title: Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state.
abstract: Many studies have demonstrated a biphasic effect of peroxynitrite in the myocardium, but few studies have investigated this biphasic effect on beta-adrenergic responsiveness and its dependence on contractile state. We have previously shown that high 3-morpholinosydnonimine (SIN-1) (source of peroxynitrite, 200 micromol/L) produced significant anti-adrenergic effects during maximal beta-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 micromol/L) will predominate during low contractility. Isolated murine cardiomyocytes were field stimulated at 1 Hz, and [Ca(2+)](i) transients and shortening were recorded. After submaximal isoproterenol (ISO) (beta-adrenergic agonist, 0.01 micromol/L) stimulation, 200 micromol/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 micromol/L SIN-1 always increased contractility during low ISO stimulation, but had no effect during maximal ISO (1 micromol/L) stimulation. SIN-1 at 10 micromol/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 beta-adrenergic responsiveness and low peroxynitrite regulating basal function and low levels of beta-adrenergic stimulation.
authors.affiliation: Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kohr
authors.forename: Honglan
authors.initials: H
authors.lastname: Wang
authors.forename: Debra G
authors.initials: DG
authors.lastname: Wheeler
authors.forename: Murugesan
authors.initials: M
authors.lastname: Velayutham
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.forename: Mark T
authors.initials: MT
authors.lastname: Ziolo
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D008981:Molsidomine; D000099211:Phospholamban; C002385:linsidomine