iNOS gene expression modulates microvascular responsiveness in endotoxin-challenged mice.

Septic shock is characterized by vasodilation and decreased responsiveness to vasoconstrictors. Recent studies suggest this results from nitric oxide (NO) overproduction after expression of the calcium-independent isoform of NO synthase (iNOS) in smooth muscle cells. However, direct evidence linking iNOS (NOS2) expression and decreased microvascular responsiveness after septic stimuli is lacking. In the present study, we determined the effect of bacterial lipopolysaccharide (LPS, 20 mg/kg, IP) on smooth muscle contraction and endothelial relaxation in mesenteric resistance arteries from wild-type and iNOS knockout mice. Four hours after challenge with LPS or saline in vivo, concentration-dependent responses to norepinephrine (NE) and acetylcholine (NE+ACh) were measured in cannulated, pressurized vessels ex vivo. In vessels from wild-type mice, NE-induced contraction was markedly impaired after LPS, and pretreatment with the iNOS inhibitor aminoguanidine (AG) partly restored the NE contraction. In contrast, NE contraction in microvessels from iNOS knockout mice was unaffected by LPS. ACh-induced relaxation was unaffected by LPS in vessels from either genotype. These data provide direct evidence that iNOS gene expression mediates the LPS-induced decrease in microvascular responsiveness to vasoconstrictors. Moreover, the observation that AG did not fully restore NE contraction after LPS, whereas iNOS gene deficiency did, suggests that iNOS expression plays a central role in the development of the NO-independent effect of LPS on microvascular responsiveness. Finally, our data indicate that LPS or iNOS expression has little effect on endothelium-dependent relaxation, and eNOS activity does not appear to play a role in the decreased smooth muscle responsiveness after LPS in this model. The full text of this article is available at http://www.circresaha.org.

[1]  J. Parrillo,et al.  Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase. , 2000, Circulation research.

[2]  R. Devereux,et al.  Echocardiographic and survival studies in mice undergoing endotoxic shock: effects of genetic ablation of inducible nitric oxide synthase and pharmacologic antagonism of platelet-activating factor. , 1999, The Journal of surgical research.

[3]  J. A. Rodríguez-Feo,et al.  NO from smooth muscle cells decreases NOS expression in endothelial cells: role of TNF-α. , 1999, American journal of physiology. Heart and circulatory physiology.

[4]  B. Nilsson.  Biological effects of aminoguanidine: An update , 1999, Inflammation Research.

[5]  R. Andriantsitohaina,et al.  Induction of nitric oxide synthase and dual effects of nitric oxide and cyclooxygenase products in regulation of arterial contraction in human septic shock. , 1999, Circulation.

[6]  R. García,et al.  Aspirin inhibits inducible nitric oxide synthase expression and tumour necrosis factor‐α release by cultured smooth muscle cells , 1999, European journal of clinical investigation.

[7]  P. Sarathchandra,et al.  Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase‐1 , 1998, British journal of pharmacology.

[8]  C. Tribble,et al.  Protective roles of nitric oxide and testosterone in endotoxemia: evidence from NOS-2-deficient mice. , 1998, American journal of physiology. Heart and circulatory physiology.

[9]  S. Gardiner,et al.  The influence of antibodies to TNF‐α and IL‐1β on haemodynamic responses to the cytokines, and to lipopolysaccharide, in conscious rats , 1998 .

[10]  R. Hotchkiss,et al.  Nitric oxide inhibits stress-induced endothelial cell apoptosis. , 1998, Critical care medicine.

[11]  J. Catravas,et al.  Effects of antisense oligonucleotide to iNOS on hemodynamic and vascular changes induced by LPS. , 1998, The American journal of physiology.

[12]  D. Heistad,et al.  Vascular effects of LPS in mice deficient in expression of the gene for inducible nitric oxide synthase. , 1998, American journal of physiology. Heart and circulatory physiology.

[13]  D. J. Wolff,et al.  Mechanism of inducible nitric oxide synthase inactivation by aminoguanidine and L-N6-(1-iminoethyl)lysine. , 1998, Biochemistry.

[14]  I. Joshua,et al.  Role of tumor necrosis factor-alpha in small intestinal microcirculation. , 1998, The American surgeon.

[15]  T. Shiga,et al.  Platelet-activating factor receptor antagonist attenuates endotoxin-induced vascular hyporeactivity in the pithed rat. , 1998, European journal of pharmacology.

[16]  A. Choi,et al.  Regulation of heme oxygenase-1 gene expression in vascular smooth muscle cells by nitric oxide. , 1997, American journal of physiology. Lung cellular and molecular physiology.

[17]  R. Busse,et al.  Inhibition of inducible nitric oxide synthase restores endothelium-dependent relaxations in proinflammatory mediator-induced blood vessels. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[18]  T. Warner,et al.  Characterization of the induction of nitric oxide synthase and cyclo‐oxygenase in rat aorta in organ culture , 1997, British journal of pharmacology.

[19]  I. Chaudry,et al.  Endothelial nitric oxide synthase is downregulated during hyperdynamic sepsis. , 1997, Biochimica et biophysica acta.

[20]  W. Durante,et al.  Nitric oxide induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle cells. , 1997, Circulation research.

