Special Sensitization Pattern in Adenosine-Induced Myocardial Responses After Thyroxine-Treatment

Abstract

Chronic thyroxine treatment reduces the susceptibility of atrial myocardium to adenosine. While the possible role of membrane adenosine receptors in this action is supported by several studies, the involvement of intracellular adenosine mechanisms has not been defined. The present experiments were carried out in electrically driven euthyroid and hyperthyroid guinea pig atrial myocardium. The extracellular and intracellular actions of adenosine were analyzed pharmacologically by the use of specific blockers of membrane adenosine transport and intracellular adenosine deaminase (ADA). The involvement of phosphoprotein phosphatase, phospholamban, and sarcoplasmic reticulum Ca2+ ATPase (SERCA) in the adenosine-induced responses was also studied. The major findings were as follows: i) pD(2)- and E(max)-values for adenosine-induced decrease of mechanical activity were significantly reduced after an 8-day thyroxine treatment in atrial tissues; ii) in atria of thyroxine-treated animals, membrane purine transport inhibitors (dipyridamole, NBTI) induced similar leftward shifts in concentration-response curves for adenosine in both euthyroid and hyperthyroid atrial myocardium without altering the depressed E(max) values; iii) the leftward displacement evoked by inhibitors of intracellularly located ADA (coformycin, EHNA) was more striking in hyperthyroid than euthyroid myocardia. ADA inhibitors induced a complete reversal of the maximum adenosine actions; iv) inhibition by cantharidin of phosphoprotein phosphatases (after inhibition of ADA) reduced the adenosine-induced responses. This inhibition was stronger in hyperthyroid atria; v) pharmacological elimination of sarcoplasmic reticulum Ca2+ ATPase by cyclopiazonic acid did not alter the cardiac responses to adenosine and this was independent of thyroid status. It is suggested that distinct modulation of the extra- and intracellular adenosine actions is present in eu- and hyperthyroid hearts. In the latter, a predominance of intracellular adenosine mechanisms can be proposed.

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

“…In earlier studies, inhibition of nucleoside transport was found to augment the response to adenosine that is primarily reflected by a leftward shift (decreased EC 50 ) of the adenosine E/c curve (Szentmiklosi et al 1982;Gesztelyi et al 2003a). This phenomenon can be explained by the fact that, under well-oxygenated conditions, the net transmembrane adenosine transport is directed into the cardiomyocytes due to the rapid intracellular elimination of adenosine (Deussen et al 1999;Deussen 2000aDeussen , 2000b.…”

“…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.…”

“…No "priming" (previous adenylyl cyclase stimulation) was made, thus the direct component of negative inotropy, characteristic of the atrial A 1 receptor (Belardinelli et al 1995), was measured. According to Furchgott's method for receptor reserve estimation (Furchgott 1966), two adenosine E/c curves were generated, one before and another one after the permanent inactivation of a fraction of the A 1 receptors. For this purpose, we used FSCPX, a selective, strong and irreversible A 1 receptor antagonist (Srinivas et al 1996;Morey et al 1998).…”

FSCPX, a Chemical Widely Used as an Irreversible A1 Adenosine Receptor Antagonist, Modifies the Effect of NBTI, a Nucleoside Transport Inhibitor, by Reducing the Interstitial Adenosine Level in the Guinea Pig Atrium

“…The effects of FSCPX and NBTI on the E / c curves of adenosine receptor agonists can be divided into three components: Effects mediated by influencing the interstitial level of endogenous adenosine (that were earlier attributed exclusively to NBTI [ 26 , 27 ]), effects mediated via affecting the interstitial level of exogenous adenosine (also ascribed to NBTI [ 28 ]) and effects resulted from the permanent inactivation of a fraction of the A 1 receptor population (attributed to FSCPX [ 11 ]).…”

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

“…The thyroid state influences several regulatory mechanisms including functions of the A 1 receptor (for a brief review, see Gesztelyi et al 2012 ). Among others, thyroid hormones (T 3 , T 4 ) markedly reduce the direct negative inotropic effect (decrease of the contractile force without prior positive inotropic stimulation exerted by another agent) of A 1 receptor agonists (Szentmiklosi et al 1992 ; Kaasik et al 1994 ; Gesztelyi et al 2003a ). Hyperthyroidism is a pathological condition that, by upregulating a wide range of metabolic processes, raises the oxygen and nutrient consumption in the tissues and thus increases the work of the heart (Cini et al 2009 ; Nabbout and Robbins 2010 ).…”