Effect of inhibition of NO synthase on vascular reactivity in a rat model of hyperdynamic sepsis

Fox, George A; Paterson, Nigel A. M.; McCormack, DG

doi:10.1152/ajpheart.1994.267.4.h1377

Cited by 21 publications

(21 citation statements)

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“…3 In LPS-challenged rats with and without cirrhosis, isolated aortas are hyporeactive to phenylephrine caused by high-output NO production by iNOS expression in arterial walls. [11][12][13][14][15][16] This is confirmed by our finding that, in the LPS-alone group, isolated aortas exposed to L-NIL, a selective iNOS inhibitor, had significantly increased phenylephrine-induced contraction. Thus, iNOS induced by LPS in vivo is still present in isolated arteries.…”

Section: Discussionsupporting

confidence: 78%

Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis

et al. 2002

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In cirrhosis, lipopolysaccharide (LPS, a product of Gram-negative bacteria) in the blood may cause septic shock. LPS-elicited induction of arterial inducible nitric oxide synthase (iNOS) results in nitric oxide (NO)-induced vasodilation, which causes arterial hypotension and hyporeactivity to ␣ 1 -adrenergic constrictors. In vitro studies have suggested that vasopressin inhibits iNOS expression in cultured vascular smooth muscle cells exposed to LPS. Thus, the aim of this study was to investigate the effects of terlipressin administration (a vasopressin analog) on in vivo LPS-induced aortic iNOS in rats with cirrhosis. LPS (1 mg/kg, intravenously) was administered followed by the intravenous administration of terlipressin (0.05 mg/kg, intravenously) or placebo 1 hour later. Arterial pressure was measured, and contractions to phenylephrine (an ␣ 1 -adrenoceptor agonist), iNOS activity, and iNOS expressions (mRNA and protein) were investigated in isolated aortas. LPS-induced arterial hypotension and aortic hyporeactivity to phenylephrine were abolished in rats that received terlipressin. LPS-induced aortic iNOS activity and expression were suppressed in terlipressin-treated rats. In conclusion, in LPS-challenged rats with cirrhosis, terlipressin administration inhibits in vivo LPS-induced aortic iNOS expression. Terlipressin administration may be a novel approach for the treatment of arterial hypotension and hyporeactivity to ␣ 1 -adrenergic constrictors in patients with cirrhosis and septic shock.

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Section: Discussionsupporting

confidence: 78%

Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis

et al. 2002

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“…The existing evidence is controversial, with reports suggesting that HPV is either increased (11,12) or unchanged (13,14) after acute inhibition of NO formation with L-arginine analogs during sepsis. After an endotoxin challenge, suppression of NOS2 expression with dexamethasone and inhibition of NOS2 activity by administration of L-arginine analogs restore vascular reactivity to vasoconstrictors in both systemic (15) and pulmonary vessels (16).…”

Section: Introductionmentioning

confidence: 99%

Hypoxic pulmonary blood flow redistribution and arterial oxygenation in endotoxin-challenged NOS2-deficient mice

Ullrich

Bloch²,

Ichinose³

et al. 1999

J. Clin. Invest.

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The normal pulmonary vasculature constricts in response to alveolar hypoxia. In contrast, systemic vessels vasodilate in response to hypoxia. Hypoxic pulmonary vasoconstriction (HPV) preserves systemic arterial oxygenation by redistributing blood flow away from collapsed or poorly ventilated lung regions toward wellventilated lung regions, thereby matching pulmonary ventilation (V) with perfusion (Q).The mechanisms responsible for HPV are intrinsic to pulmonary vascular smooth muscle cells: HPV does not appear to require the presence of an intact endothelium (1). Vasoactive mediators released from a variety of pulmonary sources, including the endothelium and circulating cells, are important modulators of the pulmonary vascular response to hypoxia (2). Nitric oxide (NO) was identified as the endothelium-derived relaxing factor (EDRF) released from arteries and veins (3). NO synthases (NOSs) produce NO by conversion of Larginine to L-citrulline. Constitutive NOSs, NOS1 and NOS3 (initially isolated from neurons and endothelial cells, respectively), are calcium/calmodulin dependent and produce low levels of NO that regulate homeostatic processes and contribute to the low pulmonary vascular resistance (PVR) (4, 5). Acute inhibition of endogenous NO production has been shown to enhance HPV in normal animals (6), and inhaled NO reverses human HPV (7).In addition to its vasoregulatory function, NO participates in the response to inflammatory stimuli (8). Exposure to cytokines, such as IL-1β and TNF-α, or microbial products, such as endotoxin, stimulates cells to express an inducible NOS (NOS2) that generates greater amounts of NO than the constitutive isoforms (9). It is well established that the same inflammatory mediators that induce NOS2 also attenuate HPV, resulting in increased blood flow to poorly ventilated lung regions (V/Q mismatching), augmented right-to-left shunting of venous blood, and reduced arterial oxygenation (10) .The role of NO in the impairment of HPV during endotoxemia and sepsis is incompletely understood. The existing evidence is controversial, with reports suggesting that HPV is either increased (11, 12) or unchanged (13, 14) after acute inhibition of NO formation with L-arginine analogs during sepsis. After an endotoxin challenge, suppression of NOS2 expression with dexamethasone and inhibition of NOS2 activity by administration of L-arginine analogs restore vascular reactivity to vasoconstrictors in both systemic (15) and pulmonary vessels (16). However, the use of L-arginine analogs or dexamethasone to evaluate the role of NOS2 in the endotoxin-induced impairment of HPV is limited by the incomplete specificity of these agents for NOS2. To identify a role for NOS2 in the endotoxin-induced impairment of HPV, we compared the ability to redistribute pulmonary blood flow after left mainstem bronchus occlusion (LMBO) in wild-type mice Sepsis and endotoxemia impair hypoxic pulmonary vasoconstriction (HPV), thereby reducing arterial oxygenation and enhancing hypoxemia. Endotoxin induces nitric oxide ...

