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Critical Care
Published in: Critical Care 1/2018

Open Access 01-12-2018 | Research

Effects of hyperoxia on vascular tone in animal models: systematic review and meta-analysis

Authors: Bob Smit, Yvo M. Smulders, Etto C. Eringa, Heleen M. Oudemans - van Straaten, Armand R. J. Girbes, Kimberley E. Wever, Carlijn R. Hooijmans, Angelique M. E. Spoelstra - de Man

Published in: Critical Care | Issue 1/2018

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Abstract

Background

Arterial hyperoxia may induce vasoconstriction and reduce cardiac output, which is particularly undesirable in patients who already have compromised perfusion of vital organs. Due to the inaccessibility of vital organs in humans, vasoconstrictive effects of hyperoxia have primarily been studied in animal models. However, the results of these studies vary substantially. Here, we investigate the variation in magnitude of the hyperoxia effect among studies and explore possible sources of heterogeneity, such as vascular region and animal species.

Method

Pubmed and Embase were searched for eligible studies up to November 2017. In vivo and ex vivo animal studies reporting on vascular tone changes induced by local or systemic normobaric hyperoxia were included. Experiments with co-interventions (e.g. disease or endothelium removal) or studies focusing on lung, brain or fetal vasculature or the ductus arteriosus were not included. We extracted data pertaining to species, vascular region, blood vessel characteristics and method of hyperoxia induction. Overall effect sizes were estimated with a standardized mean difference (SMD) random effects model.

Results

We identified a total of 60 studies, which reported data on 67 in vivo and 18 ex vivo experiments. In the in vivo studies, hyperoxia caused vasoconstriction with an SMD of − 1.42 (95% CI − 1.65 to − 1.19). Ex vivo, the overall effect size was SMD − 0.56 (95% CI − 1.09 to − 0.03). Between-study heterogeneity (I2) was high for in vivo (72%, 95% CI 62 to 85%) and ex vivo studies (86%, 95% CI 78 to 98%). In vivo, in comparison to the overall effect size, hyperoxic vasoconstriction was less pronounced in the intestines and skin (P = 0.03) but enhanced in the cremaster muscle region (P < 0.001). Increased constriction was seen in vessels 15–25 μm in diameter. Hyperoxic constriction appeared to be directly proportional to oxygen concentration. For ex vivo studies, heterogeneity could not be explained with subgroup analysis.

