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Relaxant effects of adenosine analogs on guinea pig trachea in vitro: xanthine-sensitive and xanthine-insensitive mechanisms

LE Brackett and JW Daly

Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

Adenosine analogs were tested for their ability to relax carbachol- contracted trachea in vitro. The rank order of potency was: 5'-N- ethylcarboxamidoadenosine (NECA) greater than 2-chloroadenosine (2- CIADO) greater than 5'-chloroadenosine = N6-R-1-phenyl-2- propyladenosine (R-PIA) greater than N6-cyclohexyladenosine greater than 2-phenylaminoadenosine (CV1808) greater than 5'- methylthioadenosine (MTA). The rank order of potency for NECA, 2-CIADO and R-PIA is characteristic of an A2 subtype of adenosine receptor. 8- Para-sulfophenyltheophylline (8-p-ST) and 8-cyclopentyl-1, 3- dipropylxanthine (DPCPX), were used to antagonize tracheal relaxation elicited by adenosine analogs. 8-p-ST antagonized the 2-CIADO, N6- cyclohexyladenosine, R-PIA and 5'-chloroadenosine responses, but had little or no effect on the CV1808 and MTA responses. 8-p-ST antagonized responses to NECA at concentrations of NECA up to approximately 30 microM, but had no effect on responses to higher concentrations of NECA. The differences in antagonist potency of 8-p-ST and the clear biphasic response of NECA are indicative of at least two mechanisms of adenosine analog action leading to tracheal relaxation. One mechanism is mediated through a xanthine-sensitive site, at which NECA acted in a potent manner, whereas the other mechanism or mechanisms are insensitive to blockade by xanthines and account for the effects of action of MTA and CV1808, as well as for NECA at high concentrations. The low potency of the A1-selective antagonist DPCPX indicates that the xanthine-sensitive site is an A2 type receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 257, Issue 1, pp. 205-213, 04/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics




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