Abstract
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 (NOx) levels with an ED50 of 14.9 μmol/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 NOx 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 saline-challenged controls. In addition, in a model of lipopolysaccharide-induced 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.
Footnotes
-
R.T.S. is the recipient of a research grant from ALTANA Pharma AG (Konstanz, Germany).
-
doi:10.1124/jpet.105.098673.
-
ABBREVIATIONS: NOS, nitric-oxide synthase; eNOS, endothelial NOS; nNOS, neuronal NOS; iNOS, inducible NOS; l-NMMA, NG-monomethyl-l-arginine; NOx, nitrate/nitrite; BYK191023, 2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine; MAP, mean arterial pressure; ANOVA, analysis of variance; 1400W, N-(3-(amino methyl)benzyl)acetamidine; GW273629, 3-[[2-[(1-iminoethyl)amino]ethyl]sulfonyl]-l-alanine.
- Received November 15, 2005.
- Accepted December 15, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|