Conclusion

The effect of hyperoxia on vascular tone is substantially higher in vivo than ex vivo. The magnitude of the constriction is most pronounced in vessels ~ 15–25 μm in diameter and is proportional to the level of hyperoxia. Relatively increased constriction was seen in muscle vasculature, while reduced constriction was seen in the skin and intestines.
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Literature
1.
2.
Suzuki S, Eastwood GM, Peck L, Glassford NJ, Bellomo R. Current oxygen management in mechanically ventilated patients: a prospective observational cohort study. J Crit Care. 2013;28:647–54.CrossRefPubMed
3.
de Graaff AE, Dongelmans DA, Binnekade JM, de Jonge E. Clinicians’ response to hyperoxia in ventilated patients in a Dutch ICU depends on the level of FiO2. Intensive Care Med. 2011;37:46–51.CrossRefPubMed
4.
Bitterman H, Brod V, Weisz G, Kushnir D, Bitterman N. Effects of oxygen on regional hemodynamics in hemorrhagic shock. Am J Physiol Heart Circ Physiol. 1996;271:H203–11.CrossRef
5.
Hauser B, et al. Hemodynamic, metabolic, and organ function effects of pure oxygen ventilation during established fecal peritonitis-induced septic shock. Crit Care Med. 2009;37:2465–9.CrossRefPubMed
6.
Waisman D, et al. Effects of hyperoxia on local and remote microcirculatory inflammatory response after splanchnic ischemia and reperfusion. Am J Physiol Heart Circ Physiol. 2003;285:H643–52.CrossRefPubMed
7.
8.
9.
Palkovits S, et al. Retinal oxygen metabolism during normoxia and hyperoxia in healthy subjects. Invest Ophthalmol Vis Sci. 2014;55:4707–13.CrossRefPubMed
10.
Orbegozo Cortés D, et al. Normobaric hyperoxia alters the microcirculation in healthy volunteers. Microvasc Res. 2015;98:23–8.CrossRefPubMed
11.
Frisbee JC. Regulation of in situ skeletal muscle arteriolar tone: interactions between two parameters. Microcirculation. 2002;9:443–62.PubMed
12.
Jackson WF. Arteriolar oxygen reactivity: where is the sensor? Am J Phys. 1987;253:H1120–6.
13.
Messina EJ, Sun D, Koller A, Wolin MS, Kaley G. Increases in oxygen tension evoke arteriolar constriction by inhibiting endothelial prostaglandin synthesis. Microvasc Res. 1994;48:151–60.CrossRefPubMed
14.
15.
Rubanyi G, Paul RJ. O2-sensitivity of beta adrenergic responsiveness in isolated bovine and porcine coronary arteries. J Pharmacol Exp Ther. 1984;230(3):692–8.
16.
Smit B, et al. Hyperoxia does not directly affect vascular tone in isolated arteries from mice. PLoS One. 2017;12(8):e0182637.
17.
Ngai JH, Roth PS, Paul RJ. Effects of endothelium on basal tone and agonist and O2 sensitivity in porcine coronary artery. J Pharmacol Exp Ther. 1990;230(3):1053–9.
18.
Rubanyi G, Paul RJ. Two distinct effects of oxygen on vascular tone in isolated porcine coronary arteries. Circ Res. 1985;56:1–10.CrossRefPubMed
19.
20.
Moher D, Liberati A, Tetzlaff J, A. D. PRISMA 2009 flow diagram. The PRISMA statement. 2009;6:1000097.
21.
de Vries RBM, et al. A protocol format for the preparation, registration and publication of systematic reviews of animal intervention studies. Evidence-Based Preclin Med. 2015;2:e00007.CrossRef
22.
de Vries RBM, Hooijmans CR, Tillema A, Leenaars M, Ritskes-Hoitinga M. A search filter for increasing the retrieval of animal studies in Embase. Lab Anim. 2011;45:268–70.CrossRefPubMedPubMedCentral
23.
Hooijmans CR, Tillema A, Leenaars M, Ritskes-Hoitinga M. Enhancing search efficiency by means of a search filter for finding all studies on animal experimentation in PubMed. Lab Anim. 2010;44:170–5.CrossRefPubMedPubMedCentral
24.
Gibbons RD, Hedeker DR, Davis JM. Estimation of effect size from a series of experiments involving paired comparisons. J Educ Stat. 1993;18:271–9.CrossRef
25.
26.
Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006;11:193–206.CrossRefPubMed
27.
28.
Akaike H. A new look at the statistical model identification. IEEE Trans Automat Contr. 1974;19:716–23.CrossRef
