title: Effects of chronic hypoxia on soluble guanylate cyclase activity in fetal and adult ovine cerebral arteries.
abstract: 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 microM 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 approximately 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.microg 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 (pD(2) = 4.7 +/- 0.1) than adult (pD(2) = 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.
authors.affiliation: Department of Physiology, Center for Perinatal Biology, Loma Linda Univ. School of Medicine, Loma Linda, CA 92350, USA. wpearce@llu.edu
authors.forename: William J
authors.initials: WJ
authors.lastname: Pearce
authors.forename: James M
authors.initials: JM
authors.lastname: Williams
authors.forename: Charles R
authors.initials: CR
authors.lastname: White
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Lincoln
mesh_terms: D000532:Altitude Sickness / Q000150:complications / Q000201:enzymology; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D002908:Chronic Disease; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000098:blood supply*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000860:Hypoxia / Q000201:enzymology* / Q000209:etiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D011247:Pregnancy; D011810:Quinoxalines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012756:Sheep / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D045462:Endothelium-Dependent Relaxing Factors; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP