INVIVO EXAMINATION OF THE IRREVERSIBLE BETA-ADRENOCEPTOR ANTAGONIST RO-03-7894 ON CARDIAC RATE AND CONTRACTILITY

1. Two benzofuran‐2‐ethanolamines Ro 03‐5255 (l‐(5‐acetylamino‐benzo‐furan‐2‐yl)‐l‐hydroxy‐2‐isopropylaminoethane) and Ro 03‐7894 (l‐(5‐chlora‐cetyl aminobenzofuran‐2‐yl)‐l‐hydroxy‐2‐isopropylaminoethane) which had previously been shown to exhibit respectively competitive and irreversible β‐adrenoceptor antagonism in guinea‐pig isolated atria, were compared in vivo using isoprenaline‐induced tachycardia of anaesthetized guinea‐pigs and heart rate and contractility (dp/dtmax) of open‐chest anaesthetized guinea‐pigs and of conscious cats. 2. In urethane‐anaesthetized guinea‐pigs doses of 3 mg/kg, s.c. of both antagonists produced significant blockade of the rate response to an 80% of maximum dose of isoprenaline after 4 h. In other experiments, guinea‐pigs were pretreated with the antagonists and the responses to isoprenaline were then monitored. The slopes of the dose‐response curves to isoprenaline were depressed for up to 24 h by Ro 03‐7894 but this was not so with Ro 03‐5255. 3. In conscious cats the course of blockade by Ro 03‐7894 was followed in the same animals and was still evident after 48 h. In contrast, the β‐adrenoceptor blockade produced by Ro 03‐5255 was not evident 24 h after administration. 4. The persistence of blockade by Ro 03‐7894 was consistent with the irreversible mode of action demonstrated in vitro. Copyright © 1979, Wiley Blackwell. All rights reserved