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      Characterization of Endothelium- Dependent Relaxation in Guinea Pig Basilar Artery – Effect of Hypoxia and Role of Cytochrome P 450 Mono-Oxygenase

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          In the guinea pig basilar artery, acetylcholine and the calcium ionophore A23187 induced endothelium-dependent relaxations, which were not significantly affected by the nitric oxide (NO) synthase inhibitor N<sup>ω</sup>-nitro- L-arginine ( L-NOARG; 0.3 m M) or the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one; 1-10 µ M), or by these inhibitors combined. However, acetylcholine (10 µ M) and A23187 (3 µ M) each significantly increased the tissue level of cGMP in the absence but not in the presence of L-NOARG, suggesting that NO is released from the vascular endothelium in this blood vessel. Treatment with the potassium (K) channel inhibitors charybdotoxin (0.1 µ M) plus apamin (0.1 µ M), a toxin mixture previously shown to inhibit relaxations mediated by endothelium-derived hyperpolarizing factor (EDHF) in this artery, had no effect on the A23187-induced relaxation but slightly inhibited the response to acetylcholine (E<sub>max</sub> was reduced by 24%). When the action of EDHF was prevented by these K channel inhibitors, the remaining relaxation was abolished by either ODQ (1 µ M) or L-NOARG (0.3 m M), indicating that NO, apart from EDHF, contributes to the endothelium-dependent relaxations. Furthermore, ODQ (10 µ M) abolished the relaxation induced by the NO donor S-nitroso-N-acetylpenicillamine. Thus, activation of soluble guanylate cyclase seems to be the only mechanism through which NO causes relaxation in this artery. When vessels were exposed to grave hypoxia (pO<sub>2</sub> = 6 mm Hg), the NO-mediated relaxation (induced by acetylcholine in the presence of charybdotoxin plus apamin) disappeared. In contrast, EDHF-mediated responses (elicited by acetylcholine in the presence of L-NOARG) were only marginally affected by hypoxia (E<sub>max</sub> was reduced by 16%). 17-Octadecynoic acid (50 µ M) and 5,8,11,14-eicosatetraynoic acid (10 µ M), inhibitors of cytochrome P<sub>450</sub>-dependent oxidation of arachidonic acid, failed to inhibit the acetylcholine-induced relaxation in the presence of L-NOARG. The cytochrome P<sub>450</sub>-dependent arachidonic acid metabolite 11,12-epoxyecosatrienoic acid (0.3–3.0 µ M) had no relaxant effect per se. In conclusion, EDHF and NO are both mediators of endothelium-dependent relaxations in the guinea pig basilar artery. However, during grave hypoxia, EDHF alone mediates acetylcholine-induced relaxation. The results further suggest that EDHF is not a metabolite of arachidonic acid formed by cytochrome P<sub>450</sub> mono-oxygenase or generated by another oxygen-dependent enzyme in this artery.

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          Activation of K+ channel in vascular smooth muscles by cytochrome P450 metabolites of arachidonic acid.

          Arachidonic acid can be oxidatively metabolized by cytochrome P450 epoxygenase to four regioisomeric epoxyeicosatrienoic acids (5,6-; 8,9-; 11,12-; 14,15-EET), which exhibit vasorelaxant effects in vivo and in vitro with unknown mechanisms. In this study, the patch-clamp method was used to examine the effects of EETs on the Ca(2+)-activated K+ channel in cells from rabbit portal vein, rat caudal artery, guinea pig aorta and porcine coronary artery. In all four cell types, EETs in the bath activated the K+ channel in cell-attached patches by increasing the single channel open-state probability. Potencies of the four EETs did not differ significantly for each cell type. The concentrations for doubling open-state probability were 0.1 microM in portal vein and coronary artery, 0.3-1 microM in aorta and 1-3 microM in caudal artery. In caudal artery cells, K+ channel activation by 3 microM 5,6- and 1 microM 11,12-EET was blocked and reversed by glyburide at 0.5 microM. In aorta, coronary artery, and caudal artery cells, micromolar EETs induced a dose-dependent and reversible augmentation of whole-cell K+ current by 50-120% and a 5-12 mV hyperpolarization. EETs on the cytosolic side of inside-out patches produced little or no potentiation of K+ channels, implying an interaction of receptor-mediated nature. Thus, EETs may promote vasodilation by functioning as endogenous K+ channel openers.
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            Nitric oxide is the mediator of both endothelium-dependent relaxation and hyperpolarization of the rabbit carotid artery

             R A Cohen,  F Plane,  S Najibi (1997)
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              Vasoconstrictor and vasodilator effects of hypoxia.

              Hypoxia has marked effects on artery calibre, which reflects important physiological control mechanisms that are altered in disease states. Hypoxia modifies the release of mediators, especially from the endothelium, and influences smooth muscle membrane potential and Ca2+ regulation. In this review, Roger Wadsworth evaluates the vasoconstrictor and vasodilator effects of hypoxia studied in vitro. In the future, drugs developed to act on the mediators or smooth muscle may be beneficial in the therapy of, for example, pulmonary hypertension or coronary vasospasm.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                August 1998
                07 August 1998
                : 35
                : 4
                : 285-294
                Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University Hospital, Lund, Sweden
                25595 J Vasc Res 1998;35:285–294
                © 1998 S. Karger AG, Basel

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                Page count
                Pages: 10
                Research Paper


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