Adenosine deaminase inhibition enhances the inotropic response mediated by A1 adenosine receptor in hyperthyroid guinea pig atrium

Kemény-Beke, Ádám; Jakab, Ágnes; Zsuga, Judit; Vecsernyés, Miklós; Karsai, Denes; Pasztor, Fanni; Grenczer, Maria GrenczerM.; Szentmiklósi, A. József; Berta, András; Gesztelyi, Rudolf

doi:10.1016/j.phrs.2007.04.017

Cited by 11 publications

(15 citation statements)

References 31 publications

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“…A secondary consequence of ADA inhibition is a rise in extracellular adenosine, which can activate ARs. Several ADA inhibitors, including DCF, were shown to moderately raise the concentration of extracellular adenosine in guinea pig atria to augment exogenous agonist-induced myocardial A 1 AR activation [111]. Similar effects of DCF to raise endogenous adenosine levels in vivo were reported earlier.…”

Section: Anticancer Drugssupporting

confidence: 73%

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Reitman

2020

Cells

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Many ligands directly target adenosine receptors (ARs). Here we review the effects of noncanonical AR drugs on adenosinergic signaling. Non-AR mechanisms include raising adenosine levels by inhibiting adenosine transport (e.g., ticagrelor, ethanol, and cannabidiol), affecting intracellular metabolic pathways (e.g., methotrexate, nicotinamide riboside, salicylate, and 5-aminoimidazole-4-carboxamide riboside), or undetermined means (e.g., acupuncture). However, other compounds bind ARs in addition to their canonical ‘on-target’ activity (e.g., mefloquine). The strength of experimental support for an adenosine-related role in a drug’s effects varies widely. AR knockout mice are the ‘gold standard’ method for investigating an AR role, but few drugs have been tested on these mice. Given the interest in AR modulation for treatment of cancer, CNS, immune, metabolic, cardiovascular, and musculoskeletal conditions, it is informative to consider AR and non-AR adenosinergic effects of approved drugs and conventional treatments.

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Section: Anticancer Drugssupporting

confidence: 73%

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Reitman

2020

Cells

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“…If the apparent function of the receptor (that can be detected by means of an E/c curve) does not follow the pattern predicted by the model of RRM, other mechanisms (e.g., receptor sensitization or desensitization, or change in activity of an enzyme, or transporter handling the given agonist) may be suspected. Such a phenomenon was revealed in an earlier study, where, via evaluating CPA E/c curves, it was found an enhancement of the efficiency of the A 1 adenosine receptor signaling in the hyperthyroid guinea pig atrium under adenosine deaminase inhibition by pentostatin [32]. On the other hand, data provided by RRM can be applied to correct the E/c curves that are biased by an unknown (and thereby usually neglected) concentration of an agonist that has previously been accumulated in the system.…”

Section: Discussionmentioning

confidence: 67%

Accuracy and Precision of the Receptorial Responsiveness Method (RRM) in the Quantification of A1 Adenosine Receptor Agonists

Szabó

Viczjan

Erdei

et al. 2019

IJMS

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The receptorial responsiveness method (RRM) is a procedure that is based on a simple nonlinear regression while using a model with two variables (X, Y) and (at least) one parameter to be determined (cx). The model of RRM describes the co-action of two agonists that consume the same response capacity (due to the use of the same postreceptorial signaling in a biological system). While using RRM, uniquely, an acute increase in the concentration of an agonist (near the receptors) can be quantified (as cx), via evaluating E/c curves that were constructed with the same or another agonist in the same system. As this measurement is sensitive to the implementation of the curve fitting, the goal of the present study was to test RRM by combining different ways and setting options, namely: individual vs. global fitting, ordinary vs. robust fitting, and three weighting options (no weighting vs. weighting by 1/Y2 vs. weighting by 1/SD2). During the testing, RRM was used to estimate the known concentrations of stable synthetic A1 adenosine receptor agonists in isolated, paced guinea pig left atria. The estimates were then compared to the known agonist concentrations (to assess the accuracy of RRM); furthermore, the 95% confidence limits of the best-fit values were also considered (to evaluate the precision of RRM). It was found that, although the global fitting offered the most convenient way to perform RRM, the best estimates were provided by the individual fitting without any weighting, almost irrespective of the fact whether ordinary or robust fitting was chosen.

