An analysis of the mechanism of the inotropic action of some milrinone analogues in guinea‐pig isolated atria

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Abstract
It has been reported previously that the milrinone analogues, ethyl 5‐cyano‐1,6‐dihydro‐2‐methyl‐6‐oxo‐3 pyridine carboxylate (I) and ethyl 5‐cyano‐1,6‐dihydro‐2‐ethyl‐6‐oxo‐3 pyridine carboxilate (II) exert a positive inotropic effect (EC50 = 15.6 ± 0.2 μm and 40.3 ± 0.1 μm) both on spontaneously beating and on electrically driven atria from reserpine‐treated guinea‐pigs. In the present study the mechanism of the inotropic action of these two agents was investigated. In electrically driven left atrium from resperpine‐treated guinea‐pigs the EC50 values for inotropic activity for compounds (I) and (II) corresponded to that of milrinone (EC50 = 25 ± 0.1 μm) but compound (I) induced a greater maximum effect. This corresponded to a percentage increase in developed tension over control of 63 ± 0.3 whereas the maximum inotropic effect of milrinone was 48 ± 0.3 and that of compound (II) was 47 ± 0.2. The inotropic activity of compounds (I) and (II) (10–100 μm) was resistant to propranolol (0.1 μm), thus excluding the involvement of β‐adrenoceptors. Since the inotropism induced by compounds (I) and (II) was not reduced by carbachol (1 nm‐0.5 μm), an action involving changes in adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) can be excluded. The inotropic action of compounds (I) and (II) was blocked selectively by 8‐phenyltheophyline (10 μm) or adenosine deaminase (2 u ml−1). Both (I) and (II) inhibited, in an apparently competitive manner, the negative inotropic effect induced by N6‐(l‐phenylisopropyl) adenosine (l‐PIA), a stable adenosine agonist. The pA2 values for (I) and (II) were 4.79 and 4.36, respectively. In rat brain compounds (I) and (II) inhibited the specific binding of N6‐cyclohexyl[3H]‐adenosine‐([3H]‐CHA) with an IC50 of 0.18 ± 0.01 mm and 0.25 ± 0.02 mm, respectively, which were similar to their IC50 values for blocking the PIA‐induced negative inotropic effect and which are also in the range of concentrations that are effective in inducing positive inotropism in guinea‐pig atria. The results from the present study suggest that antagonism of endogenous purines causes positive inotropism without affecting intracellular cyclic AMP levels.