, Volume 339, Issue 5, pp 496-502

The inhibition of α1-adrenoceptor-mediated contractions of rabbit pulmonary artery by Ca2+-withdrawal, pertussis toxin and N-ethylmaleimide is dependent on agonist intrinsic efficacy

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Contractions were induced in rings of rabbit pulmonary artery with the preferential α1-adrenoceptor agonists, whereas St 587, clonidine and B-HT 920 were (parchloro-trifluoromethyl-phenylimino)[imidazolidine] and the preferential α2-adrenoceptor agonists, clonidine and B-HT 920 [6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d) azepine]. Phenylephrine and methoxamine acted as full agonists whereas St 587, clonidine and B-HT 920 were partial agonists (intrinsic activities 0.62, 0.38 and 0.42, respectively). Experiments with α1- and α2-adrenoceptor antagonists indicated that the receptors involved are of the α1 type only. Removal of extracellular Ca2+ inhibited maximal contractions to phenylephrine and methoxamine by 30% and 49%, respectively. The remaining contraction components of the full agonists were abolished by the “intracellular Ca2+ antagonist” TMB-8 [8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate]. Contractions to St 587, clonidine and B-HT 920 were virtually abolished in Ca2+-free medium. Pretreatment of the donor rabbits with pertussis toxin (2.5 μ/kg i. v., 5–6 days before sacrifice) attenuated the efficacies of the full agonists, phenylephrine and methoxamine by only 24% and 17%, respectively, whereas maximal contractions to the partial agonists, St 587, clonidine and B-HT 920, were inhibited by 46%, 61% and 75%, respectively. Also the sulfhydryl reagent, N-ethylmaleimide (10 μM), reduced contractile efficacies of phenylephrine and methoxamine to a lesser degree than those of St 587, clonidine and B-HT 920. When agonists were used at equieffective concentrations (i.e. EC30–40 for phenylephrine and methoxamine, EC70–80 for St 587 and EC99 for clonidine and B-HT 920) the degree of inhibition by removal of extracellular Ca2+, pertussis toxin and N-ethylmaleimide was similar for all agonists. These data suggest that a unitary al-receptor may stimulate contractions via two different mechanisms. At a low degree of receptor stimulation, contractions are mediated by a pertussis toxin- and N-ethylmaleimide-sensitive influx of external Ca2+. At a higher degree of receptor stimulation, an additional mechanism is activated which is insensitive to the two G protein inhibitors and mediated by Ca2+ mobilization from intracellular sites.

A preliminary account of these results was presented at the Fall Meeting of the German Society of Pharmacology and Toxicology, Hamburg, September 19–22,1988 (Liebau et al. 1988). The study was supported by Grant Fo 144/1–2 from the Deutsche Forschungsgemeinschaft