Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Mark J. Kohr, Honglan Wang, Debra G. Wheeler, Murugesan Velayutham, Jay L. Zweier, Mark T. Ziolo

Research output: Contribution to journalArticle

Abstract

Many studies have demonstrated a biphasic effect of peroxynitrite in the myocardium, but few studies have investigated this biphasic effect on β-adrenergic responsiveness and its dependence on contractile state. We have previously shown that high 3-morpholinosydnonimine (SIN-1) (source of peroxynitrite, 200 μmol/L) produced significant anti-adrenergic effects during maximal β-adrenergic stimulation in cardiomyocytes. In the current study, we hypothesize that the negative effects of high SIN-1 will be greatest during high contractile states, whereas the positive effects of low SIN-1 (10 μmol/L) will predominate during low contractility. Isolated murine cardiomyocytes were field stimulated at 1 Hz, and [Ca2+]i transients and shortening were recorded. After submaximal isoproterenol (ISO) (β-adrenergic agonist, 0.01 μmol/L) stimulation, 200 μmol/L SIN-1 induced two distinct phenomena. Cardiomyocytes undergoing a large response to ISO showed a significant reduction in contractility, whereas cardiomyocytes exhibiting a modest response to ISO showed a further increase in contractility. Additionally, 10 μmol/L SIN-1 always increased contractility during low ISO stimulation, but had no effect during maximal ISO (1 μmol/L) stimulation. SIN-1 at 10 μmol/L also increased basal contractility. Interestingly, SIN-1 produced a contractile effect under only one condition in phospholamban-knockout cardiomyocytes, providing a potential mechanism for the biphasic effect of peroxynitrite. These results provide clear evidence for a biphasic effect of peroxynitrite, with high peroxynitrite modulating high levels of β-adrenergic responsiveness and low peroxynitrite regulating basal function and low levels of β-adrenergic stimulation.

Original languageEnglish (US)
Pages (from-to)73-80
Number of pages8
JournalFree Radical Biology and Medicine
Volume45
Issue number1
DOIs
StatePublished - Jul 1 2008
Externally publishedYes

Keywords

  • Cardiac
  • Excitation-contraction coupling
  • Free radicals
  • Peroxynitrite
  • Phospholamban
  • Reactive nitrogen species
  • β-Adrenergic stimulation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state'. Together they form a unique fingerprint.

  • Cite this