[21]  S. Lewis,et al.  Lipopolysaccharide inhibits acetylcholine- and nitric oxide-mediated vasodilation in vivo. , 1996, The Journal of pharmacology and experimental therapeutics.

[22]  M. Arkovitz,et al.  LOW‐LEVEL EXPRESSION AND LIMITED ROLE FOR THE INDUCIBLE ISOFORM OF NITRIC OXIDE SYNTHASE IN THE VASCULAR HYPOREACTIVITY AND MORTALITY ASSOCIATED WITH CECAL LIGATION AND PUNCTURE IN THE RAT , 1996, Shock.

[23]  M. Serio,et al.  Hyporeactivity of mesenteric vascular bed in endotoxin-treated rats. , 1996, European journal of pharmacology.

[24]  R. Andriantsitohaina,et al.  Alteration by lipopolysaccharide of the relationship between intracellular calcium levels and contraction in rat mesenteric artery , 1996, British journal of pharmacology.

[25]  J. Cobb,et al.  Nitric oxide and septic shock. , 1996, JAMA.

[26]  O. Griffith,et al.  NO in septic shock: good, bad or ugly? Learning from iNOS knockouts. , 1996, Trends in microbiology.

[27]  O. Smithies,et al.  Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[28]  D. Rees.  Role of nitric oxide in the vascular dysfunction of septic shock. , 1995, Biochemical Society transactions.

[29]  C. Nathan,et al.  Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase , 1995, Cell.

[30]  M. Currie,et al.  Regulation of prostaglandin production by nitric oxide; an in vivo analysis , 1995, British journal of pharmacology.

[31]  T. Evans,et al.  In vivo treatment with endotoxin induces nitric oxide synthase in rat main pulmonary artery. , 1995, The American journal of physiology.

[32]  W. Boyle,et al.  Endothelium‐independent Vasoconstricting and Vasodilating Actions of Halothane on Rat Mesenteric Resistance Blood Vessels , 1995, Anesthesiology.

[33]  W. Graier,et al.  Escherichia coli endotoxin inhibits agonist-mediated cytosolic Ca2+ mobilization and nitric oxide biosynthesis in cultured endothelial cells. , 1994, Circulation research.

[34]  P. Söderkvist,et al.  Different induction mechanisms of mRNA for inducible nitric oxide synthase in rat smooth muscle cells in culture and in aortic strips , 1994, FEBS letters.

[35]  E. Vicaut,et al.  Role of nitric oxide in effects of tumor necrosis factor-alpha on microcirculation in rat. , 1993, Journal of applied physiology.

[36]  M. Currie,et al.  Nitric oxide activates cyclooxygenase enzymes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[37]  T. Ogihara,et al.  Nitric oxide mediates interleukin-1-induced prostaglandin E2 production by vascular smooth muscle cells. , 1993, Biochemical and biophysical research communications.

[38]  C. H. Baker,et al.  Arteriolar endothelium-dependent vasodilation occurs during endotoxin shock. , 1993, The American journal of physiology.

[39]  C. Thiemermann,et al.  Nitric oxide‐mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock , 1993, British journal of pharmacology.

[40]  J. Parrillo,et al.  Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to endothelin-1 in septic rats. , 1993, The American journal of physiology.

[41]  Berne Rm,et al.  Endothelial-dependent and -independent responses in the thoracic aorta during endotoxic shock. , 1991 .

[42]  J. Parratt,et al.  Enadotoxin-induced of vascular smooth contractions elicited by different mechanisms , 1990 .

[43]  B. Roth,et al.  Alterations in rat aortic alpha 1-adrenoceptors and alpha 1-adrenergic stimulated phosphoinositide hydrolysis in intraperitoneal sepsis. , 1988, Circulatory shock.

[44]  C. Nathan,et al.  Perspectives Series : Nitric Oxide and Nitric Oxide Synthases Inducible Nitric Oxide Synthase : What Difference Does It Make ? , 2013 .

[45]  D. Macintyre,et al.  Lipopolysaccharide-induced hypotension and vascular hyporeactivity in the rat: tissue analysis of nitric oxide synthase mRNA and protein expression in the presence and absence of dexamethasone, NG-monomethyl-L-arginine or indomethacin. , 1995, The Journal of pharmacology and experimental therapeutics.

[46]  D. J. Wolff,et al.  Aminoguanidine is an isoform-selective, mechanism-based inactivator of nitric oxide synthase. , 1995, Archives of biochemistry and biophysics.

[47]  井上 卓夫.  Nitric oxide mediates interleukin-1-induced prostaglandin E[2] production by vascular smooth muscle cells , 1994 .

[48]  M. Mcdaniel,et al.  Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. , 1993, European journal of pharmacology.

[49]  G. Rubanyi,et al.  The role of endothelium in cardiovascular homeostasis and diseases. , 1993, Journal of cardiovascular pharmacology.

[50]  J. Zimmerberg,et al.  Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to catecholamines in septic rats. , 1993, The American journal of physiology.

[51]  R. Berne,et al.  Endothelial-dependent and -independent responses in the thoracic aorta during endotoxic shock. , 1991, Circulatory shock.

[52]  J. Parratt,et al.  Endotoxin-induced impairment of vascular smooth muscle contractions elicited by different mechanisms. , 1990, European journal of pharmacology.