Muscarinic regulation of Ca2+ signaling in mammalian atrial and ventricular myocardium

doi:10.1016/S0014-2999(99)00231-9

European Journal of Pharmacology

Volume 375, Issues 1–3, 30 June 1999, Pages 177-196

https://doi.org/10.1016/S0014-2999(99)00231-9 Get rights and content

Abstract

The differential regulation of the contractility of mammalian atrial and ventricular myocardium upon activation of muscarinic receptors can be ascribed, for the most part, to alterations in intracellular Ca²⁺ transients. However, alterations in myofibrillar sensitivity to Ca²⁺ ions also contribute to such regulation. In atrial muscle, the following actions are all associated with the corresponding alterations in the amplitude of Ca²⁺ transients in the same direction as those in the strength of the contractile force: (1) the direct inhibitory action on the basal force of contraction; (2) the increase (recovery) in force that is induced during the prolonged stimulation of muscarinic receptors; and (3) the rebound increase in force induced by washout of muscarinic receptor agonists. In addition, for a given decrease in force induced by muscarinic receptor stimulation in atrial muscle, the amplitude of Ca²⁺ transients is decreased to a smaller extent than the decrease in amplitude induced by reduction of extracellular Ca²⁺ concentration ([Ca²⁺]_o), an indication that muscarinic receptor stimulation might increase myofibrillar sensitivity to Ca²⁺ ions simultaneously with the reduction in the amplitude of Ca²⁺ transients during induction of the direct inhibitory action. In mammalian ventricular myocardium, the direct inhibitory action of muscarinic receptor stimulation exhibits a wide range of species-dependent variation. A pronounced direct inhibitory action is induced in ferret papillary muscle, which is also associated with a definite increase in myofibrillar sensitivity to Ca²⁺ ions. By contrast, in the ventricular myocardium of other species including the rabbit and the dog, muscarinic receptor stimulation scarcely affects the baseline Ca²⁺ transients and the force, but it results in a pronounced decrease in Ca²⁺ transients and force when applied in the presence of β-adrenoceptor stimulation, a phenomenon known as `accentuated antagonism' or the `indirect inhibitory action' of muscarinic receptor stimulation in mammalian ventricular myocardium. During induction of the indirect inhibitory action in mammalian ventricular myocardium, muscarinic receptor stimulation reverses all the effects induced by β-adrenoceptor stimulation, including the increase in Ca²⁺ transients, the positive inotropic and lusitropic effects, and the decrease in myofibrillar sensitivity to Ca²⁺ ions. The relationship between the amplitude of Ca²⁺ transients and force is unaffected during induction of the indirect inhibitory action in rabbit and dog ventricular myocardium. The direct and indirect inhibitory actions of muscarinic receptor stimulation on Ca²⁺ transients have clearly different dependences on frequency: the former is more pronounced at a higher rate of stimulation, while the latter is more pronounced at a lower rate. The more complex interaction of muscarinic receptor and β-adrenoceptor stimulation in mammalian atrial muscle and ferret ventricular muscle might be explained by the contribution of both the direct and the indirect regulatory mechanisms to the interaction.

Introduction

The heart is able to alter its pump function considerable in order to adapt to the hemodynamic requirements of the body. Cardiac contractile regulation can be achieved via the intrinsic contractile properties of cardiac muscle and via external regulatory mechanisms that involve neuronal and humoral interventions. External regulatory mechanisms under physiological conditions can be classified as facilitatory regulation and inhibitory regulation: the former is primarily achieved by β-adrenoceptor stimulation subsequent to sympathetic nerve activation, while the latter involves muscarinic and adenosine receptors. Intimate cross-talk occurs between the two regulatory systems.

The regulation of the contractility of mammalian cardiac muscle that is induced by stimulation of muscarinic receptors is complex and varies among species of experimental animals (e.g., ferret vs. other mammals), among regions of the heart (e.g., atrium vs. ventricle) and with the physiological conditions (e.g., frequency of contraction) and the biochemical or metabolic conditions (e.g., cellular cyclic AMP (cAMP) level) under which the muscarinic receptor stimulation is applied (for reviews, see Blinks and Koch-Weser, 1963; Higgins et al., 1973; Löffelholz and Pappano, 1985). At least four different components can be distinguished in the overall inotropic response to muscarinic receptor stimulation, although some of the components might be mutually related and traceable to a common signal-transduction process. Since the early 1950s, intracellular signaling processes involved in these components have been analyzed in relation to the alterations of membrane electrophysiology induced by muscarinic receptor stimulation and a key role for the modulation of intracellular Ca²⁺ signaling has been proposed in contractile regulation. The variability of the inotropic response to muscarinic receptor stimulation can be attributed to differences in the relative prominence of four components, which can be specified as described in the following paragraphs.