29.
Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56:455–63.CrossRefPubMed
30.
Zwetsloot PP, et al. Standardized mean differences cause funnel plot distortion in publication bias assessments. Elife. 2017;6
31.
Frisbee JC, Lombard JH. Parenchymal tissue cytochrome P450 4A enzymes contribute to oxygen-induced alterations in skeletal muscle arteriolar tone. Microvasc Res. 2002;63:340–3.CrossRefPubMed
32.
Jackson WF. Prostaglandins do not mediate arteriolar oxygen reactivity. Am J Phys. 1986;250:H1102–8.
33.
Rafi JA, Boegehold MA. Microvascular responses to oxygen and muscle contraction in hypertensive dahl rats. Int J Microcirc Clin Exp. 1993;13:83–97.PubMed
34.
Sauls BA, Boegehold MA. Arteriolar wall PO(2) and nitric oxide release during sympathetic vasoconstriction in the rat intestine. Am J Physiol Heart Circ Physiol. 2000;279:H484–91.CrossRefPubMed
35.
Sauls BA, Boegehold MA. Adenosine linking reduced O2 to arteriolar NO release in intestine is not formed from extracellular ATP. Am J Physiol Heart Circ Physiol. 2001;281:H1193–200.CrossRefPubMed
36.
Sullivan SM, Johnson PC. Effect of oxygen on arteriolar dimensions and blood flow in cat sartorius muscle. Am J Phys. 1981;241:H547–56.
37.
Sakai N, Mizuno R, Ono N, Kato H, Ohhashi T. High oxygen tension constricts epineurial arterioles of the rat sciatic nerve via reactive oxygen species. Am J Physiol Heart Circ Physiol. 2007;293:H1498–507.CrossRefPubMed
38.
Duling BR. Oxygen sensitivity of vascular smooth muscle. II. In vivo studies. Am J Phys. 1974;227:42–9.
39.
Milstein DMJ, et al. Sublingual microvascular perfusion is altered during normobaric and hyperbaric hyperoxia. Microvasc Res. 2016;105:93–102.CrossRefPubMed
40.
Ngo AT, Riemann M, Holstein-Rathlou N-H, Torp-Pedersen C, Jensen LJ. Significance of K(ATP) channels, L-type Ca2+ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles in vivo. BMC Physiol. 2013;13:8.CrossRefPubMedPubMedCentral
41.
Ngo AT, Jensen LJ, Riemann M, Holstein-Rathlou N-H, Torp-Pedersen C. Oxygen sensing and conducted vasomotor responses in mouse cremaster arterioles in situ. Pflugers Arch. 2010;460:41–53.CrossRefPubMed
42.
Riemann M, et al. Oxygen-dependent vasomotor responses are conducted upstream in the mouse cremaster microcirculation. J Vasc Res. 2010;48:79–89.CrossRefPubMed
43.
Bertuglia S, Colantuoni A, Coppini G, Intaglietta M. Hypoxia- or hyperoxia-induced changes in arteriolar vasomotion in skeletal muscle microcirculation. Am J Physiol Heart Circ Physiol. 1991;260:H362–72.CrossRef
44.
Cabrales P, Tsai AG, Intaglietta M. Nitric oxide regulation of microvascular oxygen exchange during hypoxia and hyperoxia. J Appl Physiol. 2006;100:1181–7.CrossRefPubMed
45.
Tsai AG, Cabrales P, Winslow RM, Intaglietta M. Microvascular oxygen distribution in awake hamster window chamber model during hyperoxia. Am J Physiol Heart Circ Physiol. 2003;285:H1537–45.CrossRefPubMed
46.
Kalsner S. Intrinsic prostaglandin release. A mediator of anoxia-induced relaxation in an isolated coronary artery preparation. Blood Vessels. 1976;13:155–66.PubMed
47.
Fredricks KT, Liu Y, Lombard JH. Response of extraparenchymal resistance arteries of rat skeletal muscle to reduced PO2. Am J Phys. 1994:H706–15.
48.
Frisbee JC, Krishna UM, Falck JR, Lombard JH. Role of prostanoids and 20-HETE in mediating oxygen-induced constriction of skeletal muscle resistance arteries. Microvasc Res. 2001;62:271–83.CrossRefPubMed
49.
Frisbee JC, Maier KG, Falck JR, Roman RJ, Lombard JH. Integration of hypoxic dilation signaling pathways for skeletal muscle resistance arteries. Am J Physiol Regul Integr Comp Physiol. 2002;283:R309–19.CrossRefPubMed
50.
Liu Y, Fredricks KT, Roman RJ, Lombard JH. Response of resistance arteries to reduced PO2 and vasodilators during hypertension and elevated salt intake. Am J Phys. 1997;273:H869–77.
51.
