Regulation of Beta-adrenoceptors in the Guinea-pig Sinoatrial Node

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 1994 May 1

PMID 7915007

Citations 4

Authors

F D Russell

A R Kompa

P Molenaar

R J Summers

Affiliations

Soon will be listed here.

Abstract

This study examined the changes of beta-adrenoceptors in the guinea-pig sinoatrial nodal region following 7 day (-)-isoprenaline (400 micrograms/kg/h s.c.) infusion and the relationship between beta-adrenoceptor desensitization and receptor down-regulation. Changes in beta 1- and beta 2-adrenoceptor density were measured using quantitative autoradiography and function in organ bath studies. (-)-Isoprenaline treatment produced a marked decrease in total (from 57.5 to 33.9 fmol/mg protein), beta 1- (from 49.4 to 32.8 fmol/mg protein), and beta 2-adrenoceptor density (from 8.1 to 1.05 fmol/mg protein) in the sinoatrial node. In adjacent right atrium, treatment produced no change in total (39.5 and 36.7 fmol/mg protein) or beta 1-adrenoceptors (35.9 and 36.4 fmol/mg protein) but did decrease beta 2-adrenoceptors (from 3.7 to 0.3 fmol/mg protein). Chronotropic effects were measured in spontaneously beating right atrium. Procaterol, a selective beta 2-adrenoceptor agonist, caused a biphasic chronotropic response in control right atria, the first part of which was abolished in the tissue from treated animals. The maximum increase in right atrial rate to RO363, a beta 1-adrenoceptor selective partial agonist, was reduced from 114 bpm in control to 43 bpm in treated animals. In electrically driven right atrium with the sinoatrial node removed procaterol failed to produce a positive inotropic response via beta 2-adrenoceptors, but the maximum response to RO363 was reduced from 0.75 g in the control tissue to 0.12 g in the treated tissue. This study showed that changes in beta 2-adrenoceptor density following 7 day (-)-isoprenaline infusion are compatible with reduced functional responsiveness in the SA node. The reduction of beta 1-adrenoceptor number in the SA node was also compatible with the reduced chronotropic response in this tissue. However the lack of effect on beta 1-adrenoceptor density in the right atrium was not consistent with the decrease in beta 1-adrenoceptor mediated inotropic response in this tissue. This suggests that beta-adrenoceptor desensitization is not always associated with receptor down-regulation but depends also on the changes in the cell signalling system beyond the level of the receptor which differ according to the cardiac location.

Citing Articles

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Functional analysis of desensitization of the beta-adrenoceptor signalling pathway in rat cardiac tissues following chronic isoprenaline infusion.

McMartin L, Summers R Br J Pharmacol. 1999; 127(4):1012-20.

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Chronic (-)-isoprenaline infusion down-regulates beta 1- and beta 2-adrenoceptors but does not transregulate muscarinic cholinoceptors in rat heart.

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References

Nanoff C, Freissmuth M, TUISL E, Schutz W . A different desensitization pattern of cardiac beta-adrenoceptor subtypes by prolonged in vivo infusion of isoprenaline. J Cardiovasc Pharmacol. 1989; 13(2):198-203. DOI: 10.1097/00005344-198902000-00004. View

Majewski H . Modulation of noradrenaline release through activation of presynaptic beta-adrenoreceptors. J Auton Pharmacol. 1983; 3(1):47-60. DOI: 10.1111/j.1474-8673.1983.tb00496.x. View

Motomura S, Daul A, Brodde O . On the physiologic role of beta-2 adrenoceptors in the human heart: in vitro and in vivo studies. Am Heart J. 1990; 119(3 Pt 1):608-19. DOI: 10.1016/s0002-8703(05)80284-4. View

Harden T . Agonist-induced desensitization of the beta-adrenergic receptor-linked adenylate cyclase. Pharmacol Rev. 1983; 35(1):5-32. View

Molenaar P, Russell F, Shimada T, Summers R . Densitometric analysis of beta 1- and beta 2-adrenoceptors in guinea-pig atrioventricular conducting system. J Mol Cell Cardiol. 1990; 22(4):483-95. DOI: 10.1016/0022-2828(90)91483-n. View

