INDOMETHACIN ANTAGONIZES THE EFFECTS OF ADENOSINE RECEPTOR AGONISTS ON THE CONTRACTILITY AND EFFECTIVE REFRACTORY PERIOD OF GUINEA-PIG PAPILLARY-MUSCLE

The effects of adenosine receptor agonists N-6-cyclohexyladenosine (CH A) and 5'-(N-ethylcarboxamido)-adenosine (NECA) on the force of contra ction (Fc), rate of rise of force (+dF/dt), rate of fall of force (-dF /dt) and effective refractory period (ERP) of isolated guinea pig hear t papillary muscle was examined. Additionally, the influence of potent cycloxygenase inhibitor indomethacin on above mentioned parameters as well as on the effects induced by CHA and NECA were studied. It was f ound that CHA produced direct negative inotropic action in the concent ration range of 3x10(-10) to 3x10(-9) M, and decreased the duration of ERP significantly. NECA, in the presence of 2x10(-9) M of 1,3-dipropy l-8-p-sulfophenyl-xanthine (DPSX), (adenosine receptor antagonist with slight selectivity to A(1) receptor), produced positive inotropic act ion and a significant prolongation of the ERP duration (1x10(-9) to 3x 10(-8)). On the other hand, indomethacin applied in rising concentrati ons (1x10(-6) to 1x10(-5)) had no effect on contractility but, signifi cantly increased the duration of ERP. When the treatment however start ed with the dose of 1x10(-5) M of indomethacin, a sustaining significa nt increase in Fc, +dF/dt, -dF/dt and ERP by about 50% above control v alue was observed. What is more, the pretreatment with 1x10(-5) M of i ndomethacin completely abolished the positive inotropic effect of NECA and strongly shifted to the right the concentration-response curve fo r negative inotropic effect of CHA. The possible explanation for these effects of indomethacin could be a consequently increase in leukotrie nes concentration induced by inhibition of cycloxygenase driven pathwa y. (C) 1996 The Italian Pharmacological Society.