This effect is prominent in mammalian and amphibian atrial musculature and in ferret ventricular muscle but is scarcely present in the ventricular myocardium of most other mammals (Löffelholz and Pappano, 1985; Endoh, 1987; Boyett et al., 1988). This direct inhibitory action is strongly influenced by the frequency of contraction, that is to say, it becomes less pronounced when the interval between individual contractions is prolonged and it is absent when the interval between contractions is long enough (Blinks and Koch-Weser, 1963). The direct inhibitory action occurs in association with a substantial reduction in the duration of action potentials (Burgen and Terroux, 1953; Trautwein and Dudel, 1958; Baumann et al., 1963; Gertjegerdes et al., 1979). It probably reflects a cumulative depletion of intracellular stores of Ca²⁺ ions subsequent to curtailment of the entry of Ca²⁺ ions due to the abbreviation of successive action potentials that is induced by stimulation of muscarinic receptors. The direct inhibitory action of muscarinic receptor stimulation is also associated with a substantial abbreviation of contraction (Burgen and Terroux, 1953).

It has been proposed that the positive inotropic effect during the recovery phase might result from accumulation of Na⁺ ions in myocardial cells, which leads, in turn, to increased storage of Ca²⁺ ions in stores in the sarcoplasmic reticulum through the Na⁺–Ca²⁺ exchanger (Korth and Kühlkamp, 1985; Saeki et al., 1997; Protas et al., 1998). The onset of this effect might be manifested as a `recovery' from the direct inhibitory action during prolonged exposure to muscarinic receptor agonists. Because its offset is slower than that of the direct inhibitory action, the effect might lead to a `rebound' or `overshoot' in contractility above the baseline control level during washout of the muscarinic receptor agonist or after cessation of vagal nerve stimulation. Under such circumstances, this type of positive inotropic effect of muscarinic receptor stimulation is present in a relatively pure form and contractions are somewhat prolonged, even though the duration of action potentials is not altered significantly (Baumann et al., 1963; Gertjegerdes et al., 1979). While the receptor kinase-dependent desensitization of muscarinic receptors during prolonged exposure to muscarinic receptor agonists might contribute, in part, to the recovery phenomenon (Shui et al., 1995), there appears to be a definite positive inotropic component that reverses the direct inhibitory action, which is responsible for the rebound phenomenon, as will be discussed below.

This negative inotropic effect, associated with a characteristic electrophysiological effect, is assumed to result from attenuation of previously promoted, cAMP-mediated, intracellular signal-transduction processes (Watanabe and Besch, 1975; Endoh, 1979; Biegon and Pappano, 1980; Rardon and Pappano, 1986). This effect can be readily investigated in mammalian ventricular myocardium, in general, where the direct inhibitory action is scarcely present, but the effect is present in atrial muscle also (for reviews, see Higgins et al., 1973; Löffelholz and Pappano, 1985; Endoh, 1987). This inhibitory action is termed an `indirect inhibitory action' (secondary to inhibition of facilitated cAMP-mediated processes), an `anti-adrenergic effect', or an `accentuated antagonism' because the effect has been observed most often as an antagonistic effect on the β-adrenoceptor-mediated positive inotropic effect (Hollenberg et al., 1965; Levy, 1971).

This effect is not prominent at standard experimental concentrations of muscarinic receptor agonists but is observed at relatively high concentrations of muscarinic receptor agonists. It does not represent an effect of the stimulation of muscarinic receptors on cardiac muscle cells. Therefore, we shall not consider further in relation to the regulation of Ca²⁺ signaling in myocardial cells in the present study. Characteristics of this effect in the regulation of cardiac Ca²⁺ signaling are similar to those of the β-adrenoceptor stimulation that is mediated by the accumulation of cAMP (Kurihara and Konishi, 1987; Endoh and Blinks, 1988; Okazaki et al., 1990).

