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Background and Purpose: β-Adrenoceptor (β-AR)-mediated inotropic effects are attenuated and G(i) proteins are up-regulated in heart failure (HF). Muscarinic receptors constitutively inhibit cAMP formation in normal rat cardiomyocytes. We determined whether constitutive activity of muscarinic receptors to inhibit adenylyl cyclase (AC) increases in HF and if so, whether it modifies the reduced β-AR- or emergent 5-HT₄-mediated cAMP-dependent inotropic effects.Experimental Approach: Contractility and AC activity were measured and related to each other in rat ventricle with post-infarction HF and sham-operated (Sham) controls with or without blockade of muscarinic receptors by atropine and inactivation of G(i) protein by pertussis toxin (PTX).Key Results: Isoprenaline-mediated inotropic effects were attenuated and basal, isoprenaline- and forskolin-stimulated AC activity was reduced in HF compared with Sham. Atropine or PTX pretreatment increased forskolin-stimulated AC activity in HF hearts. β-AR-stimulated AC and maximal inotropic response were unaffected by atropine in Sham and HF. In HF, the potency of serotonin (5-HT) to evoke an inotropic response was increased in the presence of atropine with no change in the maximal inotropic response. Interestingly, PTX pretreatment reduced the potency of 5-HT to evoke inotropic responses while increasing the maximal inotropic response.Conclusions and Implications: Although muscarinic constitutive inhibition of AC is increased in HF, it does not contribute to the reduced β-AR-mediated inotropic effects in rat ventricle in HF. The data support the hypothesis that there are differences in the functional compartmentation of 5-HT₄ and β-AR AC signalling in myocardium during HF. [ABSTRACT FROM AUTHOR]

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. Mandarin translation of abstract [ABSTRACT FROM AUTHOR]