Substance P‐induced relaxation and hyperpolarization in human cerebral arteries

Petersson, Jesper; Zygmunt, Peter M.; Brandt, Lennart; Högestätt, Edward D.

doi:10.1111/j.1476-5381.1995.tb15893.x

Cited by 58 publications

(40 citation statements)

References 40 publications

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“…24 Other endothelium-derived factors, such as EDHF, have been shown to be involved in the regulation of small artery tone and are likely to contribute to the vasorelaxant properties of acetylcholine. [25][26][27][28] We also observed an increased smooth muscle sensitivity to contractile agents. The maximal contraction elicited by 127 mmol/L KCl physiological salt solution was not different between the 2 groups of arteries, but responses to PE, serotonin, and an intermediate depolarizing solution were significantly greater in eNOS Ϫ arteries.…”

Section: Characterization Of Enos ؊ Micesupporting

confidence: 57%

Nitric Oxide Inhibits α ₂ -Adrenoceptor–Mediated Endothelium-Dependent Vasodilation

Thorin

Huang²,

Fishman³

et al. 1998

Circulation Research

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Abstract-This study was designed to investigate the interaction between the NO/L-arginine pathway and the ␣ 2 -adrenoceptor-mediated endothelium-dependent vasorelaxation. Reactivity of isolated resistance mesenteric arterial segments from mice lacking the gene for constitutive endothelial NO synthase (eNOS Ϫ mice, nϭ14) and from their wild-type controls (WT mice, nϭ46) was studied in isometric conditions in the presence of indomethacin (blocker of cyclooxygenase). Oxymetazoline (OXY, 0.01 to 30 mol/L; a selective ␣ 2 -adrenoceptor agonist) induced an endothelium-dependent relaxation of eNOS Ϫ but not WT arteries preconstricted either with phenylephrine or serotonin. In the presence of N -nitro-L-arginine (l-NNA, 100 mol/L), an inhibitor of NOS, OXY induced an endotheliumdependent relaxation of WT mesenteric arteries. l-NNA had no effect on the relaxation caused by OXY in eNOS Ϫ arterial rings. Therefore, the relaxation caused by OXY was independent of NO formation. To demonstrate the inhibitory role of NO on the ␣ 2 -adrenoceptor-mediated relaxation, subthreshold (0.1 nmol/L) to threshold (1 nmol/L) concentrations of sodium nitroprusside (donor of NO) were added to l-NNA-treated arteries before OXY challenges: in these conditions, the ␣ 2 -adrenoceptor-mediated relaxation of eNOS Ϫ and WT arteries was inhibited. OXY-induced relaxation was restored on readdition of methylene blue (1 mol/L, inhibitor of guanylate cyclase), suggesting that cGMP may be the mechanism of inhibition of the ␣ 2 -adrenergic pathway in the presence of NO. Finally, OXY-mediated relaxation was blocked by tetraethylammonium (1 mmol/L) but not glibenclamide (1 mol/L), suggesting the involvement of an endothelium-derived hyperpolarizing factor that activates Ca 2ϩ -activated K ϩ channels. In conclusion, ␣ 2 -adrenoceptor activation caused relaxation of isolated murine mesenteric arteries that was functionally blocked by NO through a mechanism that may involve activation of the soluble guanylate cyclase and cGMP formation. The endothelium-dependent ␣ 2 -adrenoceptor-mediated relaxation is likely to be due to an endothelium-derived hyperpolarizing factor, whose release and/or production is reduced by concurrent NO formation. (Circ Res. 1998;82:1323-1329.) Key Words: nitric oxide Ⅲ ␣ 2 -adrenoceptor Ⅲ vasodilation T he ␣ 2 -adrenoceptors are widely distributed in the cardiovascular system. Whereas activation of presynaptic ␣ 2 -adrenoceptors decreases sympathetic activity, 1,2 activation of smooth muscle ␣ 2 -adrenoceptors induces contraction.3,4 ␣ 2 -Adrenoceptors are also functionally expressed on the vascular endothelium. Their activation induces relaxation of isolated arteries from various vascular beds. [5][6][7] Most of the data gathered involving ␣ 2 -adrenoceptor-induced relaxation have been obtained from studies performed in large conductance vessels. 6,8 A few studies, however, have focused on the mechanisms coupling ␣ 2 -adrenoceptor activation and relaxation of resistance arteries, which are clearly different from those identified in ...

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Section: Characterization Of Enos ؊ Micesupporting

confidence: 57%

Nitric Oxide Inhibits α ₂ -Adrenoceptor–Mediated Endothelium-Dependent Vasodilation

Thorin

Huang²,

Fishman³

et al. 1998

Circulation Research

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“…EDHF is distinct from nitric oxide (NO) and prostanoids and contributes significantly to vasodilatation in several vascular regions in different species including man (Zygmunt et al, 1994a,b;Garland et al, 1995;Petersson et al, 1995). Although it is believed to be a diffusible factor, the identity of EDHF has not yet been established.…”

Section: Introductionmentioning

confidence: 99%

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Zygmunt

Edwards

Weston

et al. 1996

British J Pharmacology

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1 The possibility that the endothelium-derived hyperpolarising factor (EDHF) in the rat hepatic artery is a cytochrome P450 mono-oxygenase metabolite of arachidonic acid was examined in the present study. In this preparation, acetylcholine elicits EDHF-mediated relaxations in the presence of the nitric oxide (NO) synthase and cyclo-oxygenase inhibitors No-nitro-L-arginine (L-NOARG) and indomethacin, respectively.2 17-Octadecynoic acid (17-ODYA, 50 gM), a suicide-substrate inhibitor of the cytochrome P450 mono-oxygenases responsible for the production of 5, 8, 11,[12][13][14], had no effect on acetylcholine-induced relaxations in the presence of L-NOARG (0.3 mM) plus indomethacin (10 gM). Furthermore, 5, 8, 11, Clotrimazole (3 gM) was without effect on these responses. The relaxant actions of the NO donor, 3-morpholino-sydnonimine, were unaffected by proadifen (10 gM). 5 The relaxant effects of the opener of ATP-sensitive potassium channels, levcromakalim, were abolished by proadifen (10 gM) and strongly attenuated by clotrimazole (3 gM). Proadifen (10 gM) also abolished the hyperpolarization induced by levcromakalim (1 gM). 6 The lack of effect of 17-ODYA on relaxations mediated by EDHF, together with the failure of extracellularly-applied EETs to produce relaxation, collectively suggest that EDHF is not an EET in the rat hepatic artery. It seems likely that inhibition of ion channels in the smooth muscle rather than reduced EDHF formation in the endothelium offers a better explanation for the actions of the cytochrome P450 inhibitors proadifen and clotrimazole.

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“…[1][2][3][4] In common with peripheral arteries, the importance of EDHF appears to increase as vessel size decreases. 5,6 However, cerebrovascular smooth muscle does display a number of unique characteristics, so it is perhaps not surprising that the EDHF response, at least with certain agonists, also seems to have some unique features.…”

mentioning

confidence: 99%

“…10 A significant drawback in defining and interpreting such mechanisms is the small number of studies reporting direct measurements of hyperpolarization. To date, this is limited to responses in rabbit and rat middle cerebral arteries to ACh and ATP, respectively, and in human pial arteries to substance P, 3,6,11 in which smooth muscle hyperpolarization ranged between 15 and 25 mV. Furthermore, a recent study 10 used a voltage-sensitive dye in pressurized rat middle cerebral arteries to indirectly demonstrate endothelial cell hyperpolarization to UTP.…”

mentioning

confidence: 99%

Possible Role for K ⁺ in Endothelium-Derived Hyperpolarizing Factor–Linked Dilatation in Rat Middle Cerebral Artery

McNeish

Dora

Garland

2005

Stroke

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Background and Purpose-Endothelium-derived hyperpolarizing factor (EDHF) and K ϩ are vasodilators in the cerebral circulation. Recently, K ϩ has been suggested to contribute to EDHF-mediated responses in peripheral vessels. The EDHF response to the protease-activated receptor 2 ligand SLIGRL was characterized in cerebral arteries and used to assess whether K ϩ contributes as an EDHF. Methods-Rat middle cerebral arteries were mounted in either a wire or pressure myograph. Concentration-response curves to SLIGRL and K ϩ were constructed in the presence and absence of a variety of blocking agents. In some experiments, changes in tension and smooth muscle cell membrane potential were recorded simultaneously. Results-SLIGRL (0.02 to 20 mol/L) stimulated concentration and endothelium-dependent relaxation. In the presence of N G -nitro-L-arginine methyl ester, relaxation to SLIGRL was associated with hyperpolarization and sensitivity to a specific inhibitor of IK Ca , 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (1mol/L), reflecting activation of EDHF. Combined inhibition of K IR with Ba 2ϩ (30mol/L) and Na ϩ /K ϩ -ATPase with ouabain (1 mol/L) markedly attenuated the relaxation to EDHF. Raising extracellular [K ϩ ] to 15 mmol/L also stimulated smooth muscle relaxation and hyperpolarization, which was also attenuated by combined application of Ba 2ϩ and ouabain. Conclusions-SLIGRL evokes EDHF-mediated relaxation in the rat middle cerebral artery, underpinned by hyperpolarization of the smooth muscle.

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Substance P‐induced relaxation and hyperpolarization in human cerebral arteries

Cited by 58 publications

References 40 publications

Nitric Oxide Inhibits α ₂ -Adrenoceptor–Mediated Endothelium-Dependent Vasodilation

Nitric Oxide Inhibits α ₂ -Adrenoceptor–Mediated Endothelium-Dependent Vasodilation

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Possible Role for K ⁺ in Endothelium-Derived Hyperpolarizing Factor–Linked Dilatation in Rat Middle Cerebral Artery

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Substance P‐induced relaxation and hyperpolarization in human cerebral arteries

Cited by 58 publications

References 40 publications

Nitric Oxide Inhibits α 2 -Adrenoceptor–Mediated Endothelium-Dependent Vasodilation

Nitric Oxide Inhibits α 2 -Adrenoceptor–Mediated Endothelium-Dependent Vasodilation

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Possible Role for K + in Endothelium-Derived Hyperpolarizing Factor–Linked Dilatation in Rat Middle Cerebral Artery

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Nitric Oxide Inhibits α ₂ -Adrenoceptor–Mediated Endothelium-Dependent Vasodilation

Nitric Oxide Inhibits α ₂ -Adrenoceptor–Mediated Endothelium-Dependent Vasodilation

Possible Role for K ⁺ in Endothelium-Derived Hyperpolarizing Factor–Linked Dilatation in Rat Middle Cerebral Artery