The activation of P₁‐ and P₂‐purinoceptors in the guinea‐pig left atrium by diadenosine polyphosphates

Abstract

1 The effects of P', P2-di(adenosine) pyrophosphate (AP2A), P',P3-di(adenosine) triphosphate (AP3A), P',P"-di(adenosine) tetraphosphate (AP4A), P',P5-di(adenosine) pentaphosphate (AP5A), ATP, a,,Bmethylene ADP and 2-chloroadenosine (2-ClAd) were examined in the guinea-pig driven left atrium.2 All these purine compounds except a,#-methylene ADP produced a negative inotropic response with a rank order of potency of: 2-ClAd > > AP2A > ATP > AP4A = AP3A = AP5A. The ECs, value for 2-ClAd was approximately 1 guM, while those for the remaining compounds were in the range 10 guM-100 MM, a,f,-Methylene ADP (10-300 gM), a selective P2Y-purinoceptor agonist, produced a small positive inotropism.3 The P1-purinoceptor antagonist, 8-para-sulphophenyltheophylline 20 gM) caused a rightward shift in the concentration-response curves for 2-ClAd, ATP and AP2A, but converted the responses of AP3A, AP4A, and AP5A into positive inotropisms.4 The non-selective P2-purinoceptor antagonist, suramin (300 gM), had no significant effect on the concentration-response curves for 2-ClAd, ATP or AP2A, but significantly antagonized inhibitory responses to AP3A, AP4A and AP5A, and excitatory responses to a,,B-methylene ADP.5 In the presence of 8-pSPT (20 gM), suramin (300 gM) abolished the positive inotropic responses evoked by the dinucleotides. 6 ATP was degraded far more rapidly than any of the dinucleotides, and AP3A was the least stable of the diadenosine compounds. The relative order of stability was AP2A > AP4A = AP5A > AP3A > > ATP.Suramin (300 gM) reduced the rate of degradation of ATP and AP3A by approximately 30%. Suramin had no significant effect on the degradation of AP2A, AP4A or AP5A.7 It is concluded that the diadenosine polyphosphates cause negative inotropic responses via PIpurinoceptors and a hitherto undefined suramin-sensitive P2-purinoceptor, and that they appear to have positive inotropic effects mediated via another suramin-sensitive P2-purinoceptor.

Cardiac electrophysiological effects of platelet-derived substances

“…Hoyle (1990) proposed that diadenosine polyphosphates interact with receptors distinct from P1-and Pµ-purinoceptors, yet studies using intact preparations suggest that some of the effects of diadenosine polyphosphates are mediated by purinoceptors. Hoyle et al (1996) reported that the negative inotropic responses of guinea-pig left atria to diadenosine polyphosphates are mediated by P1-and Pµ-purinoceptors. In the rat, the responses to APÛA were shown to involve P1-purinoceptors (Kengatharan et al 1994), while the responses of isolated human and guinea-pig ventricular preparations to APÜA appear to involve P1-purinoceptors (Vahlensieck et al 1996).…”

Effects of Diadenosine Polyphosphates on the Intracellular Ca²⁺ Concentration in Endothelial Cells

“…In anesthetized dogs and pigs, Ap4A caused a decrease in mean arterial pressure [12,13] which we demonstrated recently also for Ap4A, Ap5A and Ap6A [14]. Diadenosine polyphosphates induce negative chronotropic and inotropic responses in guineapig, canine, and human cardiac preparations [1,6,12]. The vascular tone in several organs is influenced by diadenosine polyphosphates.…”

“…The diadenosine polyphosphates have recently received considerable attention due to their cardiovascular effects [1][2][3][4][5][6]. Members of this class of compounds consist of two adenosine moieties connected via 5)-ribose linkage to each end of a polyphosphate chain.…”

Heart & Cardiac Muscle

“…Diadenosine polyphosphates (AP nA) represent a group of platelet and chromaffin cell-derived mediators with various effects in the cardiovascular system. In multicellular preparations of the heart their actions resemble those of adenosine (Ado) and are sensitive to Al receptor antagonists (Hoyle et al 1996;Vahlensick et al 1996). We have studied AP nA (n = 4-6) in isolated atrial myocytes by measuring G protein-gated IK(ACh)' an established target of Al receptors.…”