Selective versus non-selective suppression of nitric oxide synthase on regional hemodynamics in rats with or without LPS-induced endotoxemia

Cheng, Xing; Leung, Susan W.S.; Lo, Lawrence; Pang, Catherine C.Y.

doi:10.1007/s00210-002-0684-1

Cited by 14 publications

(8 citation statements)

References 41 publications

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“…4, A and B) were all substantially attenuated in ampicillin-pretreated rats. Together, these findings, complemented by the ability of 1400W to attenuate the hypotensive response to endotoxic shock (Cheng et al, 2003), strongly support our hypothesis that an endotoxin-mediated facilitation of cardiac iNOS expression accounts, at least partly, for the hemodynamic effects of ethanol in female rats. It is noteworthy that the spontaneous locomotor activity of rats was not affected by ethanol, 1400W, or their combination, which precludes any possible role for behavioral factors in the antagonistic ethanol-1400W hemodynamic interaction.…”

supporting

confidence: 78%

“…2C) may represent a counter-regulatory mechanism to offset the ethanol-evoked reductions in CO and BP. Remarkably, the hypodynamic state (high TPR and low CO) induced by ethanol in this study resembles that produced by lipopolysaccharide during septic shock (Cheng et al, 2003). The latter is believed to trigger a surge in plasma levels of vasoconstrictors, e.g., angiotensin II, endothelin-1, and vasopressin, which increase TPR to counterbalance the BP/CO falls (Brackett et al, 1985;Gardiner et al, 1996;Mitaka et al, 1999).…”

mentioning

confidence: 63%

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Endotoxemia-Mediated Induction of Cardiac Inducible Nitric-Oxide Synthase Expression Accounts for the Hypotensive Effect of Ethanol in Female Rats

El‐Mas

Fan²,

Abdel‐Rahman³

2007

J Pharmacol Exp Ther

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We have recently shown that intragastric (i.g.) ethanol lowers blood pressure (BP) in conscious female rats via a reduction in cardiac output (CO). However, the mechanisms implicated in these hemodynamic effects of ethanol are not known. Therefore, we tested the hypothesis that ethanol-evoked endotoxemia mediates the reduction in CO via enhanced myocardial inducible nitric-oxide synthase (iNOS) expression. Immunoblot (myocardial iNOS), biochemical (plasma endotoxin and nitrite/ nitrate), and integrative [BP, heart rate, CO, stroke volume (SV), and total peripheral resistance (TPR)] studies were conducted in conscious female rats that received i.g. ethanol (1 g/kg) in the absence or presence of 1400W (N-(3-[aminomethyl]benzyl) acetamidine) or ampicillin to selectively inhibit iNOS and to eliminate endogenous endotoxin, respectively. Ethanol-evoked hypotension coincided with reductions in CO and SV and increases in: 1) TPR, 2) plasma endotoxin and nitrite/nitrate, and 3) myocardial iNOS expression. These effects of ethanol were virtually abolished in rats pretreated with ampicillin (200 mg/kg/ day for 2 days by gavage) or with 1400W (5 mg/kg i.p.) except for the increase in plasma endotoxin, which persisted in 1400W-pretreated rats. These findings yield insight into the mechanistic role of endotoxin-myocardial iNOS signaling in the cardiodepressant action of ethanol, which accounts for its hypotensive effect in conscious female rats.Ethanol elicits hypotension in female, but not in age-matched male, rats (El-Mas and Abdel-Rahman, 1999a). Furthermore, the hypotensive effect of ethanol is estrogen-dependent (El-Mas and Abdel-Rahman, 1999b). It is imperative also to note that moderate ethanol consumption is associated with lower BP in young but not in old women (Klatsky, 1990), which highlights the clinical relevance of the reported experimental findings. The precise mechanism by which ethanol elicits hypotension in female rats is not known. It is noteworthy that there are similarities between the cardiovascular effects of ethanol and estrogen, which include inhibition of calcium influx (Turlapaty et al., 1979;Zhang et al., 1994), enhancement of NOS activity (Weiner et al., 1994;Wang and Abdel-Rahman, 2005;Zhang et al., 2005), and reduction of ␣-adrenergic receptor responsiveness (Abdel-Rahman et al., 1985;Sudhir et al., 1997). Indeed, the NOS-derived NO seems to be the major mediator of the estrogen-dependent hypotensive effect of ethanol because NO is directly or indirectly linked to vasodilation and reduces cardiac contractility (Yeh et al., 2005). It is possible, therefore, that ethanol may interact synergistically with estrogen to produce vascular and/or cardiac changes that might lead to hypotension.Built on the premise that ethanol enhances iNOS signaling (Durante et al., 1995), we demonstrated in a recent study the ability of ethanol to increase vascular (aortic) iNOS expression in female rats (El-Mas et al., 2006). Such a response could not be mechanistically linked to the hypotensive effect of ethan...

