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

Drug Development Research

2001

The main action of adenosine on vascular beds is vasodilation via A 2 receptors. In addition, A 1 receptors are found in some blood vessels, where they cause contraction. Traditionally, adenosineinduced vasodilation in vitro has been attributed to A 2A receptor activation; however, it is now clear that A 2B receptors are also involved in the regulation of vascular tone. Endothelium dependence of A 2 receptormediated responses is variable; in some tissues they are blocked by removal of endothelium and/or inhibition of NO-synthase and in some they are not. In addition to A 2 receptor-mediated relaxation, there is much evidence that relaxations to adenosine and some of its analogues can also be mediated by a mechanism which cannot be blocked by adenosine receptor antagonists. There is evidence that these responses are endothelium-and NO-independent and that, under conditions where adenosine is taken up into cells, relaxations to the endogenous ligand are entirely mediated by this mechanism, suggesting it is of physiological significance. Drug Dev. Res. 52:346-349, 2001.

Section: Vascular Effects Of Purinesmentioning

confidence: 83%

Vascular effects of adenosine and its analogues

Drug Development Research

2001

“…Collis & Brown (1983) also noted relaxations in the guinea-pig aorta to adenosine and analogues which were refractory to blockade by 8-phenyltheophylline and which were depressed in the presence of the uptake inhibitor dipyridamole, indicating the presence in this tissue of an intracellular site. Xanthine-resistant sites have also been noted in guinea-pig taenia caecum (Prentice et al, 1995;Prentice & Hourani, 1996b), guinea-pig trachea (Brackett & Daly, 1991) and frog aorta (Knight & Burnstock, 1996). It may be that all of these relaxant responses are mediated by the same site.…”

Section: Controlmentioning

confidence: 88%

“…In some tissues it was necessary to precontract with the thromboxane A 2 mimetic U46619 (9,11-dideoxy-11a,9a-epoxymethano-prostaglandin F 2a ) and in this case relaxant responses were expressed as % decrease in contraction to U46619. Where possible midpoint location ([A] 50 ), upper asymptote (a) and midpoint slope parameter estimates (n H ) were obtained by logistic curve ®tting (see Prentice et al, 1995) and for display purposes the average logistic ®tting parameters were used to generate a line upon which the average data points were superimposed. To allow ®tting of NECA E/[A] curves the data were analysed, the 100 and 300 mM responses being omitted.…”

Section: Methodsmentioning

confidence: 99%

Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery

Payne

Hourani

1997

British J Pharmacology

1 In this study we have characterized the receptor(s) in the rat mesenteric artery mediating relaxant responses to adenosine and a number of adenosine analogues, N 6 -R-phenylisopropyladenosine (R-PIA), N 6 -cyclopentyladenosine (CPA) . We have also studied the e ects of endothelial removal and uptake inhibition by nitrobenzylthioinosine (NBTI) and the e ects of the A 3 receptor antagonist 1,3-dipropyl-8-(4-acrylate)phenylxanthine (BWA1433). 2 Adenosine, NECA, CPA and R-PIA all elicited relaxant responses in tissues precontracted with phenylephrine (1 mM) with the following potency order: NECA4R-PIA4adenosine=CPA. However, E/[A] curves to NECA were biphasic. CGS 21680 was inactive at concentrations up to 30 mM and IB-MECA elicited relaxant responses which were resistant to blockade by 8-SPT and BWA1433 (100 mM). 3 Removal of the endothelium produced a small but signi®cant decrease in the asymptote of the high potency phase of E/[A] curves to NECA with no change in p[A] 50 . E/[A] curves to adenosine were not altered by removal of the endothelium. However, there were small rightward shifts of E/[A] curves to CPA and R-PIA in the absence of endothelium. 4 Inhibition of uptake by NBTI (1 mM) had no e ect on E/[A] curves to NECA, CPA or R-PIA, but E/[A] curves to adenosine were signi®cantly left-shifted in the presence of NBTI. 5 8-SPT (10 ± 100 mM) caused signi®cant rightward shifts of the high potency phase of the E/[A] curves to NECA (pA 2 =5.63+0.26). The second phase of the concentration-response curve to NECA appeared to be resistant to blockade by 8-SPT, as were E/[A] curves for adenosine, CPA or R-PIA. However, in the presence of NBTI (1 mM), 8-SPT (100 mM) gave signi®cant rightward shifts of E/[A] curves to adenosine. 6 ZM 241385 (0.1 ± 1 mM) produced signi®cant rightward shifts of the high potency phase of NECA E/[A] curves (pA 2 =7.65+0.25 in the presence and 7.20+0.12 in the absence of endothelium), while curves to R-PIA were not signi®cantly shifted by 1 mM ZM 241385. In the presence of NBTI E/[A] curves to adenosine were signi®cantly rightward shifted by ZM 241385 (0.1 mM, pA 2 =7.50+0.16). 7 In conclusion, the results suggest activation of A 2B receptors located primarily on the smooth muscle by low concentrations of NECA and by adenosine under conditions of uptake blockade, and of another, as yet unde®ned site which may be intracellular, by higher concentrations of NECA, by CPA, R-PIA and adenosine under conditions where uptake is operational.,

