Atypical responses of rat ileum to pindolol, cyanopindolol and iodocyanopindolol

Abstract

Pindolol, cyanopindolol (CYP) and iodocyanopindolol (IodoCYP) have been reported to act either as antagonists, agonists or partial agonists at the β3-adrenoceptor in different preparations. A comprehensive investigation has not yet been described with these compounds tested in one tissue from one species. This study was conducted to delineate the pharmacological effects of pindolol, CYP and IodoCYP and to provide data on their affinities at the predominant β-adrenoceptor in rat ileum.

The β-adrenoceptors present in rat ileum were characterized in the presence of CGP 20712A and ICI 118 551, atropine and corticosterone, with (−)−isoprenaline used as an agonist. The role of the β1 and β2-adrenoceptors was determined by the omission of either CGP 20712A, ICI 118 551, or both, from the buffers. Conversely, the effectiveness of the β1- and β2-adrenoceptor blockade was examined by use of the β1-adrenoceptor-selective agonist, RO 363 and the β2-adrenoceptor-selective agonist, salbutamol.

There was no evidence for the presence of functional β1-adrenoceptors, and no strong evidence that β2-adrenoceptor stimulation contributed to the relaxant effects of (−)−isoprenaline. (−)−Phenylephrine did not produce relaxation of the tissue and 5-hydroxytryptamine produced contraction.

The β3-adrenoceptor-selective agonist, BRL 37344 and (−)−isoprenaline were potent full agonists (pD2 8.35 ± 0.04 and 7.76 ± 0.14 respectively), whereas ICI D7114 was less potent (pseudo pD2 6.92 ± 0.15). These results indicate that the predominant functional β-adrenoceptors in rat ileum are β3-adrenoceptors.

Partial agonist effects were produced by CYP (pD2 5.28 ± 0.26) and IodoCYP (pD2 7.0 ± 0.26), but not pindolol. All three compounds antagonized the effects of (−)−isoprenaline with pKb values of 6.68 ± 0.10, 7.59 ± 0.07 and 7.59 ± 0.11 for pindolol, CYP and IodoCYP respectively. Likewise, CYP and IodoCYP antagonized the effects of BRL 37344 with pKb values of 7.20 ± 0.22 and 7.21 ± 0.14 respectively. This study provides the first functional data on the effects of IodoCYP, the ligand with the highest known affinity for the β3-adrenoceptor, at the characterized rat ileum β3-adrenoceptor.

In conclusion, whereas pKb values suggest that CYP and IodoCYP have a similar affinity for the β3-adrenoceptor in rat ileum, the higher potency of IodoCYP suggests that it promotes a greater coupling efficiency, or that its partial agonist effects are produced through a site other than the β3-adrenoceptor. The similar pKb values for CYP and IodoCYP at the β3-adrenoceptor contrast with their order of known affinities at the β1 and β2-adrenoceptors, where IodoCYP is far more potent than CYP. This provides evidence of further differences in the characteristics of the β3-adrenoceptors compared to the β1- and β2-adrenoceptors. Finally, the utility of IodoCYP as a β3-adrenoceptor antagonist would appear to be limited because of the greater magnitude of partial agonist effects that it produces.