelium-derived NO and failure to activate a cGMP-dependent depolarizing current essential for the initiation of agonist-induced vasomotion in this vessel (11,41). In contrast, in the present study, incubation with the NO synthase inhibitor L-NAME augmented vasomotion of the basilar artery and improved the synchronization of [Ca 2ϩ ] i oscillations in individual smooth muscle cells, consistent with previous studies of cerebral artery vasomotion (5,17,24). Furthermore, a cGMP-activated depolarizing current is unlikely to be important for initiating vasomotion in the basilar artery because the smooth muscle membrane potential was not altered by endothelium removal or inhibition of NO.…”

Section: Discussionsupporting

confidence: 90%

Endothelial coordination of cerebral vasomotion via myoendothelial gap junctions containing connexins 37 and 40

Haddock

Grayson²,

Brackenbury³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

115

116

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Control of cerebral vasculature differs from that of systemic vessels outside the blood-brain barrier. The hypothesis that the endothelium modulates vasomotion via direct myoendothelial coupling was investigated in a small vessel of the cerebral circulation. In the primary branch of the rat basilar artery, membrane potential, diameter, and calcium dynamics associated with vasomotion were examined using selective inhibitors of endothelial function in intact and endothelium-denuded arteries. Vessel anatomy, protein, and mRNA expression were studied using conventional electron microscopy high-resolution ultrastructural and confocal immunohistochemistry and quantitative PCR. Membrane potential oscillations were present in both endothelial cells and smooth muscle cells (SMCs), and these preceded rhythmical contractions during which adjacent SMC intracellular calcium concentration ([Ca 2ϩ ]i) waves were synchronized. Endothelium removal abolished vasomotion and desynchronized adjacent smooth muscle cell [Ca 2ϩ ]i waves. N G -nitro-L-arginine methyl ester (10 M) did not mimic this effect, and dibutyryl cGMP (300 M) failed to resynchronize [Ca 2ϩ ]i waves in endothelium-denuded arteries. Combined charybdotoxin and apamin abolished vasomotion and depolarized and constricted vessels, even in absence of endothelium. Separately, 37,43 Gap27 and 40 Gap27 abolished vasomotion. Extensive myoendothelial gap junctions (3 per endothelial cell) composed of connexins 37 and 40 connected the endothelial cell and SMC layers. Synchronized vasomotion in rat basilar artery is endothelium dependent, with [Ca 2ϩ ]i waves generated within SMCs being coordinated by electrical coupling via myoendothelial gap junctions.connexin; electron microscopy; endothelial function; potassium channel; membrane potential VASOMOTION is an intrinsic feature of many arteries and arterioles under normal and pathological conditions and may contribute to regulation of blood flow and pressure (1,14). Both spontaneous and agonist-induced vasomotion occur when oscillations in the concentration of intracellular calcium ([Ca 2ϩ ] i ) become synchronized among adjacent smooth muscle cells, giving rise to global oscillations in [Ca 2ϩ ] i across the vessel wall (13,15,26,27,33,41,(47)(48)(49).There is clear heterogeneity in the mechanisms that underlie vasomotion, and specifically whether the endothelium plays a mandatory or modulatory role. In the rat iris arteriole, rabbit ear, and superior mesenteric artery, vasomotion is reported to be endothelium independent (3, 18, 39), whereas in the rat mesenteric, rabbit femoral artery, and hamster aorta, vasomotion is suggested to be endothelium dependent, as shown by its abolition with endothelium denudation (12,21,34,38,40).Endothelium-dependent effects on vasomotion have been attributed to the vasodilatory factors nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). In some studies, endothelial cells play an essential role in synchronizing the activity of smooth muscle cells through the rel...

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“…This finding is particularly interesting in the light of our previous observations showing that the cerebral vasoconstriction induced by inhibition of the resting NO synthesis is partly due to the increased reactivity of the cerebral vessels to TXA 2 (Benyó et al, 1998;Lacza et al, 2001a). During chronic NOS blockade, however, the reduction of vasoconstrictor prostanoid release may compensate this vascular hyperreactivity and contribute to the normalization of the cerebral vascular resistance and blood flow.…”

Section: Discussionmentioning

confidence: 54%

Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids

et al. 2007

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The aim of our study was to investigate the adaptation of the hypothalamic circulation to chronic nitric oxide (NO) deficiency in rats. Hypothalamic blood flow (HBF) remained unaltered during chronic oral administration of the NO synthase (NOS) inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 1 mg/ml drinking water) although acute NOS blockade by intravenous L-NAME injection (50 mg/kg) induced a dramatic HBF decrease. In chronically NOS blocked animals, however, acute L-NAME administration failed to influence the HBF. Reversal of chronic NOS blockade by intravenous L-arginine infusion evoked significant hypothalamic hyperemia suggesting the appearance of a compensatory vasodilator mechanism in the absence of NO. In order to clarify the potential involvement of vasodilator prostanoids in this adaptation, cyclooxygenase (COX) mRNA and protein levels were determined in the hypothalamus, but none of the known isoenzymes (COX-1, COX-2, COX-3) showed upregulation after chronic NOS blockade. Furthermore, levels of vasodilator prostanoid (PGI 2 , PGE 2 and PGD 2 ) metabolites were also not elevated. Interestingly, however, hypothalamic levels of vasoconstrictor prostanoids (TXA 2 and PGF 2α ) decreased after chronic NOS blockade. COX inhibition by indomethacin but not by diclofenac decreased the HBF in control animals. However, neither indomethacin nor diclofenac induced an altered HBF-response after chronic L-NAME treatment. Although urinary excretion of PGI 2 and PGE 2 metabolites markedly increased during chronic NOS blockade, indicating COX activation in the systemic circulation, we conclude that the adaptation of the hypothalamic circulation to the reduction of NO synthesis is independent of vasodilator prostanoids. Reduced release of vasoconstrictor prostanoids, however, may contribute to the normalization of HBF after chronic loss of NO.

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

Cited by 38 publications

References 41 publications

Testosterone treatment increases thromboxane function in rat cerebral arteries

Testosterone treatment increases thromboxane function in rat cerebral arteries

Endothelial coordination of cerebral vasomotion via myoendothelial gap junctions containing connexins 37 and 40

Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids

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