Pharmacological characterization of A2-adenosine receptors in guinea-pig ventricular cardiomyocytes.
The aim of the present study was to elucidate the question of whether cardiomyocytes possess stimulatory adenylyl cyclase-coupled A2-adenosine receptors and whether these receptors modify contractility. In isolated electrically driven ventricular cardiomyocytes from guinea-pig hearts the effects of the A2-adenosine receptor agonist 2-[(p-2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamide-adenos ine (CGS 21680C) alone and in the presence of isoprenaline on cAMP content and contractile response were investigated. In addition, we characterized these effects with selective A1- and A2-adenosine receptor antagonists [1,3-dipropyl-8-cyclopentylxanthine, DPCPX and 9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4-triazolo-(1,5-c)quinazolin++ +-5-imine, CGS 15943A, respectively]. To investigate the signal transduction pathway, the influence of pertussis toxin, known to inhibit signal transducing GTP-binding proteins (Gi/o-proteins), on these effects was studied. CGS 21680C alone and in the presence of isoprenaline increased cAMP content concentration-dependently (0.1 nmol/l-10 mumol/l) to maximally 154% of control and 137% of isoprenaline value, respectively. In the presence of the A1-adenosine receptor antagonist DPCPX (0.3 mumol/l) or after pertussis toxin-pretreatment (18 micrograms/kg i.v. 24-26 h) the cAMP increase was further elevated. The A2-adenosine receptor antagonist CGS 15943A (0.01 mumol/l) abolished these effects, indicating that these effects are mediated by A2-adenosine receptors. The elevation in cAMP content was not accompanied by an increase in contractile response. However, in the presence of isoprenaline CGS 21680C reduced contractile response to 62% of the isoprenaline value. The A1-adenosine receptor antagonist DPCPX abolished the decrease in contractility, whereas the A2-adenosine receptor antagonist CGS 15943A did not effect contractility. Thus the reduction in contractility is mediated via cAMP-decreasing A1-adenosine receptors. The results provide evidence for the coexistence of cAMP-reducing A1- and cAMP-elevating A2-adenosine receptors on ventricular cardiomyocytes. Only stimulation of A1-adenosine receptors leads to a subsequent reduction in contractile response, whereas A2-adenosine receptors do not affect contractility.
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.
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Stein
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Schmitz
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Scholz
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Seeland
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000737:chemistry* / Q000166:cytology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D037342:Pertussis Toxin; D010627:Phenethylamines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D018047:Receptors, Purinergic P1 / Q000145:classification / Q000187:drug effects*; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D010627:Phenethylamines; D011799:Quinazolines; D011943:Receptors, Adrenergic, beta; D018047:Receptors, Purinergic P1; D014230:Triazoles; D010566:Virulence Factors, Bordetella; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases; D000241:Adenosine; D007545:Isoproterenol; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine