In vivo treatment with endotoxin induces nitric oxide synthase in rat main pulmonary artery

Griffiths, Mark; Liu, S.; Curzen, Nicholas; Messent, Mark; Evans, TW

doi:10.1152/ajplung.1995.268.3.l509

Cited by 49 publications

(44 citation statements)

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“…It is, therefore, likely that unstimulated basal production of NO in these vessels was due mainly to iNOS, which was at this time predominant in the endothelial cells. These results are consistent with previous data demonstrating induction of NOS both in endothelial and smooth muscle cell layers of PA from rats treated with endotoxin [19].…”

Section: Discussionsupporting

confidence: 93%

Induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats

Carville¹,

Adnot²,

Eddahibi³

et al. 1997

Eur Respir J

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Chronic hypoxia has recently been shown to upregulate inducible nitric oxide synthase (iNOS) gene expression in rat lung. In the present study, we questioned whether induction of NO synthesis could alter the reactivity of pulmonary arteries (PA) from chronically hypoxic (CH) rats. Dose-response curves to phenylephrine (PE) 10 -9 to 5×10 -6 M) were examined in PA rings as well as response to L-arginine analogues in isolated lungs from CH or normoxic (N) rats after various incubation times.Although maximal contraction to PE did not differ in PA from CH rats compared to N rats at time 0 (361±53 vs 506±52 mg, respectively), it was markedly decreased after prolonged incubation (149±28 vs 386±47 mg, respectively, at 4 h; p<0.001). This phenomenon persisted after endothelial-denudation, but was reversed by N G -monomethyl-L-arginine (L-NMMA) (5×10 -4 M) and prevented by actinomycin D (2×10 -6 M). In contrast, maximal contraction to PE in aorta from CH rats was similar at time 0 and 4 h. After a short incubation, PA contraction to L-NMMA was greater in CH than in N rats (96±17 vs 33±9 mg at 90 min; p<0.05), was abolished after endothelial denudation, but persisted in CH rats in the presence of calmidazolium (5×10 -4 M). At 4 h, contraction to L-NMMA was abolished in endothelium-denuded PA from N rats but only attenuated in those from CH rats. In salt solution perfused lungs, L-NMMA added 30 or 90 min after isolation did not alter baseline pressure in N rats but caused its increase in CH rats. Whereas iNOS messenger ribonucleic acid (mRNA) was detectable by reverse-transcriptase polymerase chain reaction in the PA wall of N or CH rats after 4 h of incubation, it was absent in both at the time of isolation. In contrast, there was evidence of iNOS mRNA in lungs from CH rats at the time of isolation but no signal in those from N rats.In conclusion, there is induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats after prolonged incubation, but this effect is more pronounced in pulmonary arteries from chronically hypoxic rats. Eur Respir J 1997; 10: 437-445 In recent years, there has been considerable interest in the role of nitric oxide (NO) in the normal and remodelled pulmonary circulation. Endothelium-derived NO has been shown to play an important role not only in modulating the pulmonary vascular tone but also in the control of smooth muscle proliferation associated with vascular remodelling. Indeed, vasoconstrictor responses to various stimuli, such as acute hypoxia [1,2], angiotensin II [1] and endothelin-1 [3], are potentiated by inhibitors of NO synthesis. In rats exposed to chronic hypoxia, supplying NO to the pulmonary vessels by continuous inhalation attenuates muscularization of distal vessels [4]. More recently, NO has also been shown to inhibit gene expression of endothelin [5] and various growth factors, such as platelet-derived growth factor (PDGF) [5] and vascular endothelial growth factor (VEGF) [6].In chronic hypoxic pulmonary hypertension, th...

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Section: Discussionsupporting

confidence: 93%

Induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats

Carville¹,

Adnot²,

Eddahibi³

et al. 1997

Eur Respir J

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“…This difference could lead to hypocontractile response to histamine in mesenteric but not in pulmonary arteries. Our findings may provide a basis for the results of past investigations that iNOS induction-associated vascular hypocontractility was not observed in the pulmonary circulation (Nelson et al, 1991;Suba et al, 1992;Spath et al, 1994;Fullerton et al, 1995) despite the presence of iNOS mRNA in pulmonary vessels in vivo LPS (Griffiths et al, 1995).…”

Section: Vascular Hyporesponsiveness To Vasocontractile Stimulisupporting

confidence: 77%

“…Finally, iNOS deficient mice have been found to be resistant to vascular hypocontractility (Gunnett et al, 1998). Accordingly, iNOS, which generates large amounts of NO, is likely to be a critical mediator of the diminished vascular contractility in sepsis (Fleming et al, 1991;Griffiths et al, 1995;Hom et al, 1995).…”

Section: Vascular Hyporesponsiveness To Vasocontractile Stimulimentioning

confidence: 99%

Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction

Matsuda

Hattori

2007

J Smooth Muscle Res

116

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Sepsis is the leading cause of mortality in critically ill patients. In this pathological syndrome, septic shock and sequential multiple organ failure correlate with poor outcome. The pathophysiology of sepsis with acute organ dysfunction involves a highly complex, integrated response that includes activation of number of cell types, inflammatory mediators, and the hemostatic system. Central to this process may be alterations in vascular functions. This review article provides a growing body of evidence for the potential impact of vascular dysfunction on sepsis pathophysiology with a major emphasis on the endothelium. Furthermore, the role of apoptotic signaling molecules in the mechanisms underlying endothelial cell injury and death during sepsis and its potential value as a target for sepsis therapy will be discussed, which may help in the assessment of ongoing therapeutic strategies.

