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Muscarinic receptor activation elicits an inotropic effect in failing rat ventricle through
myosin light chain phosphorylation
Rizwan I. Hussain1,2, Eirik Qvigstad1,2, Jon Arne Birkeland1,3, Ivar Sjaastad1,3,4, Annette Glende1,2,
Hilde Eikemo1,2, Trond Brattelid1,2, Jan-Bjørn Osnes1,2, Tor Skomedal1,2, Finn Olav Levy1,2, Kurt A.
Center for Heart Failure Research, Faculty of Medicine, University of Oslo
Department of Pharmacology, University of Oslo
3 Institute for Experimental Medical Research, Ullevaal University Hospital, University of Oslo
4 Department of Cardiology, Heart and Lung Center, Ullevaal University Hospital
Muscarinic receptor mediated inhibition of cAMP dependent inotropic effects is enhanced in papillary
muscles from rats with congestive heart failure (CHF). Muscarinic stimulation by the agonist carbachol
(CCh) increases myofilament Ca2+ sensitivity without an inotropic effect in normal myocardium.
Therefore, we tested the hypothesis that muscarinic activation by CCh could elicit direct inotropic
effects in ventricular myocardium from rats with CHF through enhancement of Ca 2+ sensitization.
Contractile force was measured in papillary muscles from male Wistar rats having undergone ligation
of the left coronary artery (and exhibiting CHF) or sham surgery. CCh evoked a positive inotropic
effect (20% above basal) approximating 36% of that elicited by isoproterenol (56% above basal), only
in rats with CHF. In contrast, CCh elicits only a transient negative inotropic effect in sham rats. The
CCh mediated inotropic effect did not correlate with infarction size but did correlate with increased left
ventricular end diastolic pressure, heart weight and lung weight, primary indicators of CHF severity.
The dose response curve for CCh was shifted to higher concentrations only in the presence of the
relatively specific M2 antagonist (AF-DX 116) (pD2-values with AF-DX 5.68 ± 0.12 vs. 6.28 ± 0.10
without); whereas, the antagonists nitrocaramiphen (M1) and 4-DAMP (M3/5) were without effect. The
CCh mediated inotropic effect was insensitive to pertussis toxin but was attenuated by the myosin light
chain kinase inhibitor ML-9 (8% above basal) and by the Rho-kinase inhibitor Y-27632 (9% above
basal). CCh increased phosphorylation of myosin light chain that was also attenuated by ML-9 and Y27632. In conclusion, these data indicate that muscarinic receptor activation, possibly M2, mediates
an inotropic effect in failing ventricular myocardium, not observed in normal rat heart. The muscarinic
inotropic effect occurs through a signaling pathway that enhances myosin light chain phosphorylation
and thus, likely Ca2+ sensitization.