Skip to main content
Log in

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

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

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 NG-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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1a, b.
Fig. 2.

Similar content being viewed by others

References

  • Bateson AN, Jakiwczyk OM, Schulz R (1996) Rapid increase in inducible nitric oxide synthase gene expression in the heart during endotoxemia. Eur J Pharmacol 303:141–144

    Article  CAS  PubMed  Google Scholar 

  • Boughton-Smith NK, Evans SM, László F, Whittle BJR (1993) The induction of nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat. Br J Pharmacol 110:1189–1195

    CAS  PubMed  Google Scholar 

  • Brackett DJ, Schaefer CF, Tompkins P, Fagraeus L, Peters LJ, Wilson MF (1985) Evaluation of cardiac output, total peripheral vascular resistance, and plasma concentrations of vasopressin in the conscious, unrestrained rat during endotoxemia. Circ Shock 17:273–284

    CAS  PubMed  Google Scholar 

  • Cai M, Sakamoto A, Ogawa R (1996) Inhibition of nitric oxide formation with L-canavanine attenuates endotoxin-induced vascular hyporeactivity in the rat. Eur J Pharmacol 295:215–220

    Article  CAS  PubMed  Google Scholar 

  • Cheng X, Pang CCY (1998) Pressor and vasoconstrictor effects of methylene blue in endotoxaemic rats. Naunyn-Schmiedebergs Arch Pharmacol 357:648–663

    CAS  Google Scholar 

  • Colardyn FC, Vandenbogaerde JF, Vogelaers DP, Verbeke JH (1989) Use of dopexamine hydrochloride in patients with septic shock. Crit Care Med 17:999–1003

    CAS  PubMed  Google Scholar 

  • Colasanti M, Suzuki H (2000) The dual personality of NO. Trends Pharmacol Sci 21:249–252

    CAS  PubMed  Google Scholar 

  • Fischer LG, Horstman DJ, Hahnenkamp K, Kechner NE, Rich GF (1999) Selective iNOS inhibition attenuates acetylcholine- and bradykinin-induced vasoconstriction in lipopolysaccharide-exposed rat lungs. Anesthesiology 91:1724–1732

    CAS  PubMed  Google Scholar 

  • Gardiner SM, Kemp PA, March JE, Bennett T (1995) Enhancement of the haemodynamic effects of NG-monomethyl-L-arginine by transforming growth factor-beta 1 in conscious, normal, but not endotoxaemic, rats. Br J Pharmacol 116:3042–3048

    CAS  PubMed  Google Scholar 

  • Gardiner SM, Kemp PA, March JE, Bennett T (1996) Temporal differences between the involvement of angiotensin II and endothelin in the cardiovascular responses to endotoxaemia in conscious rats. Br J Pharmacol 119:1619–1627

    CAS  PubMed  Google Scholar 

  • Garvey EP, Oplinger JA, Furfine ES, Kiff RJ, László F, Whittle BJR, Knowles RG (1997) 1400 W is a slow, tight binding, and highly selective inhibitor of inducible nitric-oxide synthase in vitro and in vivo. J Biol Chem 272:4959–4963

    CAS  PubMed  Google Scholar 

  • Hamilton LC, Warner TD (1998) Interactions between inducible isoforms of nitric oxide synthase and cyclo-oxygenase in vivo: investigations using the selective inhibitors, 1400 W and celecoxib. Br J Pharmacol 125:335–340

    CAS  PubMed  Google Scholar 

  • Hewett JA, Roth RA (1993) Hepatic and extrahepatic pathobiology of bacterial lipopolysaccharides. Pharmacol Rev 45:381–411

    CAS  Google Scholar 

  • Kiss J, Lamarque D, Moran AP, Pozsar J, Morschl E, László F, Whittle BJ (2001) Helicobacter pylori lipopolysaccharide-provoked injury to rat gastroduodenal microvasculature involves inducible nitric oxide synthase. Eur J Pharmacol 420:175–179

