Lipopolysaccharide depresses cardiac contractility and β-adrenergic contractile response by decreasing myofilament response to Ca2+ in cardiac myocytes

Satoshi Yasuda, Wilbur Y.W. Lew

Research output: Contribution to journalArticlepeer-review

Abstract

Lipopolysaccharide (LPS) plays a key role in the pathogenesis of sepsis. Cardiac function and the inotropic response to β-adrenergic stimulation are impaired in sepsis, We hypothesized that LPS, in clinically relevant levels (1 ng/mL), directly depresses contractility and β-adrenergic responses in cardiac myocytes. Cardiac myocytes were isolated from the left ventricle of adult rabbits using digestive enzymes (collagenase and protease). We depyrogenated the enzymes (LPS contamination lowered from 100 to 300 ng/mL to <0.7 ng/mL) to minimize development of LPS tolerance during cell isolation. After 6 hours of incubation with 1 ng/mL LPS, there was a decrease in the extent of active cell shortening with no change in Ca2+ transients (measured with indo 1 fluorescence), indicating decreased myofilament responsiveness to Ca2+. This was related to NO pathways, since cGMP (a second messenger of NO) increased in cardiac myocytes and LPS effects were completely reversed with a 1 mmol/L N(G)-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor). LPS did not alter the intracellular Ca2+ response to β-adrenergic stimulation with isoproterenol but attenuated the contractile response P (maximal cell shortening, 15.5±1.0% versus 23.3±1.1% in control myocytes; P<.001). LPS attenuation of the contractile response to isoproterenol was restored completely by L-NMMA and almost completely restored (to 86% of the control response) by an inhibitor of cGMP-dependent protein kinase. We conclude that LPS depresses cardiac contractility and the contractile response to β-adrenergic stimulation by a NO-cGMP-mediated decrease in myofilament responsiveness to Ca2+. The direct effects of low levels of LPS on cardiac myocytes may contribute to cardiac depression and hemodynamic decompensation during sepsis.

Original languageEnglish
Pages (from-to)1011-1020
Number of pages10
JournalCirculation research
Volume81
Issue number6
DOIs
Publication statusPublished - 1997
Externally publishedYes

Keywords

  • Ca
  • Lipopolysaccharide
  • Myofilament
  • Nitric oxide synthase
  • β- adrenergic receptor agonist

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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