8-Phenyltheophylline: A potent P1-purinoceptor antagonist

1 In the absence of adenosine uptake inhibition, adenosine produced a concentration-dependent (threshold 30 pM) relaxation of the 5-methylfurmethide pre-contracted guinea-pig taenia caecum. The relaxation was not blocked by 8-phenyltheophylline (8-PT, 3 JAM) or 1,3-dipropyl, 8-cyclopentylxanthine (DPCPX, 30 JAM). 2 In the presence of the adenosine uptake inhibitor, dipyridamole (Dip, 3 JAM), a biphasic adenosine concentration-effect curve was obtained (threshold 0.3 JAM). The time course of the responses to adenosine in the absence of Dip was similar to that of the second phase responses in the presence of Dip and occurred over the same adenosine concentration-range. 5'-(N-ethyl) carboxamido-adenosine (NECA) concentration-effect curves (in the absence of Dip) were also biphasic. Only the first phases of the concentration-effect curves obtained with NECA and adenosine (plus Dip) were inhibited by 8-PT.The pA2 values for 8-PT of 6.7 and 7.0 versus adenosine and NECA, respectively, were consistent with actions at P1-purinoceptors. There was a trend towards an increase in the upper asymptote of the first phase of the NECA curve in the presence of increasing concentrations of 8-PT. The A,-purinoceptor selective antagonist, DPCPX, also blocked only the first phase of the NECA concentration-effect curve and produced a significant increase in the upper asymptote. The pA2 value (6.8) obtained was consistent with activation of A2-subtype PI-purinoceptors by the low concentrations of NECA.3 There was no correlation between A,-purinoceptor affinity and the propensity to cause the increase in the upper asymptote of the first phase of the NECA concentration-effect curves amongst a series of 9-methyl adenine analogues, suggesting that the amplification was not due to inhibition of an underlying A,-purinoceptor-mediated contractile response. 4 DPCPX (10 JM) produced a significant increase in the upper asymptote of the NECA concentrationeffect curve, but had no effect on isoprenaline curves whereas the phosphodiesterase inhibitor Ro 20-1724 (30 JAM) produced a significant increase in the upper asymptote of both NECA and isoprenaline concentration-effect curves. Therefore the amplification of the first phase responses by DPCPX did not appear to be due to phosphodiesterase inhibition. 5 It was not possible to conclude whether second phase responses to adenosine and NECA were mediated by intracellular or extracellular sites of action. However, if intracellular sites of action were involved then adenosine did not apparently gain access by the Dip-sensitive uptake system.

Section: Effects Of Adenosinesupporting

confidence: 88%

Section: Effects Of Adenosinementioning

confidence: 97%

Pharmacological analysis of the interaction between purinoceptor agonists and antagonists in the guinea‐pig taenia caecum

Prentice

Shankley²,

Black

1995

“…In the left atrium, at the 50% response level, PACPX has an apparent pA2 of 6.15 ± 0.41 which compares well with that for 8-PT (6.24) in the same preparation (Griffith et al, 1981), i.e. PACPX is as potent as 8-PT.…”

Section: Discussionmentioning

confidence: 55%

“…For example, is more potent than theophylline in antagonizing adenosine-induced accumulation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in the guinea-pig cerebral cortex (Smellie et al, 1979) and in human fibroblasts (Bruns, 1981). In peripheral tissues, 8-PT has been shown to be more potent than theophylline in antagonizing: (a) the inotropic response to adenosine in the guinea-pig left atrium; (b) the presynaptic inhibition of cholinergic neurotransmission by adenosine in the guinea-pig ileum; and (c) the adenosine induced relaxations ofthe histamine-contracted rabbit basilar artery (Griffith et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

PACPX ‐ a substituted xanthine ‐ antagonizes both the A₁ and A₂ subclasses of the P₁‐purinoceptor: antagonism of the A₂ subclass is competitive but antagonism of the A₁ subclass is not

Burnstock

Hoyle

1985

Self Cite

xanthine (PACPX) was examined for its ability to antagonize adenosine acting on the Al and A2 subclasses of the P1-purinoceptor. Al-purinoceptors were studied in the isolated, driven left atria of the guinea-pig, and A2-purinoceptors in the isolated, carbachol-contracted taenia coli of the guinea-pig. 2 PACPX antagonized the actions of adenosine in both types of preparation and was a more potent antagonist than 8-phenyltheophylline. 3 The antagonism at the A2-purinoceptor was competitive with a pA2 of 5.95. 4 The antagonism at the A1-purinoceptor was not competitive, although antagonism at the Alpurinoceptor was greater than that at the A2-purinoceptor, based on a comparison of pD2 values. 5 The manner ofantagonism of PACPX on the A1-purinoceptors ofthe heart was different from that found for the A1-receptors in bovine brain, implying that there is a fundamental difference between these central and peripheral Al subclasses of P,-purinoceptor.

“…The adenosine antagonist 8-PT (Griffith et al, 1981; was found to abolish the increase in adenosine-stimulated cyclic GMP production ( Figure 7). This observation confirms the idea that cyclic GMP production by adenosine is mediated via adenosinereceptors.…”

Section: Discussionmentioning

confidence: 93%

Evidence for the involvement of cyclic GMP in adenosine‐induced, age‐dependent vasodilatation

Moritoki¹,

Matsugi²,

Takase³

et al. 1990

1 Adenosine-induced dilatation of rat aorta was present in aorta taken from 4 week-old rats, attenuated with increase in age of rats to 8 weeks, and was virtually absent in the aorta from 12 week-old rats. 2 Removal of the endothelium by mechanical rubbing attenuated adenosine-induced dilatation. 3 Haemoglobin and methylene blue partly reversed the adenosine-induced endothelium-dependent dilatation. 4 The order of potency of adenosine derivatives was 5'-(N-ethylcarboxamido)indicating that adenosine receptors mediating the dilatation are of the A2 subtype. 5 [3H]-NECA bound to preparations of membranes from rats of 4 weeks old; it was displaced more effectively by NECA and the A2 ligand CV-1808 than by the A1 ligands CHA and S-PIA. ligands CHA and S-PIA. 6 The number but not affinity of specific binding sites for NECA decreased considerably with increase in age of rats to 8 weeks, and binding sites for [3H]-NECA were hardly detected in membrane preparations from rats of 20 weeks old. 7 Adenosine caused a marked increase in cyclic GMP production, but did not induce an increase in the cyclic AMP level. 8 This increase in cyclic GMP production induced by adenosine was abolished by methylene blue or 8-phenyltheophylline, or by removal of the endothelium. 9 The age-associated decrease in adenosine-induced dilatation was found to be associated with a reduction in the formation of cyclic GMP, but not of cyclic AMP. 10 These results suggest that adenosine causes dilatation via A2 receptors by inducing production of an endothelium-derived relaxing factor (EDRF), which in turn stimulates soluble guanylate cyclase, and so increases production of cyclic GMP. It is also suggested that the main reason for the age-associated decrease in adenosine-induced dilatation is a decrease in the number of A2-receptors or the ability of the endothelium to produce EDRF, leading to decreased production of cyclic GMP.