    Article  CAS  PubMed  Google Scholar 

  • Klemm K, Moody FG (1998) Regional intestinal blood flow and nitric oxide synthase inhibition during sepsis in the rat. Ann Surg 227:126–133

    PubMed  Google Scholar 

  • László F, Whittle BJ (1997) Actions of isoform-selective and non-selective nitric oxide synthase inhibitors on endotoxin-induced vascular leakage in rat colon. Eur J Pharmacol 334:99–102

    Article  CAS  PubMed  Google Scholar 

  • Lautt WW, Legare DJ, d'Almeida MS (1985) Adenosine as putative regulator of hepatic arterial flow (the buffer response). Am J Physiol 248:H331–338

    CAS  Google Scholar 

  • Liu S, Adcock IM, Oild RW, Barnes PJ (1993) Lipopolysaccharide treatment in vivo induces widespread tissue expression of inducible nitric oxide synthase mRNA. Biochem Biophys Res Commun 196:1208–1213

    CAS  PubMed  Google Scholar 

  • MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M, Stevens K, Xie QW, Sokol K, Hutchinson N (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81:641–650

    CAS  PubMed  Google Scholar 

  • Mayer B, Andrew P (1998) Nitric oxide synthases: catalytic function and progress towards selective inhibition. Naunyn-Schmiedebergs Arch Pharmacol 358:127–133

    CAS  Google Scholar 

  • Millar CG, Thiemermann C (1997) Intrarenal hemodynamics and renal dysfunction in endotoxaemia: effects of nitric oxide synthase inhibition. Br J Pharmacol 121:1824–1830

    CAS  PubMed  Google Scholar 

  • Mitaka C, Hirata Y, Yokoyama K, Nagura T, Tsunoda Y, Amaha K (1999) Improvement of renal dysfunction in dogs with endotoxemia by a nonselective endothelin receptor antagonist. Crit Care Med 27:146–153

    CAS  PubMed  Google Scholar 

  • Monnier VM (1996) Aminoguanidine and diabetic neuropathy. Eur J Endocrinol 134:398–400

    CAS  PubMed  Google Scholar 

  • Mulder MF, van Lambalgen AA, Huisman E, Visser JJ (1994) Protective role of NO in the regional hemodynamic changes during acute endotoxemia in rats. Am J Physiol 266:H1558–1564

    PubMed  Google Scholar 

  • Mulder MF, van Lambalgen AA, van den Bos GC, Thijs LG (1996) The fall of cardiac output in endotoxemic rats cannot explain all changes in organ blood flow: a comparison between endotoxin and low venous return shock. Shock 5:135–140

    CAS  PubMed  Google Scholar 

  • Pang CCY (1983) Effect of vasopressin antagonist and saralasin on regional blood flow following hemorrhage. Am J Physiol 245:H749–755

    CAS  PubMed  Google Scholar 

  • Rahbar S, Yernini KK, Scott S, Gonzales N, Lalezari I (1999) Novel inhibitors of advanced glycation endproducts. Biochem Biophys Res Commun 262:651–656

    Article  CAS  PubMed  Google Scholar 

  • Rosselet A, Feihl F, Markert M, Gnaegi A, Perret C, Liaudet L (1998) Selective iNOS inhibition is superior to norepinephrine in the treatment of rat endotoxic shock. Am J Respir Crit Care Med 157:162–170

    CAS  PubMed  Google Scholar 

  • Schaller MD, Waeber B, Nussberger J, Brunner HR (1985) Angiotensin II, vasopressin, and sympathetic activity in conscious rats with endotoxemia. Am J Physiol 249:H1086–1092

    CAS  PubMed  Google Scholar 

  • Schumer W (1984) Pathophysiology and treatment of septic shock. Am J Emerg Med 2:74–77

    CAS  PubMed  Google Scholar 

  • Sharma AC, Motew SJ, Farias S, Alden KJ, Bosmann HB, Law WR, Ferguson JL (1997) Sepsis alters myocardial and plasma concentrations of endothelin and nitric oxide in rats. J Mol Cell Cardiol 29:1469–1477

