Increased Gi protein signaling potentiates the negative chronotropic effect of adenosine in the SHR right atrium
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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 A1 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 A1 receptor antagonist, inhibited the negative chronotropic effect of CPA, while simultaneous inhibition of A2 and A3 receptors, with ZM241385 and MRS1523, did not change the adenosine chronotropic effects. Moreover, 1 μg/ml pertussis toxin, which inactivates the Gαi 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 A1 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 Gαi protein-mediated.
KeywordsAdenosine receptor G protein Heart rate SHR Right atria
We thank Enio S. A. Pacini and Edilson D. S. Junior for helpful suggestions on the experimental design.
This work was supported by research grant from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) to A. Jurkiewicz (2013/20402-6) and R.O. Godinho (2015/07019-4) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 0309428/2015-7) to R.O. Godinho. J.Q.D. Rodrigues (12/22763-3) was a PhD fellow and H. Camara (2012/24828-5) an undergraduate student fellow from Fapesp.
Compliance with ethical standards
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
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