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  • Phosphodiesterase inhibition increases the intracellular

    2024-07-09

    Phosphodiesterase inhibition increases the intracellular levels of cAMP to restore spontaneous contraction (Essayan, 2001, Qi and Kwan, 1996), acting downstream of adenylyl cyclase. Therefore, cardiac arrest induced by decreased intracellular cAMP levels could be reversed by phosphodiesterase inhibitors, regardless of the upstream event that produces this decrease (Fig. 5). So, PDE inhibition may be therefore a relevant therapy for special causes of cardiac arrest. Indeed, two clinical reports have already described that cardiac arrest caused by propranolol is resistant to conventional advanced life support, although enoximone, a phosphodiesterase III inhibitor, restored spontaneous contractions in these patients (Sandroni et al., 2006). DPCPX and IBMX may act by concomitant inhibition of PDE and antagonism of A1 adenosine receptor to revert cardiac arrest. Therefore, to determine whether only inhibiting PDE or antagonizing A1 receptor still restore spontaneous contractions is an interesting open question. Answer this question is technically challenging because we could not find a drug with such specificity. This is because the majority of A1 adenosine receptor antagonists have a core xanthine group, which is known to inhibit PDE (Ukena et al., 1993). In addition, A1 adenosine receptor binding site and PDE catalytic site are similar, making it difficult to design a drug that selectively binds to these nefiracetam sale in the concentrations used in the present work. Thus, in a future work we hope to be able to use drugs that are more selective and discriminate between A1 receptor- and PDE-specific effects on cardiac arrest reversion. Here, we present proof-of-concept that receptor antagonism and phosphodiesterase inhibition are possible interventions to reverse cardiac arrest induced by receptor activation. Receptor antagonism is limited by the necessity of previous knowledge of the receptor that induced cardiac arrest, as demonstrated by the lack of effect of atropine when contractions were blocked by adenosine (Fig. 4). Phosphodiesterase inhibition could have broader applications and increase successful cardiac arrest reversion in the clinic, as reported in Sandroni et al. (2006). However, safety and efficacy of this pharmacological intervention needs to be further tested in animal models in vivo and in patients.
    Conclusion The findings of the present study support the conclusion that drug antagonism and phosphodiesterase inhibition are potential strategies to revert cardiac arrest. DPCPX restore spontaneous contractions nefiracetam sale by two effects: i) the selective antagonism of A1 adenosine receptor; ii) a secondary effect, probably the inhibition of phosphodiesterases.
    Acknowledgements
    Adenosine Receptors: a GPCR Family with Extensive Structural Information G protein-coupled receptors (GPCRs, see Glossary) are an important class of membrane proteins targeted by approximately one third of the drugs currently on the market 1, 2. They are activated by a wide variety of signaling molecules of different nature: from proteins or peptides (i.e., chemokine receptors), to small neurotransmitters and neuromodulators including nucleosides and nucleotides [3]. The latter group is where we find the four receptors activated by adenosine, consisting of the A1, A2A, A2B and A3adenosine receptors (ARs) [4]. They mediate central nervous system (CNS) depressant, anticonvulsant, sleep-promoting, antidiuretic, negative inotropic, negative chronotropic, anti-inflammatory, immunosuppressive, and angiogenic effects, and are involved in the pathophysiology of cardiovascular and neurodegenerative diseases, as well as in cancer growth and immune responses 5, 6. The interest from both academia and industry in ARs is in stark contrast to the low success of drug candidates in reaching the market. To date only one selective AR ligand, the A2Aagonist regadenoson, has gained FDA approval (as a coronary vasodilator used in cardiac imaging), while an antagonist of the same receptor, istradefylline, has been approved in Japan in combination with levodopa for the treatment of Parkinson’s disease [7].