    Google Scholar 

  • Southan GJ, Szabó C (1996) Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem Pharmacol 51:383–394

    CAS  PubMed  Google Scholar 

  • Strunk V, Hahnenkamp K, Schneuing M, Fischer LG, Rich GF (2001) Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation. Anesth Analg 92:681–687

    CAS  PubMed  Google Scholar 

  • Szabó C, Mitchell JA, Thiemermann C, Vane JR (1993) Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. Br J Pharmacol 108:786–792

    CAS  PubMed  Google Scholar 

  • Tepperman BL, Chang Q, Soper BD (2000) Protein kinase C mediates lipopolysaccharide- and phorbol-induced nitric-oxide synthase activity and cellular injury in the rat colon. J Pharmacol Exp Ther 295:1249–1257

    CAS  PubMed  Google Scholar 

  • Thiemermann C, Ruetten H, Wu CC, Vane JR (1995) The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br J Pharmacol 116:2845–2851

    CAS  PubMed  Google Scholar 

  • Van Lambalgen AA, van Kraats AA, Mulder MF, van den Bos GC, Teerlink T, Thijs LG (1993) Organ blood flow and distribution of cardiac output in dopexamine- or dobutamine-treated endotoxemic rats. J Crit Care 8:117–127

    PubMed  Google Scholar 

  • Wang YX, Zhou T, Pang CCY (1991) Pressor effects of L and D enantiomers of NG-nitro-arginine in conscious rats are antagonized by L- but not D-arginine. Eur J Pharmacol 200:77–81

    Article  CAS  PubMed  Google Scholar 

  • Wang YX, Lim SL, Pang CCY (1995) Increase by NG-nitro-L-arginine methyl ester (L-NAME) of resistance to venous return in rats. Br J Pharmacol 114:1454–1458

    CAS  PubMed  Google Scholar 

  • Wei XQ, Charles IG, Smith A, Ure J, Feng GJ, Huang FP, Xu D, Muller W, Moncada S, Liew FY (1995) Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375:408–411

    Google Scholar 

  • Whittle BJ, Morschl E, Pozsar J, Moran AP, László F (2001) Helicobacter pylori lipopolysaccharide provokes iNOS-mediated acute systemic microvascular inflammatory responses in rat cardiac, hepatic, renal and pulmonary tissues. J Physiol Paris 95:257–259

    Article  CAS  PubMed  Google Scholar 

  • Winslow C, Dorinsky PM (1994) Regional blood flow distribution in endotoxin-treated dogs: modification by ibuprofen. J Crit Care 9:159–168

    Google Scholar 

  • Wolfard A, Kaszaki J, Szabó C, Balogh Z, Nagy S, Boros M (1999) Effects of selective nitric oxide synthase inhibition in hyperdynamic endotoxemia in dogs. Eur Surg Res 31:314–323

    Article  CAS  PubMed  Google Scholar 

  • Wray GM, Millar CG, Hinds CJ, Thiemermann C (1998) Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory failure, but not the organ injury/dysfunction, caused by endotoxin. Shock 9:329–335

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Heart and Stroke Foundation of B.C. and Yukon. Fellowships were awarded to Xing Cheng from the Canadian Hypertension Society/MRC/Pfizer and to Susan W.S. Leung from the Croucher Foundation of Hong Kong, and a summer studentship was awarded to Lawrence Lo from the Heart and Stroke Foundation of B.C. and Yukon.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Catherine C. Y. Pang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, X., Leung, S.W.S., Lo, L.S. et al. Selective versus non-selective suppression of nitric oxide synthase on regional hemodynamics in rats with or without LPS-induced endotoxemia. Naunyn-Schmiedeberg's Arch Pharmacol 367, 372–379 (2003). https://doi.org/10.1007/s00210-002-0684-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-002-0684-1

Keywords

Navigation