Nature of Catecholamine-like Actions of ATP and Other Energy Rich Nucleotides on the Bullfrog Atrial Muscle

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Abstract
The nature of the inotropic actions of exogeneously applied ATP and related compounds (AMP-PNP [adenylylimidodiphosphate], GTP, GMP and guanosine) was studied in comparison with that of adrenaline [epinephrine] on the bullfrog atrial muscle under voltage clamped and unclamped conditions with the double-gap method. ATP and GTP (10-6-10-3 M) produced an immediate positive inotropic effect similar to that achieved with adrenaline. Dose-respons curves of these drugs fitted the theoretical dose-response relations, but the ATP and GTP curves were not significantly altered by propranolol. Under voltage clamped conditions, ATP, AMP-PNP and GTP augmented the Ca inward current (ICa), ICa-dependent tension and the delayed outward current (Ix) as adrenaline. On the other hand, GMP and guanosine, which have a purine-ribose base but not a high energy phosphate bond, produced a negative inotropic effect, and depressed the Ix as adenosine. All these nucleotides and nucleosides inhibited the ICa-independent tonic tension. The facts that GTP and AMP-PNP showed the same effect as ATP indicated that neither the energy liberation from the phosphate bond nor the substrate for cyclic AMP formation is involved in their positive inotropic effects. The energy rich nucleotides modulate the adenylate cyclase activity, being mediated by some receptor located at the outer surface of the membrane other than .beta.-adrenergic receptor.