While these various effects of the stimulation of muscarinic receptors on myocardial contractility are transformed to yield a change in the mobilization of intracellular Ca²⁺ ions and/or a change in the sensitivity of myofilaments to intracellular Ca²⁺ concentration ([Ca²⁺]_i) in the final step of the signal transduction process, information on such changes in intact myocardial cells has been rather fragmentary and controversial because of the contributions of the various diverse components to the regulation of Ca²⁺ signaling that is induced by muscarinic receptor stimulation.

The present descriptions of the alterations of Ca²⁺ signaling that might be responsible for the regulation of myocardial contractility that is induced by stimulation of muscarinic receptors will be described on the basis of the findings in atrial and ventricular myocardium that has been loaded with the Ca²⁺-sensitive bioluminescent protein aequorin (Blinks et al., 1978, Blinks et al., 1982).

Section snippets

Methods

Hearts were excised from rabbits, guinea pigs and ferrets that had been lightly anesthetized with chloroform or ether. Pectinate muscle from rabbit and guinea-pig left atria and papillary muscles from rabbit or ferret right ventricles were dissected out in bicarbonate-buffered Krebs–Henseleit solution bubbled with 95% O₂ and 5% CO₂. The composition of the Krebs–Henseleit solution used throughout the experiments was as follows (in mM): NaCl 118, KCl 4.7, CaCl₂ 2.5, KH₂PO₄ 1.2, NaHCO₃ 24.9 and

Direct inhibitory action on rabbit and guinea-pig atrial muscle and ferret ventricular muscle

In rabbit atrial muscle, a muscarinic receptor agonist, carbachol, administered in a cumulative manner, decreased the amplitude of aequorin signals and that of isometric contractions in a concentration-dependent manner and, apparently, in parallel (Fig. 1). The maximum direct inhibitory action of carbachol on atrial muscle was reached at a concentration of 10⁻⁶ M. The EC₅₀ values for the inhibition of aequorin signals and isometric contractions were 1.5×10⁻⁹ and 3.0×10⁻⁹ M, respectively.

Direct inhibitory action of muscarinic receptor stimulation on rabbit and guinea-pig atrial muscle and ferret ventricular muscle

In mammalian atrial muscle, the direct negative inotropic effect induced by muscarinic receptor stimulation can essentially be explained in terms of changes in Ca²⁺ transients, as shown first by means of electrical field stimulation and the resultant action of endogenously released acetylcholine in pectinate muscle dissected from the endocardial surface of rabbit left atrium that was electrically stimulated at 1.25 Hz (Endoh and Blinks, 1984). In rabbit atrial muscle, the muscarinic receptor

Conclusion

The stimulation of muscarinic receptors induces a decrease and/or an increase in the amplitude of intracellular Ca²⁺ transients in mammalian cardiac muscle: the former can be classified as direct and indirect inhibitory actions depending on the involvement or non-involvement of a cAMP-mediated process. The latter is manifest as the recovery or rebound phenomenon that is observed during prolonged exposure or after washout of muscarinic receptor agonists. The direct inhibitory action, which is

Acknowledgements

The author is grateful to Dr. John Blinks for his continuous encouragement and for support of the experiments performed at the Department of Pharmacology, Mayo Clinic, Rochester, MN, as well as to Dr. Youichi Kawabata for the performance of experiments with ferret papillary muscles at the Department of Pharmacology, Yamagata University School of Medicine. The author also wishes to thank Mr. Ikuo Norota for preparation of the figures.

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ReviewMuscarinic regulation of Ca2+ signaling in mammalian atrial and ventricular myocardium

Abstract

Introduction

Section snippets

Methods

Direct inhibitory action on rabbit and guinea-pig atrial muscle and ferret ventricular muscle

Direct inhibitory action of muscarinic receptor stimulation on rabbit and guinea-pig atrial muscle and ferret ventricular muscle

Conclusion

Acknowledgements

J. Biol. Chem.

Methods Enzymol.

Prog. Biophys. Mol. Biol.

Jpn. J. Pharmacol.

Gen. Pharmacol.

Jpn. J. Pharmacol.

J. Card. Failure

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharmacol.

