Adenosine inhibits the positive inotropic effect of 3-isobutyl-1-methylxanthine in papillary muscles without effect on cyclic AMP or cyclic GMP.
1 Adenosine and the adenosine receptor agonist (-)-N6-phenylisopropyladenosine (PIA) produced a small positive and negative inotropic effect, respectively, in isolated electrically driven papillary muscles of guinea-pigs. 2 Adenosine (100 mumol l-1) had no effect on cyclic AMP or cyclic GMP content. PIA (100 mumol l-1) slightly increased cyclic AMP. 3 In the presence of 3-isobutyl-1-methylxanthine (IBMX; 60 mumol l-1), which increased force of contraction 2 fold, adenosine and PIA exerted strong negative inotropic effects. PIA was more potent than adenosine (mean IC25 2.1 and 168 mumol -1, respectively). 4 In contrast, the nucleosides did not affect the increase in force of contraction produced by elevating extracellular Ca2+ concentration. 5 The IBMX-antagonistic effects of adenosine and PIA were not accompanied by modification of the IBMX-induced increase in cyclic AMP and cyclic GMP. 6 The effects of adenosine and PIA on force of contraction were accompanied by a partial reversal of the IBMX-induced increase in the maximal rate of depolarization of slow action potentials. 7 It is concluded that adenosine and PIA are able to attenuate the positive inotropic effect of a phosphodiesterase inhibitor. This effect is unlikely to be due to a reduction of the IBMX-induced increase in cyclic AMP content. It is conceivably due to an inhibition of the stimulant action of cyclic AMP on slow Ca2+ channels leading to the reduction of the slow inward current which in turn reduces force of contraction.
Böhm
M
M
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, F.R.G.
Brückner
R
R
Neumann
J
J
Nose
M
M
Schmitz
W
W
Scholz
H
H
D015056:1-Methyl-3-isobutylxanthine / Q000037:antagonists & inhibitors*; D000200:Action Potentials / Q000187:drug effects; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D013806:Theophylline / Q000031:analogs & derivatives*
D010660:Phenylisopropyladenosine; D013806:Theophylline; D000242:Cyclic AMP; D006152:Cyclic GMP; D000241:Adenosine; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine