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

Satoshi Yasuda, Wilbur Y.W. Lew

研究成果: Article査読

108 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1011-1020
ページ数10
ジャーナルCirculation research
81
6
DOI
出版ステータスPublished - 1997
外部発表はい

ASJC Scopus subject areas

  • 生理学
  • 循環器および心血管医学

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