Adenosine-5'-triphosphate-induced sinus tachycardia mediated by prostaglandin synthesis via phospholipase C in the rabbit heart.

Effects of adenosine 5′-triphosphate (ATP) and adenosine on cardiac sinus pacemaker activity were examined in the rabbit heart. Electrocardiograms of hearts were recorded while using the Langendorff perfusion method. Both adenosine and ATP, added to the perfusate, slowed the sinus pacemaker activity in a concentration-dependent manner. But in about 40% of the cases, ATP higher than 300 μM initially accelerated and then slowed the heart. The sinus slowing caused by adenosine and ATP was blocked by theophylline (a p1 receptor antagonist) and disappeared in the hearts pre-treated with islet-activating protein (IAP). In contrast, the ATP-induced sinus acceleration was not affected by either theophylline or IAP. In about 75% of the IAP-treated hearts, ATP persistently accelerated the sinus pacemaker. In the remaining 25% of the hearts, ATP caused junctional tachycardia, which may have masked the ATP-induced sinus acceleration. Apamin specifically blocked the ATP-induced sinus acceleration, suggesting that P2 receptors are involved. Among various adenine nucleotide analogues, the order of potency in inducing tachycardia in IAP-treated hearts is adenosine-5′-[γ-thio]triphosphate > adenylyl imidodiphosphate > adenosine 5′-[α, β-methylene]triphosphate = ATP > adenosine diphosphate = adenosine 5′-[β, γ-methylene]triphosphate. ATP-induced acceleration was partially blocked by indomethacin and aspirin (cyclooxygenase inhibitors), but not by nordihydroguaiaretic acid (a lipoxygenase inhibitor). These results suggest that cyclooxygenase and not lipoxygenase metabolites of arachidonic acid, e.g. prostaglandins, may be involved in the generation of tachycardia. Consistent with this notion, exogenously applied cyclooxygenase metabolites, prostaglandin E2 and 6-keto-prostaglandin F1α, which are known to be produced by extracellular ATP in the rabbit heart [Schwartzman et al. (1981) Eur J Pharmacol 74: 167–173], accelerated the sinus rate. We also observed that the ATP-induced tachycardia was almost completely blocked by neomycin (a phospholipase C inhibitor). We suggest, therefore, that cardiac P2 receptors may be coupled to prostaglandin synthesis via an IAP-insenstive stimulation of phospholipase C.