Superoxide anion scavengers restore NO-mediated pulmonary vasodilation after lung transplantation

1999 ◽  
Vol 276 (1) ◽  
pp. H42-H46 ◽  
Author(s):  
Sumihiko Seki ◽  
Nicholas A. Flavahan ◽  
Nicholas G. Smedira ◽  
Paul A. Murray
Keyword(s):  
Xanthine Oxidase ◽  
Dose Response ◽  
Superoxide Anion ◽  
Left Lung ◽  
Calcium Ionophore ◽  
Isometric Tension ◽  
Response Curves ◽  
Superoxide Anion Production ◽  
Pulmonary Vasodilation ◽  
A 23187

Left lung autotransplantation (LLA) results in a chronic attenuation in endothelium-dependent, nitric oxide (NO)-mediated pulmonary vasodilation. We tested the hypothesis that this abnormality involves a decrease in the effective concentration of NO due to inactivation by superoxide anion. Size- and position-matched pulmonary arterial rings were isolated from the right (control) and left (LLA) lungs of seven dogs 1–5 mo post-LLA. The rings were suspended for isometric tension recording and contracted with phenylephrine, and cumulative dose-response curves for ACh or calcium ionophore (A-23187) were generated. Endothelium-dependent relaxation to ACh was inhibited post-LLA, with the maximum vasorelaxation response reduced from 88 ± 5 to 63 ± 5% ( P < 0.01) post-LLA. In contrast, after pretreatment with the superoxide anion scavengers tiron or superoxide dismutase (SOD), the dose-response relationships for ACh were similar in control and LLA rings. Oxypurinol, which inhibits superoxide anion production by endothelial xanthine oxidase, also restored the vasorelaxation response to ACh in LLA rings. The pulmonary vasorelaxant response to A-23187 was also attenuated ( P < 0.01) post-LLA, and this effect was entirely reversed by pretreatment with tiron, SOD, or oxypurinol. These results indicate that the attenuated responses to these pulmonary vasorelaxants post-LLA involve inactivation of NO by superoxide anion generated by endothelial xanthine oxidase.

Endothelial and vascular smooth muscle responses are altered after left lung autotransplantation

1994 ◽  
Vol 266 (5) ◽  
pp. H2026-H2032 ◽  
Author(s):  
N. A. Flavahan ◽  
T. D. Aleskowitch ◽  
P. A. Murray
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Left Lung ◽  
Calcium Ionophore ◽  
Selective Reduction ◽  
Isometric Tension ◽  
Maximal Response ◽  
No Donor ◽  
Significant Difference ◽  
Increased Sensitivity

Left lung autotransplantation (LLA) increased the pulmonary vasoconstriction evoked by phenylephrine and attenuated the vasodilatation caused by acetylcholine or bradykinin in conscious dogs. To study the mechanisms responsible for these changes, pulmonary arterial rings were isolated from right (control) and left (LLA) lower lobes of dogs 1-26 mo after LLA and were suspended for isometric tension recording. Compared with control rings from the same anatomic location, contractions to phenylephrine were increased after LLA in rings with or without endothelium. In arterial rings contracted to 50% of their maximal response to phenylephrine, acetylcholine, bradykinin, and calcium ionophore caused endothelium-dependent relaxations that were reduced in LLA compared with control rings. In arterial rings from control and LLA lungs, relaxations to acetylcholine were not altered by inhibition of cyclooxygenase (indomethacin) but were reduced after inhibition of NO synthase [N omega-nitro-L-arginine methyl ester (L-NAME)]. After L-NAME, there was no longer any significant difference in acetylcholine-induced relaxation between arterial rings from control and LLA lungs. Relaxation to SIN-1, a NO donor, was similar in arterial rings (without endothelium) from control and LLA lungs. The results suggest that LLA causes an increased sensitivity of vascular smooth muscle to alpha 1-adrenergic activation and endothelial dysfunction that is mediated by a selective reduction in the activity of endothelium-derived relaxing factor/NO.