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“…Nitric oxide (NO) production due to induction of NO synthase isoform II (NOS II) has been assumed to mediate sepsis-induced vasodilation (16,21). However, findings that arterial hypotension, as well as vascular hyporeactivity, is only slightly alleviated by NOS II inhibition suggest that other or additional pathways may be involved in septic circulatory failure (5,22,27,31). Alterations in vasoconstrictor mechanisms have been reported.…”

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confidence: 99%

Cytokine-mediated downregulation of vasopressin V_1Areceptors during acute endotoxemia in rats

Bucher¹,

Hobbhahn²,

Taeger³

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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The reduced pressure response to vasopressin during acute sepsis has directed our interest to the regulation of vasopressin V1A receptors. Rats were injected with lipopolysaccharide for induction of experimental gram-negative sepsis. V1A receptor gene expression was downregulated in the liver, lung, kidney, and heart during endotoxemia. Inasmuch as the concentrations of proinflammatory cytokines such as interleukin-1␤, tumor necrosis factor-␣, and interferon-␥ were highly increased during sepsis, the influence of these cytokines on V1A receptor expression was investigated in primary cultures of hepatocytes and in the aortic vascular smooth muscle cell line A7r5. V1A receptor expression was downregulated by the cytokines in a nitric oxide-independent manner. Blood pressure dose-response studies after injection of endotoxin showed a diminished responsiveness to the selective V1 receptor agonist Phe 2 ,Ile 3 ,Orn 8 -vasopressin. Our data show that sepsis causes a downregulation of V1A receptors and suggest that this effect is likely mediated by proinflammatory cytokines. We propose that this downregulation of V1A receptors contributes to the attenuated responsiveness of blood pressure in response to vasopressin and, therefore, contributes to the circulatory failure in septic shock. blood pressure; hepatocytes; vascular smooth muscle; A7r5 cell line; nitric oxide SHOCK DUE TO SEPSIS HAS INCREASED in incidence during the past 50 years and is now one of the most common causes of death in intensive care units. Despite considerable therapeutic advances, mortality from septic shock remains high. Pathogenetically, sepsis and septic shock are characterized by systemic vasodilation, leading to arterial hypotension, multiple organ dysfunction, and death (21). The pathogenetic mechanism of this vasodilation is multifactorial and not clearly understood. Nitric oxide (NO) production due to induction of NO synthase isoform II (NOS II) has been assumed to mediate sepsis-induced vasodilation (16,21). However, findings that arterial hypotension, as well as vascular hyporeactivity, is only slightly alleviated by NOS II inhibition suggest that other or additional pathways may be involved in septic circulatory failure (5,22,27,31). Alterations in vasoconstrictor mechanisms have been reported. Inappropriate low plasma vasopressin levels have been suggested to contribute to the hypotension in advanced vasodilatory septic shock (14). In models of acute sepsis, vasopressin is markedly increased (26,32,33); in addition, a reduced pressor response to the exogenous hormone has been shown (8,26,30). The pathogenetic mechanisms of this phenomenon, called vasoplegia, are not clearly understood. One could imagine that the receptors for vasoconstrictors could be altered during sepsis, leading to diminished pressor effects in response to the respective agonist. We previously demonstrated that sepsis leads to a systemic downregulation of ANG II type 1 receptors (4). Therefore, we were interested also in the regulation of the receptor mediating the ...

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Effect of inhibition of NO synthase on vascular reactivity in a rat model of hyperdynamic sepsis

Cited by 21 publications

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Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis

Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis

Hypoxic pulmonary blood flow redistribution and arterial oxygenation in endotoxin-challenged NOS2-deficient mice

Cytokine-mediated downregulation of vasopressin V_1Areceptors during acute endotoxemia in rats

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Effect of inhibition of NO synthase on vascular reactivity in a rat model of hyperdynamic sepsis

Cited by 21 publications

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Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis

Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis

Hypoxic pulmonary blood flow redistribution and arterial oxygenation in endotoxin-challenged NOS2-deficient mice

Cytokine-mediated downregulation of vasopressin V1Areceptors during acute endotoxemia in rats

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Cytokine-mediated downregulation of vasopressin V_1Areceptors during acute endotoxemia in rats