Is Ro 03–7894 an irreversible antagonist at β‐adrenoceptor sites?

Abstract

1 Ro 03-7894 (0.6 mM) produced a non-parallel shift to the right of dose-response curves to (-)-isoprenaline in K+ depolarized uterine preparations from the guinea-pig. The displacement of the curves was readily reversed by washing. A rightward shift of similar magnitude was also produced by Ro 03-7894 in transmurally stimulated ileal preparations. The relaxant effects of fenoterol in carbachol-contracted guinea-pig tracheal preparations (in the presence of 2 gM atenolol) were not altered by 0.6mM Ro 03-7894. In the three tissues there was no evidence of a reduction in the maximal inhibitory response to the agonists. 2 In uterine and tracheal preparations, Ro 03-7894 (0.6 mM) depressed contractile responses to exogenous calcium. The depression of responses was enhanced after washout of Ro 03-7894 for 80 min. Contractile responses of ileal preparations to transmural stimulation were also depressed by Ro 03-7894. 3 Concentration-effect curves for the positive inotropic effects of (-)-isoprenaline in guinea-pig left atrial preparations were markedly shifted to the right and the maximum response depressed by 0.6mM Ro 03-7894. Although the rightward shift of the curves was fully reversed during the 120 min washout period, the maximal responses remained depressed. In similar experiments, Ro 03-7894 produced a washout-resistant depression of inotropic responses to histamine and calcium.4 The results of radioligand binding studies in left atria using (-)-['"I]-iodocyanopindolol indicated that, when compared to the untreated atria, there was no reduction in the maximal density of binding sites 120 min after washout of 0.6 mM Ro 03-7894. 5 On the basis of the present results it is concluded that Ro 03-7894 induces a non-specific depressant effect on smooth and cardiac muscle preparations during exposure to the drug. This depressant effect persists following washout of the drug. There is no evidence for an irreversible effect of Ro 03-7894 at P-adrenoceptor sites.

The determination of receptor constants for histamine H2‐agonists in the guinea‐pig isolated right atrium using an irreversible H2‐antagonist

“…However, to date no results have been described for the histamine H2receptor, presumably due to the lack of a specific compound that would satisfy all the criteria for being an irreversible H2-antagonist. Care must be taken to avoid compounds with a general non-specific depressant effect as recently reported for the P-adrenoceptor antagonist Ro 03-7894 on atrial preparations (Baker & Posner, 1983;Kostew et al,1984). Using the guineapig isolated right atrium, a tissue highly suited for the investigation of histamine H2-specific effects (Black et al.,1972), we have shown that the compound E1309 meets the necessary criteria.…”

“…The concepts of spare receptors and relative efficacy are now generally accepted (Kenakin, 1984;Ruffolo, (Baker & Posner, 1983;Kostew et al,1984). Using the guineapig isolated right atrium, a tissue highly suited for the investigation of histamine H2-specific effects (Black et al.,1972), we have shown that the compound E1309 meets the necessary criteria.…”

An operational model of pharmacological agonism: the effect of E/[A] curve shape on agonist dissociation constant estimation

“…The estimation of KA by Furchgott's method would indeed be invalid as McPherson et al (1983) point out, but the result should be associated with a particular system rather than with a general principle that the method is invalid other than for hyperbolic curves. Indeed, since their initial study using Ro 03-7894, the same workers have questioned the classification of this compound as an irreversible, b-adrenoceptor antagonist (Krstew et al, 1984).…”

An operational model of pharmacological agonism: the effect of E/[A] curve shape on agonist dissociation constant estimation

“…Our analysis implies that gradients for pre-and post-inactivation curves should only remain unchanged by [R0] (1983) point out, but the result should be associated with a particular system rather than with a general principle that the method is invalid other than for hyperbolic curves. Indeed, since their initial study using Ro 03-7894, the same workers have questioned the classification of this compound as an irreversible ,-adrenoceptor antagonist (Krstew et al, 1984).…”