Rilmenidine reveals differences in the pharmacological characteristics of prejunctional α₂‐adrenoceptors in the guinea‐pig, rat and pig

Abstract

1 The a 2A and a 2D -adrenoceptor subtypes are thought to be species homologs most easily di erentiated on the basis of the potency of antagonists. In the present study we have compared the e ect of rilmenidine with two other selective a 2 -adrenoceptor agonists, UK-14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline) and clonidine, against electrically-evoked contractions in ®ve 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 electricallyevoked contractions of the rat isolated vas deferens and tail artery and the guinea-pig ileum. These inhibitory e ects were reversed by the selective a 2 -adrenoceptor antagonist, RX-811058 (1 mM), except in the rat tail artery preparations where the remaining neurogenic response was inhibited; evidence for the involvement of`innervated' a 2 -adrenoceptors. Both clonidine and UK-14304 produced concentrationdependent inhibition of responses in the porcine isolated tail artery and urinary bladder but clonidine was markedly less e cacious 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 mM and 30 mM, respectively) competitively antagonised the inhibitory e ects of UK-14304 with an estimated dissociation constant of (pK B ) 5.82 and 5.93, respectively. 4 Prazosin (1 mM) failed to alter the e ect 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 a 2D -adrenoceptors in the rat and guinea-pig and the a 2A -adrenoceptors in the pig. 5 We have demonstrated that rilmenidine, unlike clonidine and UK-14304, is devoid of any agonist activity at prejunctional a 2A -adrenoceptors in the pig, but is an e cacious agonist at a 2D -adrenoceptors in the rat and guinea-pig.

Alpha2A‐Adrenergic Versus Imidazoline Receptor Controversy in Rilmenidine's Action: Alpha2A‐Antagonism in Humans Versus Alpha2A‐Agonism in Rabbits

“…The observation that the pharmacological properties of rilmenidine, clonidine, and oxymetazoline at α 2A -adrenoceptors differ substantially between various species 3,5,14 in concert with the present molecular data suggests that the rabbit α 2Aadrenoceptor is no reliable predictive model for the action of ligands at the human α 2A -adrenoceptor. It is of interest to note that rilmenidine acts as an antagonist not only at human, but also at the pig α 2A -adrenoceptor, 14 and that the pig and human α 2A -adrenoceptor are structurally most similar among mammals in the amino acid sequence (TABLE 1). 5 Hence, the action of ligands at central α 2A -adrenoceptors in humans can be predicted most reliably from experiments performed in pig preparations.…”

No Evidence for Activation of α2‐Adrenoceptors by Methanolic Extracts of Bovine Brain and Lung Containing Clonidine‐Displacing Substance

“…The receptor in rat vas deferens has a high receptor reserve and is responsive to even weak α 2 -adrenoceptors agonists. 30 Taken together, our findings indicate that neither lung nor brain methanolic CDS extracts have the potential to activate α 2 -adrenoceptors and cast doubts on one of the central tenants of research into CDS, namely that CDS represents an endogenous, noncatecholamine agonist for α 2 -adrenoceptors. 4,9,10 Thus, our observations on the rat vas deferens provide no support for the seminal findings by Diamant and Atlas 7 that brain CDS (approximately 8 units/mL) inhibited neurogenic contractions of the rat vas deferens through a phentolamine-and yohimbine-sensitive (α 2 -adrenoceptor) mechanism.…”

“…The finding that the CDS extracts were inactive at prejunctional α 2 ‐adrenoceptors in the rat vas deferens makes it unlikely that it possesses agonist activity in other models of α 2 ‐adrenoceptors. The receptor in rat vas deferens has a high receptor reserve and is responsive to even weak α 2 ‐adrenoceptors agonists 30. Taken together, our findings indicate that neither lung nor brain methanolic CDS extracts have the potential to activate α 2 ‐adrenoceptors and cast doubts on one of the central tenants of research into CDS, namely that CDS represents an endogenous, noncatecholamine agonist for α 2 ‐adrenoceptors 4,9,10.…”

Species-Specific Pharmacological Properties of Human α 2A -Adrenoceptors

“…At a stimulation frequency of 6 Hz, at which the concentration of the endogenous norepinephrine in the synaptic cleft is much higher, leading to a more pronounced activation of the ␣ 2A -autoreceptors than at 2 Hz, rilmenidine enhanced evoked [ 3 H]norepinephrine release; in other words, it again exhibited the typical behavior of an antagonist at ␣ 2A -autoreceptors in that it disinhibited release. Interestingly, it has recently been reported that rilmenidine was also devoid of agonistic activity at the ␣ 2A -adrenoceptors in porcine tail artery and urinary bladder, 20 which are structurally most similar to the human ␣ 2A -adrenoceptors (Table 2).…”