Phosphodiesterase PDE3 Blunts the Positive Inotropic and Cyclic AMP Enhancing Effects of CGP12177 but Not of Noradrenaline in Rat Ventricle

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2005 Dec 7

PMID 16331293

Citations 13

Authors

Maria Luisa Vargas

Jesus Hernandez

Alberto J Kaumann

Affiliations

Soon will be listed here.

Abstract

1.--The cardiostimulant effects of CGP12177, mediated through a beta(1)-adrenoceptor site with low affinity for (-)-propranolol, are potentiated by the nonselective PDE inhibitor IBMX but the role of PDE isoenzymes is unknown. We studied the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4-selective inhibitor rolipram (1 microM) on the positive inotropic and cyclic AMP-enhancing effects of CGP12177 and noradrenaline in right ventricular strips of rat. 2.--CGP12177 (under (-)-propranolol 200 nM) only increased contractile force in the presence of either cilostamide or rolipram with -logEC(50)M 6.7 (E(max)=23% over basal) and 7.1 (E(max)=50%) respectively. The combination of cilostamide and rolipram caused CGP12177 to enhance contractile force with -logEC(50)M=7.7 and E(max)=178%. 3.--The positive inotropic effects of noradrenaline (-logEC(50)M=6.9) were potentiated by rolipram (-logEC(50)M=7.4) but not by cilostamide (-logEC(50)M=7.0). 4.--In the presence of rolipram and (-)-propranolol, noradrenaline (2 microM) and CGP12177 (10 microM) produced matching inotropic effects but failed to increase cyclic AMP levels. 20 microM (-)-noradrenaline increased cyclic AMP levels, a response further enhanced by rolipram. 5.--Both PDE3 and PDE4 of rat ventricle appear to hydrolyse cyclic AMP generated through the low-affinity beta(1)-adrenoceptor site, thereby preventing inotropic responses of CGP12177. When (-)-noradrenaline interacts with the beta(1)-adrenoceptor, the generated cyclic AMP is hydrolysed only by PDE4, thereby reducing cardiostimulation.

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References

Sarsero D, Molenaar P, Kaumann A, Freestone N . Putative beta 4-adrenoceptors in rat ventricle mediate increases in contractile force and cell Ca2+: comparison with atrial receptors and relationship to (-)-[3H]-CGP 12177 binding. Br J Pharmacol. 1999; 128(7):1445-60. PMC: 1571781. DOI: 10.1038/sj.bjp.0702936. View

Nicholson C, Challiss R, Shahid M . Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends Pharmacol Sci. 1991; 12(1):19-27. DOI: 10.1016/0165-6147(91)90484-a. View

Konkar A, Zhu Z, Granneman J . Aryloxypropanolamine and catecholamine ligand interactions with the beta(1)-adrenergic receptor: evidence for interaction with distinct conformations of beta(1)-adrenergic receptors. J Pharmacol Exp Ther. 2000; 294(3):923-32. View

Kaumann A, Engelhardt S, Hein L, Molenaar P, Lohse M . Abolition of (-)-CGP 12177-evoked cardiostimulation in double beta1/beta2-adrenoceptor knockout mice. Obligatory role of beta1-adrenoceptors for putative beta4-adrenoceptor pharmacology. Naunyn Schmiedebergs Arch Pharmacol. 2001; 363(1):87-93. DOI: 10.1007/s002100000336. View

Granneman J . The putative beta4-adrenergic receptor is a novel state of the beta1-adrenergic receptor. Am J Physiol Endocrinol Metab. 2001; 280(2):E199-202. DOI: 10.1152/ajpendo.2001.280.2.E199. View

Rich T, Fagan K, Tse T, Schaack J, Cooper D, Karpen J . A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell. Proc Natl Acad Sci U S A. 2001; 98(23):13049-54. PMC: 60822. DOI: 10.1073/pnas.221381398. View

Lowe M, Lynham J, Grace A, Kaumann A . Comparison of the affinity of beta-blockers for two states of the beta 1-adrenoceptor in ferret ventricular myocardium. Br J Pharmacol. 2002; 135(2):451-61. PMC: 1573134. DOI: 10.1038/sj.bjp.0704450. View

