Increased Gi protein signaling potentiates the negative chronotropic effect of adenosine in the SHR right atrium
- 49 Downloads
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.
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.
- Burnstock G (2009) Purinergic signalling: past, present and future. Brazilian Journal of Medical and Biological Research = Revista brasileira de pesquisas medicas e biologicas/Sociedade Brasileira de Biofisica [et al] 42: 3-8Google Scholar
- Council NR (2010) Guide for the care and use of laboratory animals. National Academies PressGoogle Scholar
- Fredholm BB, AP IJ, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacological. Reviews 53:527–552Google Scholar
- Furchgott RF (1966) The use of β-haloalkylamines in the differentiation of receptors and in the determination of dissociation constants of receptor-agonist complexes. Adv Drug Res 3:21–55Google Scholar
- Gergs U, Boknik P, Schmitz W, Simm A, Silber RE, Neumann J (2008) A positive inotropic effect of ATP in the human cardiac atrium. Am J Phys Heart Circ Phys 294:H1716–H1723Google Scholar
- Lau DH, Shipp NJ, Kelly DJ, Thanigaimani S, Neo M, Kuklik P, Lim HS, Zhang Y, Drury K, Wong CX, Chia NH, Brooks AG, Dimitri H, Saint DA, Brown L, Sanders P (2013) Atrial arrhythmia in ageing spontaneously hypertensive rats: unraveling the substrate in hypertension and ageing. PLoS One 8:e72416CrossRefPubMedPubMedCentralGoogle Scholar
- Mustafa SJ, Ansari HR, Abebe W (2009) P1 (adenosine) purinoceptor assays. Current protocols in pharmacology/editorial board, SJ Enna Chapter 4: Unit 4 7Google Scholar
- Neubig RR, Spedding M, Kenakin T, Christopoulos A, International Union of Pharmacology Committee on Receptor N, Drug C (2003) International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology. Pharmacological Reviews 55:597–606CrossRefPubMedGoogle Scholar
- Sassi Y, Abi-Gerges A, Fauconnier J, Mougenot N, Reiken S, Haghighi K, Kranias EG, Marks AR, Lacampagne A, Engelhardt S, Hatem SN, Lompre AM, Hulot JS (2012) Regulation of cAMP homeostasis by the efflux protein MRP4 in cardiac myocytes. FASEB J: Off Publ Fed Am Soc Exp Biol 26:1009–1017CrossRefGoogle Scholar
- Zhai P, Yamamoto M, Galeotti J, Liu J, Masurekar M, Thaisz J, Irie K, Holle E, Yu X, Kupershmidt S, Roden DM, Wagner T, Yatani A, Vatner DE, Vatner SF, Sadoshima J (2005) Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice. J Clin Invest 115:3045–3056CrossRefPubMedPubMedCentralGoogle Scholar