Day RW, Lai WW, Klitzner TS, Ignarro LJ. Oxygen-mediated regulation of neonatal and adult rabbit aortic tension. Dev Pharmacol Ther. 1992:90–8.
52.
Kwan YW, Wadsworth RM, Kane KA. Effects of hypoxia on the pharmacological responsiveness of isolated coronary artery rings from the sheep. Br J Pharmacol. 1989;96:849–56.CrossRefPubMedPubMedCentral
53.
Pasgaard T, et al. Hyperoxia reduces basal release of nitric oxide and contracts porcine coronary arteries. Acta Physiol (Oxf). 2007;191:285–96.CrossRef
54.
Chang AE, Detar R. Oxygen and vascular smooth muscle contraction revisited. Am J Physiol. 1980;238:H716–28.PubMed
55.
Pittman RN, Graham BA. Sensitivity of rabbit aorta to altered oxygen tension. Adv Exp Med Biol. 1986;200:373–83.CrossRefPubMed
56.
Vallet B, Winn MJ, Asante NK, Cain SM. Influence of oxygen on endothelium-derived relaxing factor/nitric oxide and K(+)-dependent regulation of vascular tone. J Cardiovasc Pharmacol. 1994;24:595–602.CrossRefPubMed
57.
Lombard JH, Stekiel WJ. Effect of oxygen on arteriolar diameters in the rat mesoappendix. Microvasc Res. 1985;30:346–9.CrossRefPubMed
58.
Dewhirst MW, et al. Arteriolar oxygenation in tumour and subcutaneous arterioles: effects of inspired air oxygen content. Br J Cancer Suppl. 1996:S241–6.
59.
Jackson WF, Duling BR. The oxygen sensitivity of hamster cheek pouch arterioles. In vitro and in situ studies. Circ Res. 1983;53:515–25.CrossRefPubMed
60.
Welsh DG, Jackson WF, Segal SS. Oxygen induces electromechanical coupling in arteriolar smooth muscle cells: a role for L-type Ca2+ channels. Am J Phys. 1998;274:H2018–24.
61.
Gorczynski RJ, Duling BR. Role of oxygen in arteriolar functional vasodilation in hamster striated muscle. Am J Phys. 1978;235:H505–15.
62.
Jackson WF. Lipoxygenase inhibitors block O2 responses of hamster cheek pouch arterioles. Am J Phys. 1988;255:H711–6.
63.
Jackson WF. Arteriolar oxygen reactivity is inhibited by leukotriene antagonists. Am J Phys. 1989;257:H1565–72.
64.
Jackson WF. Regional differences in mechanism of action of oxygen on hamster arterioles. Am J Phys. 1993;265:H599–603.
65.
Drenjancevic-Peric I, Greene AS, Kunert MP, Lombard JH. Arteriolar responses to vasodilator stimuli and elevated P(O2) in renin congenic and dahl salt-sensitive rats. Microcirculation. 2004;11:669–77.CrossRefPubMed
66.
Lombard JH, Stekiel WJ. Active tone and arteriolar responses to increased oxygen availability in the mesoappendix of spontaneously hypertensive rats. Microcirc Endothel. Lymphat. 1988:339–53.
67.
Jackson WF. Nitric oxide does not mediate arteriolar oxygen reactivity. Microcirc Endothel Lymphat. 1991;7:199–215.
68.
Komori M, Takada K, Ozaki M. Effects of inspired oxygen concentration on peripheral microcirculation studied by the rabbit ear chamber method. In Vivo. 2001;15:303–8.PubMed
69.
Frisbee JC, Lombard JH. Elevated oxygen tension inhibits flow-induced dilation of skeletal muscle arterioles. Microvasc Res. 1999;58:99–107.CrossRefPubMed
70.
Hedegaard ER, Stankevicius E, Simonsen U, Fröbert O, Frobert O. Non-endothelial endothelin counteracts hypoxic vasodilation in porcine large coronary arteries. BMC Physiol. 2011;11:8.CrossRefPubMedPubMedCentral
71.
Liu X, et al. Oxygen regulates the effective diffusion distance of nitric oxide in the aortic wall. Free Radic Biol Med. 2010;48:554–9.CrossRefPubMed
72.
Kunert MP, Roman RJ, Falck JR, Lombard JH. Differential effect of cytochrome P-450 omega-hydroxylase inhibition on O2-induced constriction of arterioles in SHR with early and established hypertension. Microcirculation. 2001:435–43. https://​doi.​org/​10.​1038/​sj/​mn/​7800114.
73.
Kunert MP, Roman RJ, Alonso-Galicia M, Falck JR, Lombard JH. Cytochrome P-450 omega-hydroxylase: a potential O(2) sensor in rat arterioles and skeletal muscle cells. Am J Physiol Heart Circ Physiol. 2001;280:H1840–5.CrossRefPubMed
74.
