Bacterial lipopolysaccharide-induced hyporeactivity in perfused rat resistance vessels: modulating effects of dexamethasone

Abstract

The present study was carried out on mesenteric vascular bed from LPS-injected rats in order to investigate possible mechanisms underlying hyporesponsiveness in resistance blood vessels in the course of septic shock syndrome. The involvement of L-arginine (L-Arg)/nitric oxide (NO) pathway was evaluated by administration of L-Arg, which produced a decrease in perfusion pressure in LPS-treated rats, whereas it was ineffective in control rats. Of note, dexamethasone (DEX) pretreatment in endotoxaemic rats significantly reduced the vasorelaxation by L-Arg; however, this non selective inhibitor of inducible-NOS expression was not able to prevent noradrenaline (NA) hyporeactivity. Furthermore, in order to evaluate whether hyporesponsiveness could be due to an altered contraction mechanism, the effect of endothelin (ET)-1 was tested. This peptide was able to markedly enhance the contractile response to noradrenaline in LPS-treated rats. Collectively, our findings suggest that vascular hyporesponsiveness during septic shock can only be partially explained by activation of the L-Arg/NO pathway. Other mechanisms, probably related to smooth muscle cell contractility, may be involved.

Get full access to this article

View all access options for this article.

References

Wright C.E. , Rees D.D. , Moncada S. Protective and pathological roles of nitric oxide in endotoxin shock . Cardiovasc Res 1992; 26: 48-57.

Fleming I. , Gray G.A. , Julou-Schaeffer G. et al. Incubation with endotoxin activates the L-arginine pathway in vascular tissue. Biochem Biophys Res Commun 1990; 171: 561-568.

Julou-Schaeffer G. , Gray G.A. , Fleming I. et al. Activation of the L-arginine/nitric oxide pathway is involved in vascular hyporeactivity induced by endotoxin . J Cardiovasc Pharmacol 1991; 17:S207-S212.

Fleming I. , Gray G.A. , Schott C. et al. Inducible but not constitutive production of nitric oxide by vascular smooth muscle cells. Eur J Pharmacol 1991; 200: 375-376.

Petros A. , Lamb G. , Leone A. et al. Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res 1994; 28: 34-39.

Fleming I. , Julou-Schaeffer G. , Gray G.A. et al. Evidence that an L-arginine/nitric oxide dependent elevation of tissue cyclic-GMP content is involved in depression of vascular reactivity by endotoxin. Br J Pharmacol 1991; 103: 1047-1052.

Gray G.A. , Schott C. , Julou-Schaeffer G. et al. The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anesthetized rats . Br J Pharmacol 1991; 103: 1218-1224.

Radomski M.W. , Palmer R.M.J. , Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci USA 1990; 87: 10043-10047.

Palmer R.M.J. , Bridge L. , Foxwell N.A. et al. The role of nitric oxide in endothelial cell damage and its inhibition by glucocorticoids . Br J Pharmacol 1992; 105: 11-12.

10.

Rees D.D. , Cellek S. , Palmer R.M.J. et al. Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: an insight into endotoxin shock. Biochem Biophys Res Commun 1990; 173: 541-547.

11.

Paya D. , Gray G.A. , Fleming I. et al. Effect of dexamethasone on the onset and persistence of vascular hyporeactivity induced by E. coli lipopolysaccharide in rats. Circ Shock 1993; 41: 103-106.

12.

Criscione L. , Müller K. , Forney Prescott M. Endothelial cell loss enhances the pressor response in resistance vessels. J Hypertens 1984; 2 (Suppl 3): 441-444.

13.

Wakabayashi I. , Hatake K. , Kakishita E. et al. Diminution of contractile response of the aorta from endotoxin-injected rats. Eur J Pharmacol 1987; 141: 117-120.

14.

Julou-Schaeffer G. , Gray G.A. , Fleming I. et al. Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway. Am J Physiol 1990; 259: H1038-H1043.

15.

Carcillo J.A. , Litten R.Z. , Suba E.A. et al. Alterations in rat aortic alpha 1-adrenoceptors and alpha-adrenergic stimulated phosphoinositide hydrolysis in intraperitoneal sepsis. Circ Shock 1988; 26: 331-334.

16.

Rees D.D. , Palmer R.M.J. , Hodson H.F. et al. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol 1989; 96: 418-424.

17.

Potenza M.A. , Serio M. , Montagnani M. et al. L-Arg/NO pathway contributes to LPS-induced hyporeactivity in rat mesenteric vascular bed: effect of NO-synthase inhibitors . Pharmacol Res 1995; 31 (Suppl): 63.

18.

Potenza M.A. , Serio M. , Montagnani M. et al. Role of L-arginine/nitric oxide pathway in vascular hyporesponsiveness associated with septic shock. Pharmacological study in endotoxin-injected rats. Riv It Biol Med 1995; 15: 1-11.

19.

Chernow B. , Roth B.L. Pharmacologic manipulation of the peripheral vasculature in shock: clinical and experimental approaches. Circ Shock 1986 , 18: 141-155.

20.

Brunner H.R. , Chang P. , Wallace R. et al. Angiotensin II vascular receptors. J Clin Invest 1972; 51: 58-67.

21.

Yard A.C. , Kadowitz P.J. Studies on the mechanism of hydrocortisone potentiation of vasoconstrictor response to epinephrine anesthetized animal. Eur J Pharmacol 1972; 20: 1-19.

22.

Di Rosa M. , Calignano A. , Carnuccio R. et al. Multiple control of inflammation by glucocorticoids. Agents Action 1985; 17: 284-289.

23.

Douglas S.A. , Hiley C.R. Endothelium-dependent vascular activities of endothelin-like peptides in the isolated superior mesenteric arterial bed of the rat. Br J Pharmacol 1990 ; 101: 81-88.

24.

Reynolds E.E. , Mok L.L.S. Role of thromboxane A2, prostaglandin H2 receptor in the vasoconstrictor response of rat aorta to endothelin . J Pharmacol Exp Ther 1990; 252: 91-96.