Sarsero D, Russell F, Lynham J, Rabnott G, Yang I, Fong K . (-)-CGP 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol-resistant state of the beta 1-adrenoceptor. Naunyn Schmiedebergs Arch Pharmacol. 2003; 367(1):10-21. DOI: 10.1007/s00210-002-0652-9. View

Baker J, Hall I, Hill S . Agonist actions of "beta-blockers" provide evidence for two agonist activation sites or conformations of the human beta1-adrenoceptor. Mol Pharmacol. 2003; 63(6):1312-21. DOI: 10.1124/mol.63.6.1312. View

10.

Joseph S, Lynham J, Molenaar P, Grace A, Colledge W, Kaumann A . Intrinsic sympathomimetic activity of (-)-pindolol mediated through a (-)-propranolol-resistant site of the beta1-adrenoceptor in human atrium and recombinant receptors. Naunyn Schmiedebergs Arch Pharmacol. 2003; 368(6):496-503. DOI: 10.1007/s00210-003-0835-z. View

11.

Lewis C, Gong H, Brown M, Harding S . Overexpression of beta 1-adrenoceptors in adult rat ventricular myocytes enhances CGP 12177A cardiostimulation: implications for 'putative' beta 4-adrenoceptor pharmacology. Br J Pharmacol. 2004; 141(5):813-24. PMC: 1574257. DOI: 10.1038/sj.bjp.0705668. View

12.

Joseph S, Lynham J, Grace A, Colledge W, Kaumann A . Markedly reduced effects of (-)-isoprenaline but not of (-)-CGP12177 and unchanged affinity of beta-blockers at Gly389-beta1-adrenoceptors compared to Arg389-beta1-adrenoceptors. Br J Pharmacol. 2004; 142(1):51-6. PMC: 1574932. DOI: 10.1038/sj.bjp.0705753. View

13.

Movsesian M, Smith C, KRALL J, Bristow M, Manganiello V . Sarcoplasmic reticulum-associated cyclic adenosine 5'-monophosphate phosphodiesterase activity in normal and failing human hearts. J Clin Invest. 1991; 88(1):15-9. PMC: 295996. DOI: 10.1172/JCI115272. View

14.

Katano Y, Endoh M . Effects of a cardiotonic quinolinone derivative Y-20487 on the isoproterenol-induced positive inotropic action and cyclic AMP accumulation in rat ventricular myocardium: comparison with rolipram, Ro 20-1724, milrinone, and isobutylmethylxanthine. J Cardiovasc Pharmacol. 1992; 20(5):715-22. View

15.

Beavo J . Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. 1995; 75(4):725-48. DOI: 10.1152/physrev.1995.75.4.725. View

16.

Jurevicius J, Fischmeister R . cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists. Proc Natl Acad Sci U S A. 1996; 93(1):295-9. PMC: 40225. DOI: 10.1073/pnas.93.1.295. View

17.

Pak M, Fishman P . Anomalous behavior of CGP 12177A on beta 1-adrenergic receptors. J Recept Signal Transduct Res. 1996; 16(1-2):1-23. DOI: 10.3109/10799899609039938. View

18.

Kaumann A . (-)-CGP 12177-induced increase of human atrial contraction through a putative third beta-adrenoceptor. Br J Pharmacol. 1996; 117(1):93-8. PMC: 1909374. DOI: 10.1111/j.1476-5381.1996.tb15159.x. View

19.

Kaumann A, Molenaar P . Differences between the third cardiac beta-adrenoceptor and the colonic beta 3-adrenoceptor in the rat. Br J Pharmacol. 1996; 118(8):2085-98. PMC: 1909870. DOI: 10.1111/j.1476-5381.1996.tb15648.x. View

20.

Kaumann A, Lynham J . Stimulation of cyclic AMP-dependent protein kinase in rat atria by (-)-CGP 12177 through an atypical beta-adrenoceptor. Br J Pharmacol. 1997; 120(7):1187-9. PMC: 1564608. DOI: 10.1038/sj.bjp.0701053. View