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“…In a previous study, we found that inhibition of ADA increases the signal amplification of the A 1 adenosinergic system regarding its direct negative inotropic function in the hyperthyroid guinea pig atrium (Kemeny-Beke et al 2007 ). As ADA inhibition elevates the adenosine levels and thus augments all A 1 receptor-mediated processes, it is not easy to identify this particular (efficiency-enhancing) action of ADA inhibition.…”

Section: Introductionmentioning

confidence: 87%

“…The surplus interstitial adenosine, accumulated over the basal level in response to the inhibition of nucleoside transport or ADA, modified (“biased”) the shape of the E / c curves constructed in the presence of NBTI or DCF. As DCF was found previously to influence the signaling efficiency of atrial A 1 adenosinergic system (Kemeny-Beke et al 2007 ), the modified E / c curves generated with the A 1 receptor agonist CPA were excluded from the quantification (i.e., CPA E / c curves of groups S Co (CPA), T Co (CPA), S DCF (CPA), and T DCF (CPA)). The transformation of E / c curves constructed with MC was quantified with the use of RRM (Gesztelyi et al 2004 ; Grenczer et al 2010a ) by fitting the averaged data of the modified E / c curves to the following equation: …”

Section: Methodsmentioning

confidence: 99%

The effect of adenosine deaminase inhibition on the A1 adenosinergic and M2 muscarinergic control of contractility in eu- and hyperthyroid guinea pig atria

Pák

Zsuga

Képes

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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The A1 adenosine and M2 muscarinic receptors exert protective (including energy consumption limiting) effects in the heart. We investigated the influence of adenosine deaminase (ADA) inhibition on a representative energy consumption limiting function, the direct negative inotropic effect elicited by the A1 adenosinergic and M2 muscarinergic systems, in eu- and hyperthyroid atria. Furthermore, we compared the change in the interstitial adenosine level caused by ADA inhibition and nucleoside transport blockade, two well-established processes to stimulate the cell surface A1 adenosine receptors, in both thyroid states. A classical isolated organ technique was applied supplemented with the receptorial responsiveness method (RRM), a concentration estimating procedure. Via measuring the contractile force, the direct negative inotropic capacity of N6-cyclopentyladenosine, a selective A1 receptor agonist, and methacholine, a muscarinic receptor agonist, was determined on the left atria isolated from 8-day solvent- and thyroxine-treated guinea pigs in the presence and absence of 2′-deoxycoformycin, a selective ADA inhibitor, and NBTI, a selective nucleoside transporter inhibitor. We found that ADA inhibition (but not nucleoside transport blockade) increased the signal amplification of the A1 adenosinergic (but not M2 muscarinergic) system. This action of ADA inhibition developed in both thyroid states, but it was greater in hyperthyroidism. Nevertheless, ADA inhibition produced a smaller rise in the interstitial adenosine concentration than nucleoside transport blockade did in both thyroid states. Our results indicate that ADA inhibition, besides increasing the interstitial adenosine level, intensifies the atrial A1 adenosinergic function in another (thyroid hormone-sensitive) way, suggesting a new mechanism of action of ADA inhibition.

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Adenosine deaminase inhibition enhances the inotropic response mediated by A1 adenosine receptor in hyperthyroid guinea pig atrium

Cited by 11 publications

References 31 publications

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Accuracy and Precision of the Receptorial Responsiveness Method (RRM) in the Quantification of A1 Adenosine Receptor Agonists

The effect of adenosine deaminase inhibition on the A1 adenosinergic and M2 muscarinergic control of contractility in eu- and hyperthyroid guinea pig atria

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