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Chronic Hypoxia Inhibits Contraction of Fetal Arteries by Increased Endothelium-Derived Nitric Oxide and Prostaglandin Synthesis

Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland; lthompson1{at}umm.edu

Kripamoy Aguan, PhD

Hui Zhou, MS

Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland

Objective: Chronic hypoxia causes redistribution of fetal cardiac output by mechanisms poorly understood. We tested the hypothesis that chronic hypoxia alters vascular reactivity of arteries from near-term fetal guinea pigs.

Methods: Pregnant guinea pigs (50 days, term = 65 days) were exposed to either normoxia (room air) or hypoxia (12% O₂) for 14 days. Carotid artery ring segments from anesthetized fetuses were mounted onto myographs for measurement of force. Contractile responses to cumulative addition of prostaglandin F₂ (PGF₂, 10^-9 M to 10^-5 M), U46619, a thromboxane mimetic (10^-12 M to 12^-6 M), and KCl (10 to 120 mM) were measured in the presence and absence of INDO (INDO, 10^-5 M) alone and INDO plus mintro-L-arginine (LNA, 10^-4 M), or INDO plus N⁶-iminoethyl-L-lysine (LNIL, 5 x 10^-5 M, a selective iNOS inhibitor), and measured in endothelium-intact and denuded arteries. Nitric oxide synthase (NOS) activity was measured in isolated arteries by ¹⁴C-L-arginine to ¹⁴C-L-citrulline conversion.

Results: Hypoxia decreased contractile responses to both PGF₂ and U46619 under control conditions. Maximal contraction to both agonists was increased in hypoxemic arteries after INDO alone and INDO + LNA compared to normoxic controls. Endothelium-denudation abolished the differences between the groups. KCl contration was unaffected by hypoxia. LNIL potentiated maximal PGF₂ contraction but was similar between groups. Hypoxia increased (P < .05) total and Ca²⁺-dependent NOS activities by 1.7- and 2.1-fold, respectively, but had no effect on Ca²⁺-independent activity.

Conclusion: Chronic hypoxia alters vascular reactivity of fetal carotid arteries by increasing the contribution of both vasodilator prostaglandins and nitric oxide and suggests that changes in local vascular mechanisms may be altered by chronic hypoxia.

Key Words: Nitric oxide • nitric oxide synthase • endothelium • vascular smooth muscle • hypoxemia

Journal of the Society for Gynecologic Investigation, Vol. 11, No. 8, 511-520 (2004)
DOI: 10.1016/j.jsgi.2004.05.008


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