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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.

Pak K, Zsuga J, Kepes Z, Erdei T, Varga B, Juhasz B, Szentmiklosi AJ, Gesztelyi R - Naunyn Schmiedebergs Arch. Pharmacol. (2015)

Bottom Line: The A1 adenosine and M2 muscarinic receptors exert protective (including energy consumption limiting) effects in the heart.Via measuring the contractile force, the direct negative inotropic capacity of N(6)-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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Nagyerdei krt. 98, 4032, Debrecen, Hungary.

ABSTRACT
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 N(6)-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.

No MeSH data available.


Related in: MedlinePlus

a–f The corrected direct negative inotropic effect values of concentration–effect curves generated in the presence of NBTI or DCF, plotted versus the concentration of the administered MC or CPA, together with the corresponding control concentration–effect curves (in their original form). The correction was made for the direct negative inotropic effect of the surplus interstitial adenosine produced by NBTI or DCF in a manner that this effect value has been incorporated into the effect data depicted herein. The x-axis indicates the agonist concentration on a base-10 logarithmic scale, and the y-axis shows the effect as a percentage decrease in the initial contractile force of atria. The symbols (open/thin solvent treatment, filled/thick T4 treatment) represent the corrected effects computed from the raw effects averaged within the groups
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Fig9: a–f The corrected direct negative inotropic effect values of concentration–effect curves generated in the presence of NBTI or DCF, plotted versus the concentration of the administered MC or CPA, together with the corresponding control concentration–effect curves (in their original form). The correction was made for the direct negative inotropic effect of the surplus interstitial adenosine produced by NBTI or DCF in a manner that this effect value has been incorporated into the effect data depicted herein. The x-axis indicates the agonist concentration on a base-10 logarithmic scale, and the y-axis shows the effect as a percentage decrease in the initial contractile force of atria. The symbols (open/thin solvent treatment, filled/thick T4 treatment) represent the corrected effects computed from the raw effects averaged within the groups

Mentions: The corrected MC E/c curves (generated in the presence of NBTI) ended somewhat below their control curves (Fig. 9a, b). Thus, if we consider the observed small difference between maximal values of the corrected and control E/c curves to be an error, it can be concluded that NBTI does not affect the efficiency of the M2 muscarinergic signaling, irrespective of the thyroid state (Fig. 9a, b).Fig. 9


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

Pak K, Zsuga J, Kepes Z, Erdei T, Varga B, Juhasz B, Szentmiklosi AJ, Gesztelyi R - Naunyn Schmiedebergs Arch. Pharmacol. (2015)

a–f The corrected direct negative inotropic effect values of concentration–effect curves generated in the presence of NBTI or DCF, plotted versus the concentration of the administered MC or CPA, together with the corresponding control concentration–effect curves (in their original form). The correction was made for the direct negative inotropic effect of the surplus interstitial adenosine produced by NBTI or DCF in a manner that this effect value has been incorporated into the effect data depicted herein. The x-axis indicates the agonist concentration on a base-10 logarithmic scale, and the y-axis shows the effect as a percentage decrease in the initial contractile force of atria. The symbols (open/thin solvent treatment, filled/thick T4 treatment) represent the corrected effects computed from the raw effects averaged within the groups
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4495724&req=5

Fig9: a–f The corrected direct negative inotropic effect values of concentration–effect curves generated in the presence of NBTI or DCF, plotted versus the concentration of the administered MC or CPA, together with the corresponding control concentration–effect curves (in their original form). The correction was made for the direct negative inotropic effect of the surplus interstitial adenosine produced by NBTI or DCF in a manner that this effect value has been incorporated into the effect data depicted herein. The x-axis indicates the agonist concentration on a base-10 logarithmic scale, and the y-axis shows the effect as a percentage decrease in the initial contractile force of atria. The symbols (open/thin solvent treatment, filled/thick T4 treatment) represent the corrected effects computed from the raw effects averaged within the groups
Mentions: The corrected MC E/c curves (generated in the presence of NBTI) ended somewhat below their control curves (Fig. 9a, b). Thus, if we consider the observed small difference between maximal values of the corrected and control E/c curves to be an error, it can be concluded that NBTI does not affect the efficiency of the M2 muscarinergic signaling, irrespective of the thyroid state (Fig. 9a, b).Fig. 9

Bottom Line: The A1 adenosine and M2 muscarinic receptors exert protective (including energy consumption limiting) effects in the heart.Via measuring the contractile force, the direct negative inotropic capacity of N(6)-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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Nagyerdei krt. 98, 4032, Debrecen, Hungary.

ABSTRACT
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 N(6)-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.

No MeSH data available.


Related in: MedlinePlus