Effects of prolonged exposure to oxygen-derived free radicals in canine pulmonary arteries

1996 ◽  
Vol 270 (6) ◽  
pp. H2184-H2190 ◽  
Author(s):  
L. Wiklund ◽  
C. G. McGregor ◽  
V. M. Miller
Keyword(s):  
Superoxide Dismutase ◽  
Free Radicals ◽  
Xanthine Oxidase ◽  
Vascular Injury ◽  
Prolonged Exposure ◽  
Isometric Force ◽  
Pulmonary Arteries ◽  
Calcium Ionophore ◽  
Oxygen Derived Free Radicals ◽  
A 23187

Experiments were designed to evaluate endothelium-dependent responses of pulmonary arteries following prolonged exposure to oxygen-derived free radicals. Rings of canine pulmonary arteries with and without endothelium were suspended for measurement of isometric force in organ chambers and incubated with xanthine (10(-4)M) plus xanthine oxidase (0.015 U/ml) for 1 h in the absence and presence of either superoxide dismutase (SOD, 150 U/ml), catalase (1,200 U/ml), deferoxamine (10(-3)M), or a combination of all three scavengers. Xanthine plus xanthine oxidase caused significantly greater contractions of rings without compared with those with endothelium. In rings with endothelium, contractions were reduced by SOD or catalase but not by deferoxamine. Following 1 h of exposure to xanthine plus xanthine oxidase, endothelium-dependent relaxations to ADP were reduced but not those to bradykinin or the calcium ionophore A-23187 (calcimycin). Relaxations to ADP were not corrected by incubation with the antioxidants used singly or in combination during the exposure to xanthine plus xanthine oxidase. These results suggest that oxygen-derived free radicals generated from exogenously applied xanthine plus xanthine oxidase cause contractions of canine pulmonary arteries. In addition, even when contractions of rings with endothelium were prevented by SOD and catalase, subsequent expression of some but not all endothelium-dependent relaxations were reduced. Therefore, scavenging of oxygen-derived free radicals may prevent some but not all of the vascular injury caused by oxygen-derived free radicals.

Superoxide anion is an endothelium-derived contracting factor

1989 ◽  
Vol 257 (1) ◽  
pp. H33-H37 ◽  
Author(s):  
Z. S. Katusic ◽  
P. M. Vanhoutte
Keyword(s):  
Superoxide Dismutase ◽  
Xanthine Oxidase ◽  
Superoxide Anion ◽  
Cerebral Arteries ◽  
Calcium Ionophore ◽  
Calcium Ionophore A23187 ◽  
Heat Inactivation ◽  
Ionophore A23187 ◽  
Excitatory Effect ◽  
Basilar Arteries

The calcium ionophore A23187 causes endothelium-dependent contractions in canine basilar arteries. Removal of the endothelium, or treatment with indomethacin or superoxide dismutase (SOD), prevented the endothelium-dependent excitatory effect of the calcium ionophore. Catalase and deferoxamine were without effect. Superoxide anion generated by xanthine plus xanthine oxidase in the presence of catalase caused contractions of the vascular smooth muscle, which were abolished by SOD or heat inactivation of xanthine oxidase. The A23187-induced production of prostaglandins F2 alpha and E2 and thromboxane B2 was abolished by the removal of endothelium and by treatment with indomethacin but was not affected by the presence of SOD plus catalase. These observations are consistent with the hypothesis that superoxide anion, rather than prostaglandins generated by hydroperoxidase activity of cyclooxygenase, is an endothelium-derived contracting factor in canine cerebral arteries.

In vitro reactivity of ventral aorta to acetylcholine and noradrenaline in yellow freshwater eel (Anguilla anguilla L.) acclimatized to 10.1 MPa hydrostatic pressure

2000 ◽  
Vol 78 (11) ◽  
pp. 897-903 ◽  
Author(s):  
François Guerrero ◽  
Mickael Theron ◽  
Philippe Sebert
Keyword(s):  
Smooth Muscle ◽  
Hydrostatic Pressure ◽  
Vascular Smooth Muscle ◽  
Dose Response ◽  
Vascular Reactivity ◽  
Anguilla Anguilla ◽  
Dry Weight ◽  
Isometric Tension ◽  
Response Curves

