What leads to different mediators of alkalosis-induced  vasodilation in isolated and in situ pulmonary vessels?

We previously found that nitric oxide synthase (NOS) inhibition fully blocked alkalosis-induced relaxation of piglet pulmonary artery and vein rings. In contrast, NOS inhibition alone had no effect on alkalosis-induced pulmonary vasodilation in isolated piglet lungs. This study sought to identify factors contributing to the discordance between isolated and in situ pulmonary vessels. The roles of pressor stimulus (hypoxia vs. the thromboxane mimetic U-46619), perfusate composition (blood vs. physiological salt solution), and flow were assessed. Effects of NOS inhibition on alkalosis-induced dilation were also directly compared in 150–350-μm-diameter cannulated arteries and 150–900-μm-diameter, angiographically visualized, in situ arteries. Finally, effects of NOS inhibition on alkalosis-induced vasodilation were measured in intact piglets. NOS inhibition with N ω-nitro-l-arginine fully abolished alkalosis-induced vasodilation in all cannulated arteries but failed to alter alkalosis-induced vasodilation in intact lungs. The results indicate that investigation of other factors, such as perivascular tissue (e.g., adventitia and parenchyma) and remote signaling pathways, will need to be carried out to reconcile this discordance between isolated and in situ arteries.

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Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00425.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. H1812-H1820 ◽

Cited By ~ 88

Author(s):

Girija G. Konduri ◽

Ivane Bakhutashvili ◽

Annie Eis ◽

Kirkwood Pritchard

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Nitric Oxide Synthase ◽

Pulmonary Artery ◽

Ductus Arteriosus ◽

Oxidant Stress ◽

Pulmonary Arteries ◽

Persistent Pulmonary Hypertension ◽

Pulmonary Vasodilation ◽

Oxide Synthase

Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased NO release and impaired pulmonary vasodilation. We investigated the hypothesis that increased superoxide (O2•−) release by an uncoupled endothelial nitric oxide synthase (eNOS) contributes to impaired pulmonary vasodilation in PPHN. We investigated the response of isolated pulmonary arteries to the NOS agonist ATP and the NO donor S-nitroso- N-acetylpenicillamine (SNAP) in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus and in sham-ligated controls in the presence or absence of the NOS antagonist nitro-l-arginine methyl ester (l-NAME) or the O2•− scavenger 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron). ATP caused dose-dependent relaxation of pulmonary artery rings in control lambs but induced constriction of the rings in PPHN lambs. l-NAME, the NO precursor l-arginine, and Tiron restored the relaxation response of pulmonary artery rings to ATP in PPHN. Relaxation to NO was attenuated in arteries from PPHN lambs, and the response was improved by l-NAME and by Tiron. We also investigated the alteration in heat shock protein (HSP)90-eNOS interactions and release of NO and O2•− in response to ATP in the pulmonary artery endothelial cells (PAEC) from these lambs. Cultured PAEC and endothelium of freshly isolated pulmonary arteries from PPHN lambs released O2•− in response to ATP, and this was attenuated by the NOS antagonist l-NAME and superoxide dismutase (SOD). ATP stimulated HSP90-eNOS interactions in PAEC from control but not PPHN lambs. HSP90 immunoprecipitated from PPHN pulmonary arteries had increased nitrotyrosine signal. Oxidant stress from uncoupled eNOS contributes to impaired pulmonary vasodilation in PPHN induced by ductal ligation in fetal lambs.

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Multiple Ca2+-dependent modulators mediate alkalosis-induced vasodilation in newborn piglet lungs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.3.l519 ◽

2001 ◽

Vol 280 (3) ◽

pp. L519-L526 ◽

Cited By ~ 9

Author(s):

