The influence of affinity, efficacy, and slope factor on the estimates obtained by the receptorial responsiveness method (RRM): a computer simulation study

Grenczer, Maria GrenczerM.; Zsuga, Judit; Kemény-Beke, Ádám; Juhász, Béla; Szodoray, Péter; Tósaki, Árpád; Gesztelyi, Rudolf

doi:10.1139/y10-078

Cited by 12 publications

(50 citation statements)

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“…The model of RRM is a simplified mathematical description of the co-action of two agonists (evoking the same response of a biological system), if one of these agonists exerts its effect prior to the other one, and the former effect is disregarded (thereby causing a "bias") [11,14]. RRM has been originally developed as a concentration determining method that is based on the fitting of its model (Equation (2)) to an E/c curve that was constructed in the presence of a "biasing" concentration that is to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that the traditional methods to determine receptor reserve have not proved to be useful for adenosine due to the short half-life of adenosine [33], although receptor reserve values in the cardiac adenosinergic system seem to be of importance, even in terms of diagnostic aspects [34]. Finally, of course, data that were obtained with RRM can serve as input data for in silico investigations dealing with the RRM itself [14,15], and with the adenosinergic mechanisms in the atrial myocardium [35,36].…”

Section: Discussionmentioning

confidence: 99%

“…One of these concentrations is indicated by the x-axis, while the other one, c x , is a concentration of the agonist used for the E/c curve that is equieffective with the agonist added in a single extra dose. If the two agonists in question are the same, c x is a real concentration, and, if not, c x is a surrogate parameter of the single extra concentration of the other agonist [14,15]. The application of RRM might be useful when the concentration of this extra agonist is unknown and difficult to determine in any other manners [12,13].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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 biased adenosine E/c curves were not suitable for the assessment of A 1 adenosine receptor reserve, the goal of the present study. Therefore, effects of adenosine E/c curves biased by NBTI were corrected by means of RRM, our method validated for quantifying changes in agonist concentrations in the microenvironment of the receptors (Gesztelyi et al 2004;Grenczer et al 2010aGrenczer et al , 2010b.…”

Section: Strategy Of the Mathematical Correctionmentioning

confidence: 99%

“…Because NBTI strongly affects the fate of exogenous adenosine used to generate an E/c curve (Szentmiklosi et al 1982;Gesztelyi et al 2003a), adenosine could not be used as an agonist for the E/c curves essential for RRM (Karsai et al 2006). However, RRM enables replacement of a degradable agonist with a stable one (Gesztelyi et al 2004;Grenczer et al 2010aGrenczer et al , 2010b. Thus, the surplus interstitial adenosine accumulated by NBTI was quantified using E/c curves generated with CPA, an A 1 receptor agonist with a significantly longer half-life in living tissues than adenosine (see Eq.…”

Section: Strategy Of the Mathematical Correctionmentioning

confidence: 99%

The guinea pig atrial A1 adenosine receptor reserve for the direct negative inotropic effect of adenosine

Kiss

Pák

Zsuga

et al. 2014

gpb

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Although the A1 adenosine receptor (A1 receptor), the main adenosine receptor type in cardiac muscle, is involved in powerful cardioprotective processes such as ischemic preconditioning, the atrial A1 receptor reserve has not yet been quantified for the direct negative inotropic effect of adenosine. In the present study, adenosine concentration-effect (E/c) curves were constructed before and after pretreatment with FSCPX (8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-N1-propylxanthine), an irreversible A1 receptor antagonist, in isolated guinea pig atria. To prevent the intracellular elimination of the administered adenosine, NBTI (S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine), a nucleoside transport inhibitor, was used. As expected, NBTI alone and FSCPX-pretreatment alone shifted the adenosine E/c curve to the left and right, respectively. However, in the presence of NBTI, FSCPX-pretreatment appeared to increase the maximal response to adenosine. By means of the receptorial responsiveness method (RRM), our recently developed procedure, adenosine E/c curves generated in the presence of NBTI were corrected for the bias caused by the endogenous adenosine accumulated by NBTI. The corrected curves indicate a substantial A1 receptor reserve for the direct negative inotropy evoked by adenosine. In addition, our results suggest that accumulation of an endogenous agonist may bias the E/c curve constructed with the same or similar agonist that can lead to seemingly paradoxical results.

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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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The influence of affinity, efficacy, and slope factor on the estimates obtained by the receptorial responsiveness method (RRM): a computer simulation study

Cited by 12 publications

References 12 publications

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

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

The guinea pig atrial A1 adenosine receptor reserve for the direct negative inotropic effect of adenosine

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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The influence of affinity, efficacy, and slope factor on the estimates obtained by the receptorial responsiveness method (RRM): a computer simulation study

Cited by 12 publications

References 12 publications

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

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

The guinea pig atrial A1 adenosine receptor reserve for the direct negative inotropic effect of adenosine

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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The guinea pig atrial A1 adenosine receptor reserve for the direct negative inotropic effect of adenosine