Macica C, Balazy M, Falck JR, Mioskowski C, Carroll MA. Characterization of cytochrome P-450-dependent arachidonic acid metabolism in rabbit intestine. Am J Phys. 1993;265:G735–41.
75.
Rousseau A, Steinwall I, Woodson RD, Sjöberg F. Hyperoxia decreases cutaneous blood flow in high-perfusion areas. Microvasc Res. 2007;74:15–22.CrossRefPubMed
76.
Stub D, et al. Air versus oxygen in ST-segment elevation myocardial infarction. Circulation. 2015;131:2143–50.CrossRefPubMed
77.
Guensch DP, Fischer K, Shie N, Lebel J, Friedrich MG. Hyperoxia exacerbates myocardial ischemia in the presence of acute coronary artery stenosis in swine. Circ Cardiovasc Interv. 2015;8:e002928.CrossRefPubMed
78.
Meier J, et al. Regional blood flow during hyperoxic haemodilution. Clin Physiol Funct Imaging. 2005;25:158–65.CrossRefPubMed
79.
Sukhotnik I, et al. The effect of 100% oxygen on intestinal preservation and recovery following ischemia-reperfusion injury in rats. Crit Care Med. 2009;37:1054–61.CrossRefPubMed
80.
Ishikawa K, et al. Coronary artery constriction by oxygen breathing in patients with coronary disease. Tohoku J Exp Med. 1981;134:265–71.CrossRefPubMed
81.
Ishikawa K, Hayashi T, Tashi M. Reduction in diameter of coronary arteries by oxygen breathing in patients with coronary artery disease. Med.J Kinki Univ. 1978:7–13.
82.
Gao Z, et al. Vitamin C prevents hyperoxia-mediated coronary vasoconstriction and impairment of myocardial function in healthy subjects. Eur J Appl Physiol. 2012;112:483–92.CrossRefPubMed
83.
McNulty PH, et al. Effects of supplemental oxygen administration on coronary blood flow in patients undergoing cardiac catheterization. AJP Hear Circ Physiol. 2005;288:H1057–62.CrossRef
84.
McNulty PH, et al. Effect of hyperoxia and vitamin C on coronary blood flow in patients with ischemic heart disease. J Appl Physiol. 2007;102:2040–5.CrossRefPubMed
85.
Davis MJ, Joyner WL, Gilmore JP. Microvascular pressure distribution and responses of pulmonary allografts and cheek pouch arterioles in the hamster to oxygen. Circ Res. 1981:125–32.
86.
87.
Taguchi A. Microcirculation during inhalation of 100% oxygen in rabbits. Masui. 1992;41:67–71.PubMed
88.
Pries AR, Heide J, Ley K, Klotz KF, Gaehtgens P. Effect of oxygen tension on regulation of arteriolar diameter in skeletal muscle in situ. Microvasc Res. 1995;49:289–99.CrossRefPubMed
89.
Harder DR, et al. Identification of a putative microvascular oxygen sensor. Circ Res. 1996;79:54–61.CrossRefPubMed
90.
Lombard JH, et al. Cytochrome P-450 omega-hydroxylase senses O2 in hamster muscle, but not cheek pouch epithelium, microcirculation. Am J Phys. 1999;276:H503–8.
91.
Frisbee JC, Lombard JH. Increased intravascular pressure does not enhance skeletal muscle arteriolar constriction to oxygen or angiotensin II. Microvasc Res. 2000;59:176–80.CrossRefPubMed
92.
Frisbee JC, Falck JR, Lombard JH. Contribution of cytochrome P-450 (omega)-hydroxylase to altered arteriolar reactivity with high-salt diet and hypertension. Am J Physiol Heart Circ Physiol. 2000;278:H1517–26.CrossRefPubMed
93.
Kunert MP, Friesma J, Falck JR, Lombard JH. CYP450 4A inhibition attenuates O2 induced arteriolar constriction in chronic but not acute Goldblatt hypertension. Microvasc Res. 2009;78:442–6.CrossRefPubMedPubMedCentral
94.
Wang J, et al. Modulation of vascular O2 responses by cytochrome 450-4A omega-hydroxylase metabolites in dahl salt-sensitive rats. Microcirculation. 2009;16:345–54.CrossRefPubMedPubMedCentral
Metadata
Title
Effects of hyperoxia on vascular tone in animal models: systematic review and meta-analysis
Authors
Bob Smit
Yvo M. Smulders
Etto C. Eringa
Heleen M. Oudemans - van Straaten
Armand R. J. Girbes
Kimberley E. Wever
Carlijn R. Hooijmans
Angelique M. E. Spoelstra - de Man
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2018
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-018-2123-9

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