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    • When added to the culture medium extracellular ATP

    2024-03-20

    When added to the culture medium, extracellular ATP is metabolized into adenosine by ectonucleotidases, and ARs are then activated by adenosine with concentrations in the micromolar range [27]. However, our study showed that activation of ARs by exogenous adenosine could not induce the odontoblastic differentiation of HDPCs independently, without induction of ATP. This may be because P2 receptors, activated by ATP/ADP, played a more important role in this process [15]. Therefore, ARs and P2 receptors may be co-regulators in the HDPC odontoblastic differentiation induced by ATP. In summary, to the best of our knowledge, our study is the first to demonstrate the positive impact of ARs on ATP-induced odontogenetic differentiation. Among the four AR subtypes, A1R, and particularly A2BR, may enhance the ATP-induced HDPC odontoblastic differentiation. However, the activation of ARs by adenosine, a hydrolysate of ATP, cannot induce the odontoblastic differentiation of HDPCs independently, without the induction of ATP. Therefore, the ATP-induced odontoblastic differentiation of HDPCs was probably due to the combined administration of ARs and P2 receptors, and between these two receptors, P2 receptors may play a main role.
    Conflict of interest
    Acknowledgments This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We would like to thank Editage [www.editage.cn] for English language editing.
    Introduction Cardiac arrest is an outcome of necrotic or apoptotic myocyte death in numerous cardiac pathologies (Kajstura et al., 1996a, Kajstura et al., 1996b). It is usually related to unexpected death from a cardiovascular cause in an individual with or without pre-existing hiv protease inhibitor disease (Deo and Albert, 2012). Moreover, it is a main public health problem that accounted for approximately 350,000 deaths in the United States in 2012 (Deo and Albert, 2012), increasing the demand for pharmacological interventions to improve successful resuscitation rates upon cardiac arrest. In some cases, cardiac arrest is followed by a massive overload of noradrenaline and ATP (Shainberg et al., 2009), the latter being converted into adenosine (Vassort, 2001). ATP and adenosine reduce the chronotropism of rat right atrial preparations and induce cardiac arrest at millimolar concentrations (Camara et al., 2015). The negative chronotropic effect of ATP and adenosine is mediated via membrane-bound A1 adenosine receptors in right atria of rats (Camara et al., 2015). Activation of A1 adenosine receptors causes inhibition of adenylate cyclase (Godinho et al., 2015, Londos et al., 1980) and induction of potassium outward currents that shortens the action potential duration and hence reduces cardiac excitability (Bohm et al., 1984, Camara et al., 2015). Due to the receptor-mediated action of adenosine, the antagonism of A1 adenosine receptors represents a potential mechanism to revert cardiac arrest mediated by the purine signaling. DPCPX is a widely used competitive antagonist of A1 adenosine receptor (Duarte et al., 2012, Lohse et al., 1987). DPCPX has a core xanthine group, also present in phosphodiesterase inhibitors like IBMX (Beavo et al., 1970, Essayan, 2001), with 1,3-dipropyl and 8-cyclopentyl substitutions to enhance affinity and selectivity to the A1 adenosine receptor (Ford and Broadley, 1997, Lohse et al., 1987).
    Materials and methods
    Results
    Discussion We observed that DPCPX and atropine could revert the cardiac arrest produced by activation of adenosine and muscarinic receptors, respectively. This demonstrates that antagonizing these specific receptors could be a mechanism to restore pacemaker function when cardiac arrest is induced by these receptors. In addition, DPCPX reversed cardiac arrest induced by muscarinic receptor activation, demonstrating that an additional mechanism of action for this A1 adenosine receptor antagonist may be present. Based on structural and chronotropic response relationships with IBMX, we propose that the secondary mechanism of DPCPX is related to PDE inhibition. PDE inhibition acts downstream of adenylyl cyclase to restore spontaneous contraction and therefore can be used to revert cardiac arrest induced by different Gi-coupled receptors (Fig. 6).