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This Article Full Text Full Text (PDF) All Versions of this Article: 107/1/192    most recent 00233.2009v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Pearce, W. J. Articles by Lincoln, T. M. PubMed PubMed Citation Articles by Pearce, W. J. Articles by Lincoln, T. M.

Effects of chronic hypoxia on soluble guanylate cyclase activity in fetal and adult ovine cerebral arteries

¹Departments of Physiology, Pharmacology, and Biochemistry, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California; and ²Department of Physiology, University of South Alabama, Mobile, Alabama

Submitted 2 March 2009 ; accepted in final form 24 April 2009

A broad variety of evidence obtained largely in pulmonary vasculature suggests that chronic hypoxia modulates vasoreactivity to nitric oxide (NO). The present study explores the general hypothesis that chronic hypoxia also modulates cerebrovascular reactivity to NO, and does so by modulating the activity of soluble guanylate cyclase (sGC), the primary target for NO in vascular smooth muscle. Pregnant and nonpregnant ewes were maintained at either sea level or at 3,820 m for the final 110 days of gestation, at which time middle cerebral arteries from term fetal lambs and nonpregnant adults were harvested. In both fetal and adult arteries, NO-induced vasodilatation was attenuated by chronic hypoxia and completely inhibited by 10 µM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of sGC. sGC abundance (in ng sGC/mg protein) measured via Western immunoblots was 10-fold greater in fetal (17.6 ± 1.6) than adult (1.7 ± 0.3) arteries but was not affected by chronic hypoxia. The specific activity of sGC (in pmol cGMP·µg sGC^–1·min^–1) was similar in fetal (255 ± 64) and adult (280 ± 75) arteries and was inhibited by chronic hypoxia in both fetal (120 ± 10) and adult (132 ± 26) arteries. Rates of cGMP degradation (in pmol cGMP·mg protein^–1·min^–1) were similar in fetal (159 ± 59) and adult (134 ± 36) arteries but were not significantly depressed by chronic hypoxia in either fetal (115 ± 25) or adult (108 ± 25) arteries. The cGMP analog 8-(p-chlorophenylthio)-cGMP was a more potent vasorelaxant in fetal (pD₂ = 4.7 ± 0.1) than adult (pD₂ = 4.3 ± 0.1) arteries, but its ability to promote vasodilatation was not affected by chronic hypoxia in either age group. Together, these results reveal that hypoxic inhibition of NO-induced vasodilatation is attributable largely to attenuation of the specific activity of sGC and does not involve significant changes in sGC abundance, cGMP-phosphodiesterase activity, or the vasorelaxant activity of protein kinase G.

cGMP; nitric oxide; phosphodiesterase; protein kinase G; smooth muscle