We examined in vitro vascular reactivity of eels previously acclimatized to 10.1 MPa hydrostatic pressure (HP) for 21 days. The isometric tension developed by ventral aortic rings was measured at atmospheric pressure. Dose-response curves for either acetylcholine (ACh) or noradrenaline (NA), as well as contractions evoked by 80 mM K+, were compared with time-matched experiments conducted on rings obtained from control eels. Results showed that neither the optimal tension nor the maximal force of the K+-evoked contraction were significantly modified, suggesting that acclimatization to high HP did not change the vascular smooth muscle contractile machinery. The dose-response curve to ACh was not significantly changed. Conversely, although NA always relaxed aortic rings, the response of acclimatized eels was significantly reduced over the entire range of the agonist concentration tested (10-8 to 10-3 M), except for the lowest one (10-9 M). The maximal amplitude of the NA-induced relaxation was significantly reduced in aortic rings from acclimatized eels as compared with non-acclimatized samples (339.3 ± 86.5 vs. 744.3 ± 72.1 mg·mg-1 dry weight, P < 0.005). Our results suggest that acclimatization to high HP could selectively alter the control of vascular tone by catecholamines.Key words: fish, high pressure, vascular smooth muscle, adrenoceptors, cholinergic receptors.

scholarly journals Vascular function in arteries of intertidal fish Girella laevifrons(Kyphosidae)

2014 ◽  
Vol 74 (3) ◽  
pp. 739-743 ◽  
Author(s):  
FA Moraga ◽  
N Urriola-Urriola
Keyword(s):  
Dose Response ◽  
Vascular Function ◽  
Isometric Tension ◽  
Mesenteric Arteries ◽  
Response Curves ◽  
Cholinergic Pathways ◽  
Cholinergic Pathway ◽  
Dose Response Curves ◽  
Intertidal Fish ◽  
Low Sensitivity

Preliminary studies showed that dorsal artery contraction mediated by acetylcholine (ACh) is blocked with indomethacin in intertidal fish (Girella laevifrons). Our objective was to characterise the cholinergic pathway in several artery vessels of the G. laevifrons. Afferent and efferent branchial, dorsal and mesenteric arteries were dissected of 6 juvenile specimens, isometric tension studies were done using dose response curves (DRC) for Ach (10–13 to 10–3 M), and cholinergic pathways were obtained by blocking with atropine or indomethacin. CRC to ACh showed a pattern of high and low sensitivity. Furthermore, these contractions were blocked in the presence of atropine and indomethacin in all vessels. Our results suggest that contraction observed with acetylcholine is mediated by receptors that activate a cyclooxygenase contraction pathway.

Halothane Attenuates Endothelium-dependent Pulmonary Vasorelaxant Response to Lemakalim, an Adenosine Triphosphate (ATP)-sensitive Potassium Channel Agonist

1997 ◽  
Vol 87 (3) ◽  
pp. 625-634 ◽  
Author(s):  
Sumihiko Seki ◽  
Mayumi Horibe ◽  
Paul A. Murray
Keyword(s):  
Adenosine Triphosphate ◽  
Inhibitory Effect ◽  
Isometric Tension ◽  
Maximal Response ◽  
Response Curves ◽  
Nitric Oxide Synthase Inhibitor ◽  
Pulmonary Vasodilation ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Channel Agonist

