title: Endothelium-dependent vasodilation of cerebral arteries is altered with simulated microgravity through nitric oxide synthase and EDHF mechanisms.
abstract: Cephalic elevations in arterial pressure associated with microgravity and prolonged bed rest alter cerebrovascular autoregulation in humans. Using the head-down tail-suspended (HDT) rat to chronically induce headward fluid shifts and elevate cerebral artery pressure, previous work has likewise shown cerebral perfusion to be diminished. The purpose of this study was to test the hypothesis that 2 wk of HDT reduces cerebral artery vasodilation. To test this hypothesis, dose-response relations for endothelium-dependent (2-methylthioadenosine triphosphate and bradykinin) and endothelium-independent (nitroprusside) vasodilation were determined in vitro in middle cerebral arteries (MCAs) from HDT and control rats. All in vitro measurements were done in the presence and absence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (10(-5) M) and cyclooxygenase inhibitor indomethacin (10(-5) M). MCA caveolin-1 protein content was measured by immunoblot analysis. Endothelium-dependent vasodilation to 2-methylthioadenosine triphosphate and bradykinin were both lower in MCAs from HDT rats. These lower vasodilator responses were abolished with N(G)-nitro-L-arginine methyl ester but were unaffected by indomethacin. In addition, HDT was associated with lower levels of MCA caveolin-1 protein. Endothelium-independent vasodilation was not altered by HDT. These results indicate that chronic cephalic fluid shifts diminish endothelium-dependent vasodilation through alterations in the endothelial nitric oxide synthase signaling mechanism. Such decrements in endothelium-dependent vasodilation of cerebral arteries could contribute to the elevations in cerebral vascular resistance and reductions in cerebral perfusion that occur after conditions of simulated microgravity in HDT rats.
authors.affiliation: Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia 26506, USA. mdelp@hsc.wvu.edu
authors.forename: Rhonda D
authors.initials: RD
authors.lastname: Prisby
authors.forename: M Keith
authors.initials: MK
authors.lastname: Wilkerson
authors.forename: Elke M
authors.initials: EM
authors.lastname: Sokoya
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bryan
authors.forename: Emily
authors.initials: E
authors.lastname: Wilson
authors.forename: Michael D
authors.initials: MD
authors.lastname: Delp
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000502:physiology; D000818:Animals; D001685:Biological Factors / Q000032:analysis / Q000502:physiology*; D001920:Bradykinin / Q000502:physiology; D051242:Caveolin 1 / Q000032:analysis / Q000502:physiology; D002536:Cerebral Arteries / Q000737:chemistry / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000737:chemistry / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D019417:Hindlimb Suspension / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013873:Thionucleotides / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology; D014893:Weightlessness
chemical_list: D001685:Biological Factors; D051242:Caveolin 1; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D013873:Thionucleotides; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009599:Nitroprusside; D000255:Adenosine Triphosphate; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin; C008501:2-methylthio-ATP