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1 The effects of ATP, a,-methylene ATP and P,T-methylene ATP on the contractile tension of guinea-pig isolated left atria were evaluated. 2 ATP (1-100 t4M) produced a concentration-dependent negative inotropic effect; this response was converted to a positive inotropic effect in the presence of the antagonist of adenosine Al receptors, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 0.1 JLM), and in the presence of 8-phenyltheophylline (10 JIM), an antagonist of Al and A2 receptors.3 The positive inotropic effect of ATP was antagonized by the P2 receptor antagonist, suramin (500 ;IM). Reactive blue 2 (30-500 JAM), a putative P2y receptor antagonist, concentration-dependently reduced and finally abolished the effect of ATP. 4 In the presence of 8-phenyltheophylline, the stable analogues of ATP, a,-methylene ATP and P,y-methylene ATP (1-30 jAM), produced a concentration-dependent increase in atrial contractility of a lesser degree than that induced by ATP. 5 The results suggest that when inhibitory adenosine receptors are blocked, ATP produces a positive inotropic effect, probably mediated by P2y receptor stimulation.

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1The effects of prostaglandin E2 (PGE2) and of several synthetic prostanoids on the cardiac response to sympathetic nerve stimulation in guinea-pig atria have been evaluated. 2 PGE2 (0.01-100nM), sulprostone (0.01-100nM) and misoprostol (0.1-100nM), but not butaprost (0.1-100nM), dose-dependently reduced the increase in cardiac contractility induced by electrical field stimulation of sympathetic terminals.3 The EP1 antagonist AH6809 (1,uM) did not modify the inhibition of cardiac response induced by PGE2, sulprostone and misoprostol. 4 In preparations preloaded with [3H]-noradrenaline, tritium overflow induced by electrical field stimulation was greatly and significantly reduced by 100nm PGE2 and by 100nm sulprostone. 5 These results indicate that PGE2 and other synthetic prostanoids reduce noradrenaline release from cardiac adrenergic nerve terminals acting on prejunctional inhibitory receptors belonging to the EP3 subtype.

The positive inotropic effect of dopamine has been studied in isolated ventricular strips of guinea-pig heart. The concentration-inotropic response curve for dopamine was significantly shifted to the right by pretreatment with reserpine. In preparations obtained from animals pretreated with reserpine (2.5 mg/kg, 24 h prior to the experiment) the dose-response curve was not significantly affected by haloperidol, a dopamine vascular receptor antagonist (10(-6)-3X10(-6) M). The inotropic effect of dopamine was antagonized by practolol (3X10(-7)-10(-6) M), but not by phentolamine (3X10(-6)-10(-5) M); moreover the alpha-adrenoceptor blocking drug (10(-5) M) did not affect the curve for dopamine in the presence of practolol (3X10(-7) M). In preparations in which fast sodium channels were blocked by K+ -rich medium, slow electrical responses (calcium-mediated action potentials) as well as contractions were induced by high concentrations of dopamine (10(-4)-3X10(-4) M); again these responses were unaffected by phentolamine or haloperidol, but were blocked by practolol. It was concluded that in the guinea-pig ventricular muscle dopamine induced a positive inotropic effect through both indirect and direct action, and that the latter is due to the activation of beta-adrenoceptors.