Increased Gi protein signaling potentiates the negative chronotropic effect of adenosine in the SHR right atrium

Hypertension is a risk factor for cardiovascular diseases, which have been associated with dysfunction of sympathetic and purinergic neurotransmission. Therefore, herein, we evaluated whether modifications of adenosine receptor signaling may contribute to the cardiac dysfunction observed in hypertension. Isolated right atria from spontaneously hypertensive (SHR) or normotensive Wistar rats (NWR) were used to investigate the influence of adenosine receptor signaling cascade in the cardiac chronotropism. Our results showed that adenosine, the endogenous agonist of adenosine receptors, and CPA, a selective agonist of A(1) receptor, decreased the atrial chronotropism of NWR and SHR in a concentration- and time-dependent manner, culminating in cardiac arrest (0 bpm). Interestingly, a 3-fold lower concentration of adenosine was required to induce the negative chronotropic effect in SHR atria. Pre-incubation of tissues from both strains with DPCPX, a selective A(1) receptor antagonist, inhibited the negative chronotropic effect of CPA, while simultaneous inhibition of A(2) and A(3) receptors, with ZM241385 and MRS1523, did not change the adenosine chronotropic effects. Moreover, 1 mu g/ml pertussis toxin, which inactivates the G alpha i protein subunit, reduced by 80% the negative chronotropic effects of adenosine in the NWR atrium, with minor effects in SHR tissue. These data indicate that the negative chronotropic effect of adenosine in right atrium depends exclusively on the activation of A(1) receptors. Moreover, the distinct responsiveness of NWR and SHR atria to pertussis toxin reveals that the enhanced negative chronotropic response of SHR right atrium is probably due to an increased activity of G alpha i protein-mediated.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Univ Fed Sao Paulo UNIFESP, Dept Pharmacol, Escola Paulista Med, Rua Tres de Maio 100,3 Andar, BR-04044020 Sao Paulo, BrazilUniv Fed Sao Paulo UNIFESP, Dept Pharmacol, Escola Paulista Med, Rua Tres de Maio 100,3 Andar, BR-04044020 Sao Paulo, BrazilFAPESP: 2013/20402-6FAPESP: 2015/07019-4FAPESP: 12/22763-3FAPESP: 2012/24828-5CNPq: 0309428/2015-7Web of Scienc