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“…50 LPS produces impaired eNOSdependent relaxation in vessels, 14,15,18 and expression of iNOS has been demonstrated in blood vessels after LPS. 3,4,9 Responses to pharmacological inhibitors, such as aminoguanidine, suggest that iNOS mediates impaired endothelial function after LPS. 12,20,21 However, inhibition of neuronal NO synthase also improves endothelium-dependent relaxation during inflammation.…”

Section: Effects Of Inos On Vasorelaxationmentioning

confidence: 99%

“…1,2 In general, proinflammatory stimuli produce the expression of iNOS within the vessel wall. [3][4][5][6][7][8] Expression of iNOS during systemic inflammation contributes to impaired contraction, 3,4,9,10 but effects of iNOS on vasorelaxation have not been clearly established. Several studies suggest that vasorelaxation is impaired after inflammatory stimuli, such as lipopolysaccharide (LPS), [11][12][13][14] but others report normal vasorelaxation after LPS.…”

mentioning

confidence: 99%

NO-Dependent Vasorelaxation Is Impaired After Gene Transfer of Inducible NO-Synthase

Gunnett

Lund

Chu

et al. 2001

ATVB

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Abstract-Proinflammatory stimuli produce expression of inducible NO-synthase (iNOS) within blood vessels and are associated with impaired endothelium-dependent relaxation. Gene transfer of iNOS was used to test the hypothesis that expression of iNOS in blood vessels produces impairment of NO-dependent relaxation as well as contraction. An adenoviral vector containing cDNA for murine iNOS, AdCMViNOS, and a control virus, AdCMVBglII, were used for gene transfer to rabbit carotid arteries in vitro and in vivo. After gene transfer of iNOS in vitro, contractile responses to KCl, phenylephrine, and U46619 were impaired. Relaxation in response to acetylcholine, ADP, A23187, and nitroprusside was also impaired. For example, maximum relaxation of vessels to acetylcholine (10 mol/L) was 78Ϯ4% (meanϮSE) after AdBglII (10 10.5 plaque-forming units) and 34Ϯ5% after AdiNOS (10 10.5 plaque-forming units, PϽ0.05). NO-independent relaxation in response to 8-bromo-cGMP and papaverine was not impaired after AdiNOS. Contraction and relaxation were improved in carotid arteries expressing iNOS by aminoguanidine and L-N-iminoethyl lysine, inhibitors of iNOS. After intraluminal gene transfer of iNOS in vivo, contraction of vessels in vitro was normal, but responses to acetylcholine were impaired. In summary, the major finding is that NO-dependent relaxation is impaired in arteries after gene transfer of iNOS in vitro and in vivo. Key Words: superoxide Ⅲ NO-dependent relaxation Ⅲ adenovirus Ⅲ acetylcholine Ⅲ nitroprusside A lthough normal blood vessels do not express inducible NO-synthase (iNOS), vascular expression of iNOS occurs in pathological settings, including cerebrovascular disease and stroke. 1,2 In general, proinflammatory stimuli produce the expression of iNOS within the vessel wall. [3][4][5][6][7][8] Expression of iNOS during systemic inflammation contributes to impaired contraction, 3,4,9,10 but effects of iNOS on vasorelaxation have not been clearly established. Several studies suggest that vasorelaxation is impaired after inflammatory stimuli, such as lipopolysaccharide (LPS), 11-14 but others report normal vasorelaxation after LPS. 15,16 The goal of these studies was to examine effects of iNOS on contraction and relaxation of blood vessels by using gene transfer of iNOS. See page 1259Endothelium-dependent vasorelaxation mediated by endothelial NO synthase (eNOS) is impaired in response to several inflammatory stimuli that induce iNOS in blood vessels. 12,[17][18][19] Pharmacological inhibitors of iNOS improve endothelium-dependent relaxation after LPS. 12,20,21 The findings suggest that expression of iNOS is associated with decreased function of eNOS. However, pharmacological inhibitors of iNOS are not entirely selective for iNOS, and inhibition of neuronal NO synthase also improves endothelium-dependent relaxation during inflammation. 20 Therefore, it is not known whether iNOS, per se, affects relaxation of blood vessels.The goal of the present study was to use gene transfer of iNOS, in vitro and in vivo, to directly e...

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In vivo treatment with endotoxin induces nitric oxide synthase in rat main pulmonary artery

Cited by 49 publications

References 0 publications

Induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats

Induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats

Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction

NO-Dependent Vasorelaxation Is Impaired After Gene Transfer of Inducible NO-Synthase

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