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

Abstract

The late phase of severe septic shock is associated with reduced cardiac output (CO) and activation of the inducible isoform of nitric oxide synthase (NOS). This study examined the effects of 1400 W (N-3-aminomethyl-benzyl-acetamidine), a new selective inhibitor of inducible NOS (iNOS), relative to those of N(G)-nitro-L-arginine (L-NNA, non-selective inhibitor of NOS) and the vehicle, on mean arterial pressure (MAP), CO, total peripheral resistance (TPR) and tissue blood flow (BF) in thiobutabarbital-anesthetized rats with lipopolysaccharide (LPS, 10 mg/kg, i.v.) induced endotoxemia. At 2.5 as well as 4 h after injection of LPS, MAP, CO, and BF of the stomach, skeletal muscle and skin were decreased, but TPR was increased, BF to the heart and kidneys were also decreased at 4 h after injection of LPS. Treatment of endotoxemic rats with 1400 W (3 mg/kg followed by 3 mg/kg/h, i.v.) at 2.5 h after endotoxin challenge prevented the late phase fall in MAP without exacerbating the decreases in CO and tissue BF. In contrast, treatment with L-NNA (8 mg/kg followed by 3 mg/kg/h, i.v.) at 2.5 h did not prevent the decline in MAP in the LPS-treated rats. Furthermore, CO drastically decreased, TPR markedly increased, and BF to the heart, brain, intestine and skeletal muscle were decreased at 4 h relative to the readings in saline- or 1400 W-treated endotoxemic rats. Therefore, selective inhibition of iNOS by 1400 W restores MAP without compromising CO, but non-selective inhibition of NOS is detrimental at the late stage of septic shock.

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

“…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.…”

“…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).…”

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

“…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.…”

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

“…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.…”