A study of the relationship between cardiac ?-adrenoceptor blockade and intrinsic sympathomimetic activity in rats depleted of catecholamines

Abstract

1. The intrinsic sympathomimetic activity of a range of beta-adrenoceptor antagonists and its relationship to beta-adrenoceptor blockade was studied in pentobarbitone-anaesthetized, vagotomized rats which had been depleted of catecholamines by pretreatment with syrosingopine. Dichlorisoprenaline, practolol, oxprenolol, pindolol and acebutolol, produced dose-dependent positive chronotropic responses in this preparation. 2. The relationship between the dose requirements for this intrinsic sympathomimetic activity and beta-adrenoceptor-blocking activity was not the same for all drugs: (i) dichlorisoprenaline and practolol had intrinsic activity at all beta-adrenoceptor-blocking doses; and (ii) oxprenolol, pindolol and acebutolol had predominantly beta-adrenoceptor blockade at the lower dose levels and agonist activity only became significant at high doses relative to those producing beta-adrenoceptor blockade. 3. The positive chronotropic response to both practolol and pindolol was observed in rats which had been pithed and was antagonized by propranolol (0.1-3.0 mg/kg, i.v.), indicating that beta-adrenoceptors were involved. 4. It was concluded that the intrinsic sympathomimetic activity of beta-adrenoceptor antagonists was not a simple property as it was described by the relationship between the dose requirements for intrinsic sympathomimetic activity and for beta-adrenoceptor blockade as well as the degree of partial agonist activity.

Pindolol‐the pharmacology of a partial agonist.

“…Pindolol has been reported to increase heart rate by up to 120 beats/min in syrosingopine-treated rats (Barrett & Carter, 1970;Bilski et al, 1979) and by 60 beats/min in reserpinized cats (Clark, 1976). In the spinal cat, heart rate can increase by up to 40 beats/min.…”

THE CARDIOVASCULAR EFFECTS OF ICI 118,587: A β1‐ADRENOCEPTOR PARTIAL AGONIST

“…In order to obtain a quantitative index of the potency of ICI 118,587 as an antagonist, the agonist dose or frequency-response curves obtained in the above series of experiments were analysed in the manner described by Bilski, Robertson & Wale (1979). Firstly, the curves were normalized by expressing the response as a fraction of the maximum possible response for that particular curve.…”

Effects of beta‐adrenoceptor blockade on heart rate and physiological tremor in diabetics with autonomic neuropathy. A comparative study of epanolol, atenolol and pindolol.

“…In animals, atenolol has been shown to have no PAA, while epanolol and pindolol do (Harry et al, 1974;Bilski et al, 1979;Smith et al, 1983). Pindolol stimulated the heart rate of catecholamine depleted rats (a 13i effect) to a maximum of 120 beats min-1 (Bilski et al, 1979) whereas epanolol stimulated it only to 80 beats min-1 (Data for clinical investigators on epanolol-ICI document), and therefore pindolol has more PAA than epanolol.…”