A 1 and A 2 adenosine receptor modulation of contractility in the cauda epididymis of the guinea‐pig

1 The effects of adenosine receptor agonists upon phenylephrine‐stimulated contractility and [ 3 H]‐cyclic adenosine monophosphate ([ 3 H]‐cyclic AMP) accumulation in the cauda epididymis of the guinea‐pig were investigated. The α 1 ‐adrenoceptor agonist, phenylephrine elicited concentration dependent contractile responses from preparations of epididymis. In the absence or presence of the L‐type Ca 2+ channel blocker, nifedipine (10 μ M ) the non‐selective adenosine receptor agonist, 5′‐N‐ethylcarboxamido‐adenosine (NECA, 1 μ M ) shifted phenylephrine concentration‐response curves to the left (4 and 5 fold respectively). Following the incubation of preparations with pertussis toxin (200 ng ml −1 24 h) NECA shifted phenylephrine concentration‐response curves to the right (5.7±0.9 fold). 2 In the presence of phenylephrine (1 μ M ), NECA and the A 1 adenosine receptor selective agonists, N 6 ‐cyclopentyladenosine (CPA) and (2S)‐N 6 ‐[2‐endo‐norbornyl]adenosine ((S)‐ENBA) elicited concentration‐responses dependent contractions from preparations of epididymis (pEC 50 values 8.18±0.19, 7.79±0.29 and 8.15±0.43 respectively). The A 3 adenosine receptor agonists N 6 ‐iodobenzyl‐5′‐N‐methyl‐carboxamido adenosine (IBMECA) and N 6 ‐2‐(4‐aminophenyl) ethyladenosine (APNEA) mimicked this effect (but only at concentrations greater than 10 μ M ). In the presence of 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 30 n M ) CPA concentration‐response curves were shifted, in parallel to the right (apparent pK B 8.75±0.88) and the maximal response to NECA was reduced. 3 In the presence of DPCPX (100 n M ) the adenosine agonist NECA and the A 2A adenosine receptor selective agonist, CGS 21680 (2‐ p ‐(2‐carboxyethyl)‐phenethylamino‐N‐ethylcarboxamido adenosine), but not CPA, inhibited phenylephrine (20 μ M ) stimulated contractions (pIC 50 7.15±0.48). This effect of NECA was blocked by xanthine amine congener (XAC, 1 μ M ) and the A 2A adenosine receptor‐selective antagonist 4‐(2‐[7‐amino‐2‐(2‐furyl)[1,2,4]triazolo[2,3‐a][1,3,5]triazin‐5‐ylamino]ethyl)phenol (ZM 241385; 30 n M ). 4 (S)‐ENBA (in the absence and presence of ZM 241385, 100 n M ), but not NECA or CPA inhibited the forskolin (30 μ M )‐stimulated accumulation of [ 3 H]‐cyclic AMP in preparations of the epididymis of the guinea‐pig (by 17±6% of control). In the presence of DPCPX (100 n M ) NECA and CGS 21680, but not (S)‐ENBA, increased the accumulation of [ 3 H]‐cyclic AMP in preparations of epididymis (pEC 50 values 5.35±0.35 and 6.42±0.40 respectively), the NECA‐induced elevation of [ 3 H]‐cyclic AMP was antagonised by XAC (apparent pK B 6.88±0.88) and also by the A 2A adenosine receptor antagonist, ZM 241385 (apparent pK B 8.60± 0.76). 5 These studies are consistent with the action of stable adenosine analogues at post‐junctional A 1 and A 2 adenosine receptors in the epididymis of the guinea‐pig. A 1 Adenosine receptors potentiate α 1 ‐adrenoceptor contractility, an effect blocked by pertussis toxin, but which may not be dependent upon an inhibition of adenylyl cyclase. The epididymis of the guinea‐pig also contains A 2 adenosine receptors, possibly of the A 2A subtype, which both inhibit contractility and also stimulate adenylyl cyclase.British Journal of Pharmacology (1998) 125 , 570–576; doi: 10.1038/sj.bjp.0702095