Background Lemakalim, an adenosine triphosphate (ATP)-sensitive potassium (K+(ATP)) channel agonist, causes profound pulmonary vasodilation in conscious dogs, which is attenuated during halothane anesthesia. The goal of the present study was to investigate the mechanism responsible for this attenuating effect of halothane. Methods Isolated canine pulmonary arterial rings were suspended for isometric tension recording in 25 ml organ baths. Rings with and without endothelium were contracted to 50% of their maximal response to phenylephrine, followed by the cumulative administration of lemakalim with or without exposure to halothane (0.5-1.5 minimum alveolar concentration [MAC] in dogs). Lemakalim dose-response curves were also generated in rings pretreated with the nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester (L-NAME); the cyclooxygenase inhibitor, indomethacin; or the K+(ATP) channel antagonist, glybenclamide. Results Compared with intact rings, the pulmonary vasorelaxant response to lemakalim was attenuated (P &lt; 0.05) in endothelium-denuded rings. Halothane at 0.5 MAC had no effect on the vasorelaxant response to lemakalim. Halothane at 1 MAC attenuated (P &lt; 0.05) the vasorelaxant response to lemakalim in intact rings, but not in endothelium-denuded rings. Halothane at 1.5 MAC attenuated (P &lt; 0.05) the vasorelaxant response to lemakalim in both intact and endothelium-denuded rings. In endothelium-intact rings, indomethacin attenuated (P &lt; 0.05) the vasorelaxant response to lemakalim, whereas L-NAME had no effect. Further, indomethacin, but not L-NAME, abolished the endothelium-dependent, halothane-induced attenuation of the lemakalim vasorelaxation response. Glybenclamide markedly attenuated (P &lt; 0.05) lemakalim vasorelaxation at lemakalim doses less than 10(-6) M. Conclusions Lemakalim-induced pulmonary vasorelaxation involves an endothelium-dependent and vascular smooth muscle component. Further, halothane attenuates the endothelium-dependent pulmonary vasorelaxant response to lemakalim via an inhibitory effect on vasodilator metabolites of the cyclooxygenase pathway.

Calcium-independent phospholipase A2 plays a key role in the endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat

2010 ◽  
Vol 298 (4) ◽  
pp. H1260-H1266 ◽  
Author(s):  
Michael S. K. Wong ◽  
Ricky Y. K. Man ◽  
Paul M. Vanhoutte
Keyword(s):  
Endothelial Cells ◽  
Mammalian Cells ◽  
Spontaneously Hypertensive Rat ◽  
Calcium Ionophore ◽  
Isometric Tension ◽  
Membrane Phospholipids ◽  
Spontaneously Hypertensive ◽  
A 23187 ◽  
Hypertensive Rat ◽  
Wistar Kyoto

Phospholipase A2 (PLA2), a regulatory enzyme found in most mammalian cells, catalyzes the breakdown of membrane phospholipids to arachidonic acid. There are two major cytosolic types of the enzyme, calcium-dependent (cPLA2) and calcium-independent (iPLA2) PLA2. The present study investigated whether or not iPLA2 plays a role in the endothelium-dependent contractions of the aorta of the spontaneously hypertensive rat and its normotensive counterpart, the Wistar-Kyoto rat. The presence of iPLA2 in the endothelial cells was identified by using immunochemistry and immunoblotting. Aortic rings with and without the endothelium were suspended in organ chambers for isometric tension recording. The production of prostanoids was measured by using enzyme immunoassay kits. iPLA2 was densely distributed in endothelial cells of the aorta of both strains. At 3 × 10−6 M, the selective iPLA2 inhibitor, bromoenol lactone (BEL), abrogated endothelium-dependent contractions induced by acetylcholine but not those evoked by the calcium ionophore A-23187. The effects of BEL were similar in the aortae of Wistar-Kyoto and spontaneously hypertensive rats. The nonselective PLA2 inhibitor quinacrine abolished the contractions triggered by both acetylcholine and A-23187, whereas the store-operated calcium channel inhibitor SKF-96365 prevented only the acetylcholine-induced contraction. The acetylcholine- but not the A-23187-induced release of 6-keto prostaglandin F1α was inhibited by BEL. The release of thromboxane B2 by either acetylcholine or A-23187 was not affected by BEL. In conclusion, iPLA2 plays a substantial role in the generation of endothelium-derived contracting factor evoked by acetylcholine.

