Indomethacin antagonises the effects of adenosine receptor agonists on the contractility and effective refractory period of guinea pig papillary muscle.

The effects of adenosine receptor agonists N6-cyclohexyladenosine (CHA) and 5'-(N-ethylcarboxamido)-adenosine (NECA) on the force of contraction (Fc), rate of rise of force (+dF/dt), rate of fall of force (-dF/dt) and effective refractory period (ERP) of isolated guinea pig heart 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 found that CHA produced direct negative inotropic action in the concentration range of 3 x 10(-10) to 3 x 10(-9) M and decreased the duration of ERP significantly. NECA, in the presence of 2 x 10(-9) M of 1,3-dipropyl-8-p-sulfophenyl-xanthine (DPSX), (adenosine receptor antagonist with slight selectivity to A1 receptor), produced positive inotropic action and a significant prolongation of the ERP duration (1 x 10(-9) to 3 x 10(-8). On the other hand, indomethacin applied in rising concentrations (1 x 10(-6) to 1 x 10(-5) had no effect on contractility but, significantly increased the duration of ERP. When the treatment however started with the dose of 1 x 10(-5) M of indomethacin, a sustaining significant increase in Fc, +dF/dt, -dF/dt and ERP by about 50% above control value was observed. What is more, the pretreatment with 1 x 10(-5) M of indomethacin completely abolished the positive inotropic effect of NECA and strongly shifted to the right the concentration-response curve for negative inotropic effect of CHA. The possible explanation for these effects of indomethacin could be a consequently increase in leukotrienes concentration induced by inhibition of cycloxygenase driven pathway.