Possible role of diadenosine polyphosphates as modulators of cardiac sensory-motor neurotransmission in guinea-pigs.

1. Isolated guinea-pig atria were used to study the neuromodulatory effect of diadenosine polyphosphates (APnA) on cardiac capsaicin-sensitive sensory-motor neurotransmission. 2. In the presence of atropine, guanethidine and propranolol, electrical field stimulation (EFS) of the atrial preparations evoked a positive inotropic response which is known to be mediated by release of calcitonin gene-related peptide (CGRP) from sensory-motor nerves. P1,P2-diadenosine pyrophosphate (AP2A), P1,P3-diadenosine triphosphate (AP3A), P1,P4-diadenosine tetraphosphate (AP4A), P1,P5-diadenosine pentaphosphate (AP5A) and P1,P6-diadenosine hexaphosphate (AP6A) inhibited in a concentration-dependent way (0.1-30 microM) cardiac responses to EFS. The inhibitory effect of APnA was mimicked by adenosine. 3. All the APnA tested had a direct negative inotropic effect, by reducing in a concentration-dependent manner the basal contractile tension. The inotropism of APnA was comparable to that of adenosine. 4. Both inhibition of cardiac responses to EFS and negative inotropism of AP2A, AP3A and AP4A were sensitive to the antagonism by the A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.1-1 nM). The extent of antagonism of DPCPX for the APnA tested was comparable to that for adenosine. 5. Despite the direct negative inotropism, AP4A tested at the highest concentration used did not affect the cardiac responses to the neurotransmitter CGRP, applied exogenously. 6. These results have demonstrated that in isolated guinea-pig atria APnA inhibited sensory-motor neurotransmission, without affecting cardiac responses to exogenous CGRP. The effect of APnA was sensitive to antagonism by DPCPX, which suggests it operates via the activation of prejunctional A1 adenosine receptors. A postjunctional negative inotropism was also shown, mediated by myocardial A1 adenosine receptors.