In SHR aorta, calcium ionophore A-23187 releases prostacyclin and thromboxane A2 as endothelium-derived contracting factors

2006 ◽  
Vol 291 (5) ◽  
pp. H2255-H2264 ◽  
Author(s):  
Pascale Gluais ◽  
Jerôme Paysant ◽  
Cécile Badier-Commander ◽  
Tony Verbeuren ◽  
Paul M. Vanhoutte ◽  
...  
Keyword(s):  
Calcium Ionophore ◽  
Isometric Tension ◽  
Spontaneously Hypertensive ◽  
A 23187 ◽  
Cyclooxygenase 1 ◽  
Thromboxane Synthase Inhibitor ◽  
Parallel Increase ◽  
Tp Receptors ◽  
Wistar Kyoto ◽  
Synthase Inhibitor

In mature spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), acetylcholine and the calcium ionophore A-23187 release endothelium-derived contracting factors (EDCFs), cyclooxygenase derivatives that activate thromboxane-endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine are most likely prostacyclin and prostaglandin (PG)H2, whereas those released by A-23187 remain to be identified. Isometric tension and the release of PGs were measured in rings of isolated aortas of WKY and SHR. A-23187 evoked the endothelium-dependent release of prostacyclin, thromboxane A2, PGF2α, PGE2, and possibly PGH2 (PGI2 ≫ thromboxane A2 = PGF2α = PGE2). In SHR aortas, the release of prostacyclin and thromboxane A2 was significantly larger in response to A-23187 than to acetylcholine. In response to the calcium ionophore, the release of thromboxane A2 was significantly larger in aortas of SHR than in those of WKY. In both strains of rat, the inhibition of cyclooxygenase-1 prevented the release of PGs and the occurrence of endothelium-dependent contractions. Dazoxiben, the thromboxane synthase inhibitor, abolished the A-23187-dependent production of thromboxane A2 and inhibited by approximately one-half the endothelium-dependent contractions. U-51605, an inhibitor of PGI synthase, reduced the release of prostacyclin elicited by A-23187 but induced a parallel increase in the production of PGE2 and PGF2α, suggestive of a PGH2 spillover, which was associated with the enhancement of the endothelium-dependent contractions. These results indicate that in the aorta of SHR and WKY, the endothelium-dependent contractions elicited by A-23187 involve the release of thromboxane A2 and prostacyclin with a most likely concomitant contribution of PGH2.

In vivo reactive oxygen species production induced by ischemia in muscle arterioles of mice: involvement of xanthine oxidase and mitochondria

2008 ◽  
Vol 294 (2) ◽  
pp. H821-H828 ◽  
Author(s):  
Nathalie Baudry ◽  
Elisabeth Laemmel ◽  
Eric Vicaut
Keyword(s):  
Xanthine Oxidase ◽  
Superoxide Anion ◽  
Ischemia Reperfusion ◽  
Complex Iii ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Complex ◽  
Superoxide Anion Production ◽  
Anion Production

Reactive oxygen species (ROS) participate in tissue injury after ischemia-reperfusion. Their implication in leukocyte adherence and increase in permeability at the venular side of the microcirculation have been reported, but very little is known about ROS production in arterioles. The objective of this work was to evaluate, in the arteriole wall in vivo, the temporal changes in superoxide anion production during ischemia and reperfusion and to identify the source of this production. Mouse cremaster muscle was exposed to 1 h of ischemia followed by 30 min of reperfusion, and superoxide anion production was assessed by a fluorescent probe, i.e., intracellular dihydroethidium oxidation. During ischemia, we found a significant increase in dihydroethidium oxidation; however, we observed no additional increase in fluorescence during the subsequent reperfusion. This phenomenon was significantly inhibited by pretreatment with superoxide dismutase. Allopurinol (xanthine oxidase inhibitor) or stigmatellin [Qo-site (oriented toward the intermembrane space) inhibitor of mitochondrial complex III] or simultaneous administration of these two inhibitors significantly reduced superoxide production during ischemia to 80%, 88%, and 72%, respectively, of that measured in the untreated ischemia-reperfusion group. By contrast, no significant inhibition was found when NADPH oxidase was inhibited by apocynin or when mitochondrial complex I or complex II was inhibited by rotenone or thenoyltrifluoroacetone. A significant increase in ROS was found with antimycin A [Qi-site (located in the inner membrane and facing the mitochondrial matrix) inhibitor of mitochondrial complex III]. We conclude that a significant increase in ROS production occurs during ischemia in the arteriolar wall. This increased production involves both a cytoplasmic source (i.e., xanthine oxidase) and the mitochondrial complex III at the Qo site.

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