Apparent affinity of 1,3‐dipropyl‐8‐cyclopentylxanthine for adenosine A₁ and A₂ receptors in isolated tissues from guinea‐pigs

Abstract

1 The classification of adenosine receptor subtypes (A1 and A2) in intact tissues has been based on the order of agonist potency. In this study the apparent affinity of 1,3-dipropyl-8-cyclopentylxanthine (CPX), an antagonist which has been reported to be Al selective, and the nonselective antagonist 1,3-dimethyl-8-phenylxanthine (8PT) has been evaluated on isolated tissues from the guinea-pig.2 The isolated tissues used were atria (bradycardic response, proposed Al sub-type), aorta and trachea (relaxant response, proposed A2 sub-type).3 Both the xanthines antagonized responses to adenosine in the three tissues but had little or no effect on responses to carbachol (atria), sodium nitrite (aorta) or isoprenaline (trachea).4 pA2 values for 8PT were similar on the three tissues (6.3-6.7), however, the pA2 value for CPX on the atria (7.9-8.4) was greater than that on the aorta (6.6) or trachea (6.6). 5 These results support the suggestion that the adenosine receptors which mediate bradycardia in the atrium are of the A1 sub-type and that those which mediate relaxation in the aorta and trachea are of the A2 type.

The anti‐adrenergic effect of adenosine and its blockade by pertussus toxin: a comparative study in myocytes isolated from guinea‐pig, rat and failing human hearts

“…CPX has been shown to exhibit selective Al-receptor affimity in rat brain membranes (Bruns et al, 1987) and, more recently, has been shown to be Al-selective in guinea-pig isolated tissues (Collis et al, 1989). In our experiments CPX produced an approximately 10 fold shift in the anti-adrenergic response of adenosine in guinea-pig myocytes at a concentration of 3.5 nM.…”

“…Calcium concentration-response curves were also cumulative and were performed in a phosphate-free Krebs-Henseleit solution to prevent precipitation at high concentrations of calcium (up to 25mm). 8-Cyclopentyl 1,3-dipropylxanthine (CPX) was used as a selective Al-receptor antagonist (Collis et al 1989). Cells were exposed to CPX 15 min before the adenosine concentration-response curve was carried out.…”

Incomplete reversal of β‐adrenoceptor desensitization in human and guinea‐pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors

“…The inotropic responses of PDE inhibition and P-adrenoceptor stimulation were further compared to that of maximum concentrations of CPT cyclic AMP, an analogue of cyclic AMP (Collis et al, 1989). Again there was no significant difference, from that of IBMX, in the extent of potentiation over maximum isoprenaline in either group of guinea-pig ventricular myocytes ( Figure 5).…”

The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A2a selective adenosine receptor antagonist

“…The xanthine, PD1 15199 (1,3 dipropyl-8-N-[2-dimethylamino) ethyl]-N-methyl-4-2, 3,6, 7-tetrahydro-2,6-dioxo) -benzenesulphonamidexanthine), although having higher affinity for the A2a binding site than the A2b binding site, is equipotent at A2a and A1 binding sites (Bruns et al, 1987b). PD1 16948 (8-cyclopentyl-1-3-dipropylxanthine) has higher affinity for the A1 receptor than for A2a binding sites in rat brain studies (Bruns et al, 1987a,b;Jarvis et al, 1989) and clearly demonstrated A1-selective antagonism in guinea-pig isolated tissues (Collis et al, 1989). To date, the most A2a-selective xanthine antagonist is 8-(3-chlorostyryl)-1,3-dipropylxanthine which in binding studies demonstrates A2a A1 selectivity of 520 fold but only 22 fold in functional tests (Jacobson et al, 1993).…”