Early changes in vasoreactivity after simulated microgravity are due to an upregulation of the endothelium-dependent nitric oxide/cGMP pathway.
Emerging evidence suggests that nitric oxide (NO) plays a pivotal role in the mechanism of vascular hyporesponsiveness contributing to microgravity-induced orthostatic intolerance. The cellular and enzymatic source of the NO, however, remains controversial. In addition, the time course of the endothelial-dependent contribution remains unstudied. We tested the hypotheses that the change in vasoresponsiveness seen in acute (3-day) hindlimb unweighted (HLU) animals is due to an endothelium-dependent mechanism and that endothelial-dependent attenuation in vasoreactivity is due to endothelial nitric oxide synthase (NOS-3) dependent activation. Vasoreactivity was investigated in rat aortic rings following acute HLU treatment. Dose responsiveness to norepinepherine (NE) was depressed after 3-day HLU [1,338 +/- 54 vs. 2,325 +/- 58 mg at max (NE), HLU vs. C, P < 0.001]. However, removal of the endothelium restored the vascular contractility to that of C. In addition, 1H-oxadiazole quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, restored the reduced vasoconstrictor responses to phenylephrine (PE) seen in 3-day HLU rings (1.30 +/- 0.10 vs. 0.53 +/- 0.07 g, HLU + ODQ vs. HLU, P = 0.0001). Ca(+) dependent nitric oxide synthase (NOS) activity was increased, as was vascular NO products as a result of HLU. While NOS-3 expression was not increased in HLU rats, phosphorylation of NOS-3 at serine-1177 (an activator of NOS-3) was increased while phosphorylation of serine-495 (an inactivator of NOS-3) was decreased. These findings demonstrate that changes in vasoresponsiveness in the acute HLU model of microgravity are due to an upregulation of the endothelial-dependent NO/cGMP pathway through NOS phosphorylation.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287-6568, USA.
Anthony R
AR
White
Sungwoo
S
Ryoo
Lukasz
L
Bugaj
David O
DO
Attarzadeh
Srikanth
S
Thiyagarajan
Kexun
K
Chen
Sarah
S
Attwater
Bryce
B
Abbot
Dechun
D
Li
Hunter C
HC
Champion
Artin A
AA
Shoukas
Daniel
D
Nyhan
Joshua M
JM
Hare
Dan E
DE
Berkowitz
Eric C
EC
Tuday
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D019417:Hindlimb Suspension; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects; D012694:Serine; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D018474:Weightlessness Simulation
C495537:Cav1 protein, rat; D051242:Caveolin 1; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D012694:Serine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP