Anti‐arrhythmic, local anaesthetic, and adrenergic blocking activity of some β‐receptor antagonists

Abstract

1. The antagonistic effect of the p-receptor blocking compounds propranolol, Ph QA 33 and INPEA on ouabain-induced cardiac fibrillations in guinea-pigs was compared with their local anaesthetic and p-receptor blocking properties.2. All three compounds were found capable of increasing the tolerance to ouabain and of reversing ouabain-induced fibrillations, the ED50 being 0.3 mg/kg intravenously, 0.5 mg/kg intravenously, and 1.5 mg/kg intravenously, respectively for propranolol, Ph QA 33 and INPEA. 3. Propranolol and Ph QA 33 were found to be moderate to strong local anaesthetics while INPEA had a considerably weaker though significant effect.4. The order of potency as p-receptor blocking compounds was propranolol > Ph QA 33 > INPEA, the latter compound being less than 1% as active as propranolol. 5. Despite the surprising finding that INPEA was effective against noncatecholamine-induced arrhythmias, the results support the general assumption that the anti-arrhythmic effect of p-receptor blocking compounds is related to their local anaesthetic action rather than to their P-blocking ability.Since the work by Lucchesi (1965) on the dextro and racemic form of pronethalol, several investigations have shown,that the effect of p-adrenergic blocking agents on non-catecholamine-induced arrhythmias is, to a large extent, unrelated to their p-receptor blocking action (Howe & Shanks, 1966). The unspecific anti-arrhythmic effect of P-blocking compounds is now assumed to be due chiefly to their quinidinelike or local anaesthetic action, a property common to most P-blocking agents.

THE EFFECTS OF (+)‐ AND (–)‐PROPRANOLOL ON 3H‐TRANSMITTER EFFLUX IN GUINEA‐PIG ATRIA AND THE PRESYNAPTIC β‐ADRENOCEPTOR HYPOTHESIS

“…The f-receptor antagonist is known to have other actions on neuronal tissue, such as local anaesthetic (Hermansen, 1969), as well as a well-documented myocardial depressant effect (van Zwieten, 1969), and the relationship of these less specific manifestations to the assumed presynaptic receptor activity of propranolol…”

“…Celuch et al, 1978), but also by a similar concentration of (+)-propranolol, the isomer with greatly diminished blocking properties. It has been shown elsewhere that the dextro-isomer, although less than one hundredth as potent as the laevo-isomer as a cardiac P-adrenoceptor antagonist, is roughly equipotent to it as a myocardial depressant and as a local anaesthetic and neuronal blocking agent in several test preparations (Vaughan Williams, 1966;Barrett & Cullum, 1968;Hermansen, 1969;Barrett & Nunn, 1970;Eliash & Weinstock, 1971;Mylecharane & Raper, 1973). It appears likely from the present data that the blunting of the isoprenaline effect is more intimately tied to a 'non-specific'.…”

Dependence of Deoxycorticosterone/Salt Hypertension in the Rat on the Activity of Adrenergic Cardiac Nerves

“…An antihypertensive action of propranolol could be related to its effect on central B-adrenoreceptors (Day & Roach, 1973;Dollery, Lewis, Myers & Reid, 1973) or to its local anaesthetic properties (Howe & Shanks, 1966;Hermansen, 1969). On the other hand, atenolol has been reported not to cross the blood-brain barrier (Barrett, 1977) and is devoid of local anaesthetic effects (Barrett, Carter, Fitzgerald, Hull & LeCount, 1973;Harry, Knapp & Linden, 1974).…”

Hormonal regulation of ciliary function in the oviduct: The effect of beta-adrenergic agonists

“…In our experiments we attempted to circumvent these problems by using a tissue culture preparation of oviductal ciliated cells almost devoid of mucus-secreting cells, and by applying an objective reproducible and systematically validated technique to detect and record ciliary movements. The results indicate that oviductal ciliated cells are responsive to beta-adrenergic stimulation; that this response takes place at concentrations of beta-agonist that are equivalent to or lower than the concentration of catecholamines found in the rabbit oviduct [Brundin, 19651; and that it is beta-adrenergic-specific since it can be blocked by propanolol at concentrations that have been shown to inhibit beta stimulation in other tissues including mammalian ciliated cells [Douglas et al, 1977;Hermansen, 1969;Verdugo, Johnson, and Tam, 19801. To appreciate the functional significance of the present findings, it is important to consider that in the rabbit, as well as in primates, the Fallopian tube is densely innervated by sympathetic terminals, and its content of catecholamines has been found to vary during the sexual cycle probably due to estrogen-progesterone control [Brundin, 1965;Owman et al, 1976;Rosengren and Sjoberg, 19681. A variety of hormonal and pharmacological influences, including catecholamines, can alter the rate of oviductal gamete transport and critically interfere with reproduction in mammals [Polidoro et al, 19751.…”