Desaulles E, Miesch F, Schwartz J . Evidence for the participation of beta1-adrenoceptors in isoprenaline-induced renin release from rat kidny slices in vitro. Br J Pharmacol. 1978; 63(3):421-5. PMC: 1668094. DOI: 10.1111/j.1476-5381.1978.tb07793.x. View

Hertel C, STAEHELIN M, PERKINS J . Evidence for intravesicular beta-adrenergic receptors in membrane fractions from desensitized cells: binding of the hydrophilic ligand CGP-12177 only in the presence of alamethicin. J Cyclic Nucleotide Protein Phosphor Res. 1983; 9(2):119-28. View

Ask J, Helle K, Fin R . Activation of cardiac beta 2 adrenoceptors in the human heart. Am J Cardiol. 1986; 57(12):7F-10F. DOI: 10.1016/0002-9149(86)90881-7. View

Kaumann A, Lemoine H . Direct labelling of myocardial beta 1-adrenoceptors. Comparison of binding affinity of 3H-(-)-bisoprolol with its blocking potency. Naunyn Schmiedebergs Arch Pharmacol. 1985; 331(1):27-39. DOI: 10.1007/BF00498849. View

10.

Johansson L, Persson H . Beta 2-adrenoceptors in guinea-pig atria. J Pharm Pharmacol. 1983; 35(12):804-7. DOI: 10.1111/j.2042-7158.1983.tb02900.x. View

11.

Ruffolo Jr R . Review important concepts of receptor theory. J Auton Pharmacol. 1982; 2(4):277-95. DOI: 10.1111/j.1474-8673.1982.tb00520.x. View

12.

Molenaar P, Summers R . Characterization of beta-1 and beta-2 adrenoceptors in guinea pig atrium: functional and receptor binding studies. J Pharmacol Exp Ther. 1987; 241(3):1041-7. View

13.

Dooley D, Bittiger H, Reymann N . CGP 20712 A: a useful tool for quantitating beta 1- and beta 2-adrenoceptors. Eur J Pharmacol. 1986; 130(1-2):137-9. DOI: 10.1016/0014-2999(86)90193-7. View

14.

Lemoine H, Ehle B, Kaumann A . Direct labelling of beta 2-adrenoceptors. Comparison of binding potency of 3H-ICI 118,551 and blocking potency of ICI 118,551. Naunyn Schmiedebergs Arch Pharmacol. 1985; 331(1):40-51. DOI: 10.1007/BF00498850. View

15.

Molenaar P, Smolich J, Russell F, McMartin L, Summers R . Differential regulation of beta-1 and beta-2 adrenoceptors in guinea pig atrioventricular conducting system after chronic (-)-isoproterenol infusion. J Pharmacol Exp Ther. 1990; 255(1):393-400. View

16.

Benovic J, Strasser R, Caron M, Lefkowitz R . Beta-adrenergic receptor kinase: identification of a novel protein kinase that phosphorylates the agonist-occupied form of the receptor. Proc Natl Acad Sci U S A. 1986; 83(9):2797-801. PMC: 323393. DOI: 10.1073/pnas.83.9.2797. View

17.

Hertel C, STAEHELIN M . Reappearance of beta-adrenergic receptors after isoproterenol treatment in intact C6-cells. J Cell Biol. 1983; 97(5 Pt 1):1538-43. PMC: 2112695. DOI: 10.1083/jcb.97.5.1538. View

18.

Majewski H . Angiotensin II and noradrenergic transmission in the pithed rat. J Cardiovasc Pharmacol. 1989; 14(4):622-30. DOI: 10.1097/00005344-198910000-00014. View

19.

Williams D, Summers R . SIMUL: an accurate method for the determination of receptor subtype proportions using a personal computer. Comput Methods Programs Biomed. 1990; 32(2):137-9. DOI: 10.1016/0169-2607(90)90093-o. View

20.

Hawthorn M, Broadley K . beta-Adrenoceptor ligand binding and supersensitivity to isoprenaline of ventricular muscle after chronic reserpine pretreatment. Naunyn Schmiedebergs Arch Pharmacol. 1982; 320(3):240-5. DOI: 10.1007/BF00510135. View