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supporting

confidence: 78%

mentioning

confidence: 63%

Endotoxemia-Mediated Induction of Cardiac Inducible Nitric-Oxide Synthase Expression Accounts for the Hypotensive Effect of Ethanol in Female Rats

El‐Mas

Fan²,

Abdel‐Rahman³

2007

J Pharmacol Exp Ther

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“…3). These results confirm data from infusion studies with the selective iNOS inhibitors 1400W (Wray et al, 1998;Cheng et al, 2003) and GW273629 (Alderton et al, 2005) and corroborate the view that excessive NO production by iNOS is a major mechanism underlying the development of hypotension in the course of systemic inflammation. According to our data, selective inhibition of iNOS by BYK191023 without interfering with constitutively expressed e/nNOS activity should be sufficient for the desired therapeutic effect on macrocirculation.…”

Section: In Vivo Characterization Of the Inos Inhibitor Byk191023 185supporting

confidence: 80%

In Vivo Characterization of the Novel Imidazopyridine BYK191023 [2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine], a Potent and Highly Selective Inhibitor of Inducible Nitric-Oxide Synthase

Lehner¹

2005

J Pharmacol Exp Ther

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Excessive release of nitric oxide from inducible nitric-oxide synthase (iNOS) has been postulated to contribute to pathology in a number of inflammatory diseases. We recently identified imidazopyridine derivatives as a novel class of potent nitricoxide synthase inhibitors with high selectivity for the inducible isoform. In the present study, we tested the in vivo potency of BYK191023 [2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo- [4,5-b]pyridine], a selected member of this inhibitor class, in three different rat models of lipopolysaccharide-induced systemic inflammation. Delayed administration of BYK191023 dose-dependently suppressed the lipopolysaccharide-induced increase in plasma nitrate/nitrite (NO x ) levels with an ED 50 of 14.9 mol/kg/h. In a model of systemic hypotension following high-dose lipopolysaccharide challenge, curative administration of BYK191023 at a dose that inhibited 83% of the NO x increase completely prevented the gradual decrease in mean arterial blood pressure observed in vehicle-treated control animals. The vasopressor effect was specific for endotoxemic animals since BYK191023 did not affect blood pressure in salinechallenged controls. In addition, in a model of lipopolysaccharideinduced vascular hyporesponsiveness, BYK191023 infusion partially restored normal blood pressure responses to norepinephrine and sodium nitroprusside via an L-arginine competitive mechanism. Taken together, BYK191023 is a member of a novel class of highly isoform-selective iNOS inhibitors with promising in vivo activity suitable for mechanistic studies on the role of selective iNOS inhibition as well as clinical development.Nitric-oxide synthases (NOSs) catalyze the conversion of L-arginine to citrulline and nitric oxide. The constitutively expressed endothelial NOS (eNOS) and neuronal NOS (nNOS) isoforms are involved in regulation of vascular tone and neurotransmission, respectively, and release nanomolar concentrations of nitric oxide upon activation by elevated intracellular calcium concentrations (Alderton et al., 2001). In contrast, the inducible NOS (iNOS) isoform is transcriptionally regulated and, once induced by pro-inflammatory stimuli, generates micromolar range quantities of nitric oxide (Stuehr et al., 1991). Although iNOS induction plays a beneficial role in host defense against invading pathogens, uncontrolled release of excessive amounts of nitric oxide from iNOS is postulated to contribute to pathophysiology in a number of acute and chronic inflammatory and autoimmune diseases (Cuzzocrea et al., 2002;Razavi et al., 2004).Hyperdynamic septic shock is characterized by pathological vasodilatation and reduction of vascular resistance, eventually leading to an uncompensated fall in blood pressure and inadequate organ perfusion. Infusion of catecholamine vasoconstrictors is usually employed to stabilize blood pressure in hyperdynamic septic shock states refractory to volume administration (Beale et al., 2004). Hyporesponsiveness R.T.S. is the recipient of a research grant from ALTANA Pha...

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“…A recent study compared the effects of SR141716 and AM251 in rats on the acute hypotensive effect of bacterial endotoxin (LPS) administered as an intravenous bolus. Hypotension in this model is fully attributable to the decreased cardiac contractility, whereas peripheral vascular resistance is increased, indicating vasoconstriction (Biber et al, 1988;Cheng et al, 2003). Using this model, the cardiodepressant and hypotensive effects of LPS were inhibited by SR141716 but not by AM251.…”

Section: Cardiovascular and Respiratory Disordersmentioning

confidence: 78%

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

2006

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Selective versus non-selective suppression of nitric oxide synthase on regional hemodynamics in rats with or without LPS-induced endotoxemia

Cited by 14 publications

References 41 publications

Endotoxemia-Mediated Induction of Cardiac Inducible Nitric-Oxide Synthase Expression Accounts for the Hypotensive Effect of Ethanol in Female Rats

Endotoxemia-Mediated Induction of Cardiac Inducible Nitric-Oxide Synthase Expression Accounts for the Hypotensive Effect of Ethanol in Female Rats

In Vivo Characterization of the Novel Imidazopyridine BYK191023 [2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine], a Potent and Highly Selective Inhibitor of Inducible Nitric-Oxide Synthase

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

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