“…Results for the adenosine analogues were expressed as % decrease in the contraction to phenylephrine and where possible, midpoint location ([A] 50 ), upper asymptote (α) and midpoint slope parameter estimates (n H ) were obtained by logistic curve fitting (see Prentice et al 1995). This was not possible for curves to adenosine, therefore pIC 20 values (negative log of the concentration eliciting 20% decrease in phenylephrine contraction) were estimated by linear regression.…”

Section: Methodsmentioning

confidence: 99%

Relaxation of the mouse isolated aorta and carotid artery in response to adenosine analogues in genetically-modified mice lacking the adenosine A 2A receptor

Naunyn-Schmiedeberg's Archives of Pharmacology

Kelly

Ledent

et al. 2002

The aim of this study was to characterise the receptor(s) mediating responses to adenosine and/or adenosine analogues in mouse isolated aorta and carotid artery. In addition, since mice lacking the A(2A) adenosine receptor are reported to be hypertensive, the possibility that this gene deletion or the altered phenotype results in alteration of responses mediated via adenosine analogues was investigated. This was achieved by comparing results obtained in parallel within single experiments using tissues from A(2A) knock-out animals and their wild-type littermates.In aortic rings, adenosine and 5'- N-ethylcarboxamidoadenosine (NECA) caused relaxations above 10 microM and 30 microM, respectively, which were unaffected by either 8-sulphophenyltheophylline (8-SPT, 100 microM) or A(2A) receptor knockout. 2-[ p-(2-Carbonylethyl)phenylethylamino]-5'- N-ethylcarboxamidoadenosine (CGS 21680) was virtually inactive. R- N(6)-Phenylisopropyladenosine (R-PIA) induced relaxations which were not inhibited by 8-SPT (100 microM) or altered by A(2A) receptor knockout. No A(1)-mediated contractile responses were observed in wild-type or knock-out tissues in contrast with results in mice of the same strain obtained commercially rather than from our breeding programme. In carotid artery rings NECA contracted at low concentrations (0.1-1 microM) and relaxed at higher concentrations. Curves to NECA were not different in tissues from wild-type and A(2A) receptor knock-out mice and both the contractile and relaxant phases were right-shifted by 8-SPT (100 microM) in tissues from animals of both genotype. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX, 3 nM) attenuated contractile NECA responses but did not affect relaxant responses. CGS 21680 was inactive in carotid artery rings from both wild-type and A(2A) receptor knock-out mice. In the presence of DPCPX (30 nM) to abolish contractions, R-PIA induced relaxant curves which were not different in tissues from wild-type and A(2A) knock-out mice and were not inhibited by 8-SPT (100 microM). These results confirm the absence of A(2A) or A(2B) receptors in murine aorta and suggest that relaxations to NECA in carotid artery are A(2B) receptor-mediated whilst contractions are A(1) receptor-mediated. They also indicate the presence of an antagonist-resistant site activated by R-PIA in both vascular preparations. There is no evidence for compensatory changes in responses mediated by adenosine and its analogues due to the gene deletion or the reported resulting hypertensive phenotype in either aortic or carotid arterial rings obtained from A(2A) knock-out mice.