Life Sci.

Prog. Biophys. Mol. Biol.

FEBS Lett.

J. Biol. Chem.

Calcium transients in mammalian ventricular muscle

Eur. Heart J.

Effets inotropes de l'acetylcholine sur le myocarde

Helv. Physiol. Acta

Recovery of the duration of the action potential and contractile force in a constant acetylcholine concentration

Fed. Proc.

Dual mechanism for inhibition of calcium-dependent action potentials by acetylcholine in avian ventricular muscle. Relation to cyclic AMP

Circ. Res.

Modification of myofibrillar responsiveness to Ca2+ as an inotropic mechanism

Circulation

Physical factors in the analysis of the actions of drugs on myocardial contractility

Pharmacol. Rev.

The negative inotropic effect of acetylcholine on ferret ventricular myocardium

J. Physiol.

Dissociation of cyclic GMP from the negative inotropic action of carbachol in guinea pig atria

J. Cyclic Nucleotide Res.

Cholinergic inhibition of catecholamine-stimulable cyclic AMP accumulation in murine atria

J. Cyclic Nucleotide Res.

Influence of isoproterenol and methylisobutylxanthine on the contractile and cyclic nucleotide effects of methacholine in isolated rat atria

J. Pharmacol. Exp. Ther.

α1-Adrenergic and muscarinic cholinergic stimulation of phosphoinositide hydrolysis in adult rat cardiomyocytes

Circ. Res.

On the negative inotropic effect in the cat's auricle

J. Physiol.

Ventricular cholinergic receptor system: interaction with adrenergic system

J. Pharmacol. Exp. Ther.

Are increases in cyclic GMP levels responsible for the negative inotropic effects of acetylcholine in the heart?

Biochem. Biophys. Res. Commun.

Negative and positive inotropic responses to muscarinic agonists in guinea pig and rat atria in vitro

J. Pharmacol. Exp. Ther.

Differential effects of 8-bromo-cyclic GMP on the basal contractile force and β-adrenoceptor-mediated positive inotropic action in the canine atrium

Tohoku J. Exp. Med.

Dual inhibition of myocardial function through muscarinic and adenosine receptors in the mammalian heart

J. Appl. Cardiol.

Changes in intracellular Ca2+ mobilization and Ca2+ sensitivity as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells

Jpn. Heart J.

Actions of sympathomimetic amines on the Ca2+ transients and contractions of rabbit myocardium: reciprocal changes in myofibrillar responsiveness to Ca2+ mediated through α- and β-adrenoceptors

Circ. Res.

Differential responses to carbachol, sodium nitroprusside and 8-bromo-guanosine 3′,5′monophosphate of canine atrial and ventricular muscle

Br. J. Pharmacol.

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Parasympathetic control of the heart

Pharmacol. Rev.

Biphasic action of acetylcholine on ventricular myocardium

Circ. Res.

Review
Muscarinic regulation of Ca²⁺ signaling in mammalian atrial and ventricular myocardium

Modification of myofibrillar responsiveness to Ca²⁺ as an inotropic mechanism

α₁-Adrenergic and muscarinic cholinergic stimulation of phosphoinositide hydrolysis in adult rat cardiomyocytes

Changes in intracellular Ca²⁺ mobilization and Ca²⁺ sensitivity as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells

Actions of sympathomimetic amines on the Ca²⁺ transients and contractions of rabbit myocardium: reciprocal changes in myofibrillar responsiveness to Ca²⁺ mediated through α- and β-adrenoceptors

Pronounced direct inhibitory action mediated by adenosine A₁ receptor and pertussis toxin-sensitive G protein on the ferret ventricular contraction

Different effects of α- and β-adrenergic stimulation on cytosolic pH and myofilament responsiveness to Ca²⁺ in cardiac myocytes

Nitric oxide synthase (NOS3)-mediated cholinergic modulation of Ca²⁺ current in adult rabbit atrioventricular nodal cells

Alteration in contractile properties and Ca²⁺ transients by β- and muscarinic receptor stimulation in ferret myocardium

Mechanism of the effects of acetylcholine on the contractile properties and Ca²⁺ transients in ferret ventricular muscle

Acetylcholine and adenosine activate the G protein-gated muscarinic K⁺ channel in ferret ventricular myocytes