The IN VIVO examination of the irreversible β-adrenoceptor antagonist Ro 03-7894 on cardiac rate and contractility

1440-1681

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

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.

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