Rilmenidine reveals differences in the pharmacological characteristics of prejunctional α 2 ‐adrenoceptors in the guinea‐pig, rat and pig

1 The α 2A and α 2D ‐adrenoceptor subtypes are thought to be species homologs most easily differentiated on the basis of the potency of antagonists. In the present study we have compared the effect of rilmenidine with two other selective α 2 ‐adrenoceptor agonists, UK‐14304 (5‐bromo‐6‐ [2‐imidazolin‐2‐ylamino]‐quinoxaline) and clonidine, against electrically‐evoked contractions in five isolated preparations from the rat, guinea‐pig and pig, and, where possible, determined the receptor subtype involved. 2 UK‐14034, clonidine and rilmenidine produced concentration‐dependent inhibition of the electrically‐evoked contractions of the rat isolated vas deferens and tail artery and the guinea‐pig ileum. These inhibitory effects were reversed by the selective α 2 ‐adrenoceptor antagonist, RX‐811058 (1 μ M ), except in the rat tail artery preparations where the remaining neurogenic response was inhibited; evidence for the involvement of ‘innervated’ α 2 ‐adrenoceptors. Both clonidine and UK‐14304 produced concentration‐dependent inhibition of responses in the porcine isolated tail artery and urinary bladder but clonidine was markedly less efficacious in these preparations. In contrast, rilmenidine failed to inhibit the neurogenic contractions in either preparation. 3 Although rilmenidine failed to elicit a detectable response in either the porcine isolated tail artery or urinary bladder, it (10 μ M and 30 μ M , respectively) competitively antagonised the inhibitory effects of UK‐14304 with an estimated dissociation constant of (pK B ) 5.82 and 5.93, respectively. 4 Prazosin (1 μ M ) failed to alter the effect of UK‐14304 against neurogenic contractions in the porcine isolated urinary bladder, while rauwolscine (pK B 8.87) was 10 fold more potent than phentolamine (pK B 7.56). On the other hand, phentolamine (pK B 8.42) was only marginally more potent than rauwolscine (pK 8.05) against clonidine‐induced inhibition of electrically‐evoked contractions of the guinea‐pig isolated ileum. This pharmacological evidence with antagonists supports the presence of α 2D ‐adrenoceptors in the rat and guinea‐pig and the α 2A ‐adrenoceptors in the pig. 5 We have demonstrated that rilmenidine, unlike clonidine and UK‐14304, is devoid of any agonist activity at prejunctional α 2A ‐adrenoceptors in the pig, but is an efficacious agonist at α 2D ‐adrenoceptors in the rat and guinea‐pig.British Journal of Pharmacology (1998) 125 , 127–135; doi: 10.1038/sj.bjp.0702016