Pertussis Toxin Inhibits Negative Inotropic and Negative Chronotropic Muscarinic Cholinergic Effects on the Heart

Overview

Journal Pflugers Arch

Specialty Physiology

Date 1987 Feb 1

PMID 3031579

Citations 7

Authors

S Tucek

V Dolezal

J Folbergrova

S Hynie

F Kolar

B Ostadal

Affiliations

Soon will be listed here.

Abstract

We injected rats with pertussis toxin, known to cause ADP ribosylation of the Gi regulatory protein of the adenylate cyclase complex and of another closely related GTP binding protein in the heart, and after 7 days we examined several effects of muscarinic activation on the heart. The negative chronotropic effect of carbamoylcholine on spontaneously beating perfused hearts was conspicuously diminished. While 10(-5) mol/l carbamoylcholine invariably produced heart arrest in control rats, the heart rate did not decrease by more than 20% in the toxin-treated rats even when the concentration of carbamoylcholine was raised to 10(-2) mol/l. The negative inotropic effect of carbamoylcholine examined on electrically paced ventricles perfused with isoproterenol was reduced, while the maximum positive inotropic effect of isoproterenol was substantially increased after toxin treatment. The inhibitory action of carbamoylcholine on the isoproterenol-stimulated accumulation of cyclic AMP in the heart auricles was attenuated. The weakening by pertussis toxin of the negative inotropic effect of carbamoylcholine is probably mainly due to the ADP ribosylation of the Gi regulatory protein and the subsequent loss of influence of muscarinic receptors on adenylate cyclase. The blockade of the negative chronotropic action of carbamoylcholine by pertussis toxin strongly indicates, together with other recently published evidence, that the Gi or another closely related GTP binding protein in the cardiac pacemaker cells is involved in the coupling of muscarinic receptors to the K+ channels.

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References

Sternweis P, Robishaw J . Isolation of two proteins with high affinity for guanine nucleotides from membranes of bovine brain. J Biol Chem. 1984; 259(22):13806-13. View

Sorota S, Tsuji Y, Tajima T, Pappano A . Pertussis toxin treatment blocks hyperpolarization by muscarinic agonists in chick atrium. Circ Res. 1985; 57(5):748-58. DOI: 10.1161/01.res.57.5.748. View

Osterrieder W, Brum G, Hescheler J, TRAUTWEIN W, Flockerzi V, Hofmann F . Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current. Nature. 1982; 298(5874):576-8. DOI: 10.1038/298576a0. View

Watanabe A, Lindemann J, Fleming J . Mechanisms of muscarinic modulation of protein phosphorylation in intact ventricles. Fed Proc. 1984; 43(11):2618-23. View

Hazeki O, Ui M . Modification by islet-activating protein of receptor-mediated regulation of cyclic AMP accumulation in isolated rat heart cells. J Biol Chem. 1981; 256(6):2856-62. View

Martin J, Hunter D, Nathanson N . Islet activating protein inhibits physiological responses evoked by cardiac muscarinic acetylcholine receptors. Role of guanosine triphosphate binding proteins in regulation of potassium permeability. Biochemistry. 1985; 24(26):7521-5. DOI: 10.1021/bi00347a003. View

Loffelholz K, Pappano A . The parasympathetic neuroeffector junction of the heart. Pharmacol Rev. 1985; 37(1):1-24. View

Halvorsen S, Nathanson N . Ontogenesis of physiological responsiveness and guanine nucleotide sensitivity of cardiac muscarinic receptors during chick embryonic development. Biochemistry. 1984; 23(24):5813-21. DOI: 10.1021/bi00319a021. View

Breitwieser G, Szabo G . Uncoupling of cardiac muscarinic and beta-adrenergic receptors from ion channels by a guanine nucleotide analogue. Nature. 1985; 317(6037):538-40. DOI: 10.1038/317538a0. View

10.

Biegon R, Epstein P, Pappano A . Muscarinic antagonism of the effects of phosphodiesterase inhibitor (methylisobutylxanthine) in embryonic chick ventricle. J Pharmacol Exp Ther. 1980; 215(2):348-56. View

11.

Haga K, Haga T, ICHIYAMA A, Katada T, Kurose H, Ui M . Functional reconstitution of purified muscarinic receptors and inhibitory guanine nucleotide regulatory protein. Nature. 1985; 316(6030):731-3. DOI: 10.1038/316731a0. View

12.

Kurose H, Ui M . Functional uncoupling of muscarinic receptors from adenylate cyclase in rat cardiac membranes by the active component of islet-activating protein, pertussis toxin. J Cyclic Nucleotide Protein Phosphor Res. 1983; 9(4-5):305-18. View

13.

Watanabe M . Biological activities of pertussigen from Bordetella pertussis strains of various agglutinogen types. Microbiol Immunol. 1984; 28(5):509-15. DOI: 10.1111/j.1348-0421.1984.tb00703.x. View

14.

Peterson G . A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem. 1977; 83(2):346-56. DOI: 10.1016/0003-2697(77)90043-4. View

15.

Kostyuk P . Intracellular perfusion of nerve cells and its effects on membrane currents. Physiol Rev. 1984; 64(2):435-54. DOI: 10.1152/physrev.1984.64.2.435. View

16.

Reuter H . Calcium channel modulation by neurotransmitters, enzymes and drugs. Nature. 1983; 301(5901):569-74. DOI: 10.1038/301569a0. View

17.

Pfaffinger P, Martin J, Hunter D, Nathanson N, Hille B . GTP-binding proteins couple cardiac muscarinic receptors to a K channel. Nature. 1985; 317(6037):536-8. DOI: 10.1038/317536a0. View

18.

Sokolovsky M, Gurwitz D, Kloog J . Biochemical characterization of the muscarinic receptors. Adv Enzymol Relat Areas Mol Biol. 1983; 55:137-96. DOI: 10.1002/9780470123010.ch2. View

19.

Brown H . Electrophysiology of the sinoatrial node. Physiol Rev. 1982; 62(2):505-30. DOI: 10.1152/physrev.1982.62.2.505. View

20.

Moss J, Bruni P, Hsia J, Tsai S, Watkins P, Halpern J . Pertussis toxin-catalyzed ADP-ribosylation: effects on the coupling of inhibitory receptors to the adenylate cyclase system. J Recept Res. 1984; 4(1-6):459-74. DOI: 10.3109/10799898409042567. View