Thyroid hormones decrease the affinity of 8-cyclopentyl-1,3-dipropylxanthine (CPX), a competitive antagonist, for the guinea pig atrial A1 adenosine receptor

Abstract

Abstract. The aim of the present study was to investigate whether or not thyroxine (T 4 ) treatment affects K B , the equilibrium dissociation constant of the antagonist-receptor complex, for the interaction between CPX, a selective and competitive orthosteric antagonist, and the guinea pig atrial A 1 adenosine receptor (A 1 receptor). The inotropic response to adenosine, a nonselective adenosine receptor agonist, or CPA, a selective A 1 receptor agonist, was investigated in the absence or presence of CPX in paced left atria isolated from 8-day solvent-or T 4 -treated guinea pigs. To obtain K B values, adenosine and CPA concentration-response curves were evaluated by Schild analysis. CPA but not adenosine obeyed the requirements of the Schild analysis to provide correct K B values for CPX. According to the CPA concentration-response curves, affinity of CPX for the hyperthyroid guinea pig atrial A 1 receptor (K B = 44.16 nM) was lower than that for the euthyroid one (K B = 16.63 nM). Regarding the intense reduction in the negative inotropic effect of adenosine and CPA in hyperthyroid atria, it is reasonable to assume that the moderate decrease in affinity of the guinea pig atrial A 1 receptor is only in part responsible for the diminished A 1 receptor-mediated effect in hyperthyroidism.

Approximation of A1 adenosine receptor reserve appertaining to the direct negative inotropic effect of adenosine in hyperthyroid guinea pig left atria

“…As a consequence, thyroid hormones reduce the effect of A 1 receptor agonists on atrial contractility (Szentmiklosi et al 1992;Kaasik et al 1994;Gesztelyi et al 2003; Fig. 1, 3), although the underlying mechanisms are not fully clarified yet (for more details, see: Gesztelyi et al 2012). Thus, it might be expected that thyroid hormones affect, presumably reduce, the great atrial A 1 receptor reserve belonging to the direct negative inotropic effect.…”

The influence of the way of regression on the results obtained by the receptorial responsiveness method (RRM), a procedure to estimate a change in the concentration of a pharmacological agonist near the receptor

“…The model of RRM was derived from the fusion of Eqs 1 , 3 (a procedure similar to the combination of the Hill model and the Schild equation: Waud et al, 1978 ; Motulsky and Christopoulos, 2004 ; Gesztelyi et al, 2012b ). The model of RRM can be expressed in several, algebraically equivalent forms, five of which, relevant for the present investigation, are as follows: where: c: the concentration of the agonist administered during the construction of the E/c curve; c x : the distorting concentration; E’: the distorted effect; E max , logEC 50 and n: the parameters from the Hill equation (see Eqs 1 , 2 ).…”

“…where: E': the distorted effect that was calculated as if it had exclusively been the effect of c, regardless of the presence of c x (c x , the distorting concentration, is always attributed to the same agonist as c by RRM, and in this study, c x and c belonged indeed to the same agonist); E: the intact counterpart of E′, i.e., the effect that properly reflects the co-action of c and c x ; E x : the effect of c x alone (that is also intact, similarly to E). The model of RRM was derived from the fusion of Eqs 1, 3 (a procedure similar to the combination of the Hill model and the Schild equation: Waud et al, 1978;Motulsky and Christopoulos, 2004;Gesztelyi et al, 2012b). The model of RRM can be expressed in several, algebraically equivalent forms, five of which, relevant for the present investigation, are as follows:…”

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 ).…”