Michele A. Vander Heyden ◽

Ted R. Halla ◽

Jane A. Madden ◽

John B. Gordon

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Pulmonary Artery ◽

Newborn Piglet ◽

Channel Activation ◽

Future Studies ◽

Pulmonary Vasodilation ◽

Blocking Voltage ◽

Voltage Dependent ◽

Oxide Synthase

We previously found that alkalosis-induced vasodilation was mediated by endothelium-derived nitric oxide (EDNO) in newborn piglet pulmonary artery and vein rings precontracted with the thromboxane mimetic U-46619. In contrast, prostacyclin or K+ channel activation contributed to the response in other preparations. This study was undertaken to determine whether EDNO alone also mediates alkalosis-induced pulmonary vasodilation in piglet lungs vasoconstricted with hypoxia and, if not, to identify the mediator(s) involved. Responses to alkalosis were measured during hypoxia under control conditions after blocking nitric oxide synthase ( N ω-nitro-l-arginine), cyclooxygenase (meclofenamate), or both endothelium-derived modulators (Dual); after blocking voltage-dependent (4-aminopyridine), ATP- dependent (glibenclamide), or Ca2+-dependent K+ (KCa; tetraethylammonium) K+channels; and after blocking both endothelium-derived modulators and KCa channels (Triple). Vasodilator responses measured after 20 min of alkalosis were blunted in Dual and tetraethylammonium lungs and abolished in Triple lungs. Thus alkalosis-induced vasodilation in hypoxic lungs appeared to be mediated by three Ca2+-dependent modulators: EDNO, prostacyclin, and KCa channels. In addition, a transient, unidentified modulator contributed to the nadir of the vasodilator response measured at 10 min of alkalosis. Future studies are needed to identify factors that contribute to the discordance between isolated vessels and whole lungs.

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Faculty Opinions recommendation of Effects of nitric oxide synthase inhibition by L-NAME on oxygen uptake kinetics in isolated canine muscle in situ.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1087541.540599 ◽

2007 ◽

Author(s):

Michael Reid

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Oxygen Uptake ◽

Oxygen Uptake Kinetics ◽

Uptake Kinetics ◽

Oxide Synthase

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Upregulation of nitric oxide synthase and galanin message-associated peptide in hypothalamic magnocellular neurons after hypophysectomy. Immunohistochemical and in situ hybridization studies

Brain Research ◽

10.1016/0006-8993(94)91785-x ◽

1994 ◽

Vol 650 (2) ◽

pp. 219-228 ◽

Cited By ~ 23

Author(s):

Marcelo J. Villar ◽

Sandra Ceccatelli ◽

Katarina Bedecs ◽

Tamas Bartfai ◽

David Bredt ◽

...

Keyword(s):

Nitric Oxide ◽

In Situ Hybridization ◽

Nitric Oxide Synthase ◽

Magnocellular Neurons ◽

Oxide Synthase

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Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide

Journal of Applied Physiology ◽

10.1152/jappl.2002.92.1.33 ◽

2002 ◽

Vol 92 (1) ◽

pp. 33-40 ◽

Cited By ~ 15

Author(s):

Daniel Nyhan ◽

Soonyul Kim ◽

Stacey Dunbar ◽

Dechun Li ◽

Artin Shoukas ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Pulmonary Artery ◽

Lung Tissue ◽

Rat Model ◽

Orthostatic Intolerance ◽

Volume Distribution ◽

Contractile Responses ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Vascular contractile hyporesponsiveness is an important mechanism underlying orthostatic intolerance after microgravity. Baroreceptor reflexes can modulate both pulmonary resistance and capacitance function and thus cardiac output. We hypothesized, therefore, that pulmonary vasoreactivity is impaired in the hindlimb-unweighted (HLU) rat model of microgravity. Pulmonary artery (PA) contractile responses to phenylephrine (PE) and U-46619 (U4) were significantly decreased in the PAs from HLU vs. control (C) animals. N G-nitro-l-arginine methyl ester (10−5 M) enhanced the contractile responses in the PA rings from both C and HLU animals and completely abolished the differential responses to PE and U4 in HLU vs. C animals. Vasorelaxant responses to ACh were significantly enhanced in PA rings from HLU rats compared with C. Moreover, vasorelaxant responses to sodium nitroprusside were also significantly enhanced. Endothelial nitric oxide synthase (eNOS) and soluble guanlyl cyclase expression were significantly enhanced in PA and lung tissue from HLU rats. In marked contrast, the expression of inducible nitric oxide synthase was unchanged in lung tissue. These data support the hypothesis that vascular contractile responsiveness is attenuated in PAs from HLU rats and that this hyporesponsiveness is due at least in part to increased nitric oxide synthase activity resulting from enhanced eNOS expression. These findings may have important implications for blood volume distribution and attenuated stroke volume responses to orthostatic stress after microgravity exposure.

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