Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation |
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Authors: | RI Hussain E Qvigstad JAK Birkeland H Eikemo A Glende I Sjaastad T Skomedal JB Osnes FO Levy KA Krobert |
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Affiliation: | 1.Department of Pharmacology, University of Oslo, Oslo, Norway;2.Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway;3.Institute for Experimental Medical Research, Ullevaal University Hospital, University of Oslo, Oslo, Norway;4.Department of Cardiology, Ullevaal University Hospital, Oslo, Norway |
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Abstract: | Background and purpose:Muscarinic stimulation increases myofilament Ca2+ sensitivity with no apparent inotropic response in normal rat myocardium. Increased myofilament Ca2+ sensitivity is a molecular mechanism promoting increased contractility in failing cardiac tissue. Thus, muscarinic receptor activation could elicit inotropic responses in ventricular myocardium from rats with heart failure, through increasing phosphorylation of myosin light chain (MLC).Experimental approach:Contractile force was measured in left ventricular papillary muscles from male Wistar rats, 6 weeks after left coronary artery ligation or sham surgery. Muscles were also frozen, and MLC-2 phosphorylation level was quantified.Key results:Carbachol (10 µmol·L−1) evoked a positive inotropic response only in muscles from rats with heart failure approximating 36% of that elicited by 1 µmol·L−1 isoproterenol (20 ± 1.5% and 56 ± 6.1% above basal respectively). Carbachol-evoked inotropic responses did not correlate with infarction size but did correlate with increased left ventricular end diastolic pressure, heart weight/body weight ratio and lung weight, primary indicators of the severity of heart failure. Only muscarinic receptor antagonists selective for M2 receptors antagonized carbachol-mediated inotropic effects with the expected potency. Carbachol-evoked inotropic responses and increase in phosphorylated MLC-2 were attenuated by MLC kinase (ML-9) and Rho-kinase inhibition (Y-27632), and inotropic responses were abolished by Pertussis toxin pretreatment.Conclusion and implications:In failing ventricular muscle, muscarinic receptor activation, most likely via M2 receptors, provides inotropic support by increasing MLC phosphorylation and consequently, myofilament Ca2+ sensitivity. Enhancement of myofilament Ca2+ sensitivity, representing a less energy-demanding mechanism of inotropic support may be particularly advantageous in failing hearts. |
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Keywords: | signal transduction contractility ventricular function congestive heart failure Rho-kinase Pertussis toxin |
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