J. B. Farmer

Pharmacology of AH 5158; a drug which blocks both α‐ and β‐adrenoceptors

1 AH 5158 differs from conventional adrenoceptor blocking drugs in producing competitive blockade of both α‐ and β‐adrenoceptors. 2 AH 5158 is 5–18 times less potent than propranolol in blocking β‐adrenoceptors. It resembles propranolol in its non‐selective blockade of β1‐cardiac and β2‐vascular and tracheal adrenoceptors and in its lack of intrinsic sympathomimetic activity. 3 AH 5158 is 2–7 times less potent than phentolamine in blocking α‐adrenoceptors. AH 5158 itself is more active on β‐ than α‐adrenoceptors. 4 Blockade of noradrenaline vasopressor responses by AH 5158 in anaesthetized dogs was dose‐dependent up to 1 mg/kg but no further blockade was obtained with larger doses of AH 5158. ‘Self‐limiting’ blockade was not observed in dogs pretreated with cocaine, or in untreated dogs if the vasopressor agent was oxymetazoline instead of noradrenaline. A possible cause of ‘self‐limiting’ blockade is discussed. 5 In doses higher than those required for either α‐ or β‐adrenoceptor blockade, AH 5158 produced effects on cardiac muscle that are attributable to membrane‐stabilizing activity. This was manifested as a negative inotropic action in spinal dogs and in guinea‐pig left atrial strips, as a negative chronotropic action in syrosingopine pre‐treated dogs, and as an increase in the effective refractory period of guinea‐pig left atrial strips. AH 5158 was 3–11 times less potent than propranolol in these tests. 6 In open chest dogs AH 5158 resembled propranolol in reducing cardiac output, rate and contractility, effects which are attributable to β‐adrenoceptor blockade. The drug differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger decreases in arterial blood pressure at equipotent β‐adrenoceptor blocking doses. These differences are attributable to the α‐adrenoceptor blocking actions of AH 5158. 7 In anaesthetized dogs, intravenously administered AH 5158 antagonized both catecholamine and ouabain‐induced arrhythmias. Orally administered AH 5158 lowered systolic arterial pressure in conscious renal hypertensive dogs. 8 These results show AH 5158 to possess a novel profile of activity. Possible uses of the drug in cardiovascular disorders such as hypertension, angina pectoris and cardiac arrhythmias are discussed.

Some observations on the β‐adrenoceptor agonist properties of the isomers of salbutamol

1 The pharmacological activities of the optical isomers of salbutamol have been examined. (–)‐Salbutamol was much more potent than (+)‐salbutamol on β‐adrenoceptors. 2 Both (–)‐ and (+)‐salbutamol showed high selectivity for β‐adrenoceptors in bronchial muscle compared to cardiac muscle, in this way resembling racemic salbutamol. 3 The use of isomeric activity ratio to detect differences between receptors was examined in the light of the results obtained with the isomers of salbutamol.

A new preparation of the isolated intact trachea of the guinea-pig.

A preparation is described in which the guinea‐pig isolated intact trachea is subjected to repeated transmural electrical stimulation with alternating square wave pulses. The intraluminal pressure is continuously sensed by a pressure transducer. An increase in the intraluminal pressure is the predominant response to electrical stimulation. This response is prevented by low concentrations of atropine. After the initial rise a small fall in intraluminal pressure occurs; this is prevented by low concentrations of propranolol. The sensitivity of the preparation to various drugs is described.

Differentiation of β-adrenoreceptors by the use of blocking agents

There is evidence that the P-adrenoreceptor population is comprised of a t least two types designated as 8-1 and 13-2 (Lands, Arnold & others, 1967; Lands, Luduena & Buzzo, 1967). This sub-division was proposed to account for the differing structural requirements of catecholethanolamines for initiating j?-sympathomimetic actions in different organs. The sub-division so proposed has been further supported by the recent discovery of j?-agonists, such as salbutamol, with selective 9-2 actions (Cullum, Farmer & others, 1969). If P-adrenoreceptors differ significantly in their structural requirements for agonists then it is reasonable to suppose that such receptors could have differcnt structural requirements for antagonists. Thus experiments have been made to measure quantitatively the P-adrenoreceptor blocking action (by use of PA, measurements) of two compounds, propranolol and ICI 50 172 (against isoprenaline) at typical p-1 and 8-2 type receptors. Previous workers have shown that tissues with similar receptors can be expected to give the same PA, with a given antagonist (Arunlakshana & Schild, 1959). ICI 50 172 was chosen in addition to propranolol because some selectivity of blocking action for this compound has been described (Dunlop & Shanks, 1968).

Impairment of sympathetic nerve responses by dopa, dopamine and their α‐methyl analogues

Dopa and dopamine reduced the response of the nictitating membrane to postganglionic sympathetic nerve stimulation in cats pretreated with the monoamine oxidase inhibitor pargyline. A similar reduction could be obtained with α‐methyldopa and α‐methyldopamine in untreated cats. The sensitivity of the membrane to injected noradrenaline, α‐methylnoradrenaline or adrenaline was not reduced. The possible mechanism of the anti‐hypertensive action of monoamine oxidase inhibitors and α‐methyldopa is discussed in the light of these findings.

The inducement of tone and its inhibition in isolated tracheal muscle.

We have recently described a preparation of the isolated intact trachea of the guineapig which can be used to assess the activity of bronchodilator drugs by determining their abilities to antagonize the temporary rise in intraluminal pressure induced by electrical stimulation (Farmer & Coleman, 1970). Subsequently we investigated the effect of various drugs on the resting intraluminal pressure in the non-electrically stimulated intact trachea preparation. The preparation set up, as described by Farmer & Coleman (1970), has an intraluminal pressure equal to or slightly above atmospheric pressure. Acetylcholine (0.1-30 pg/ml) and histamine (1-100 pg/ml) caused graded increases in intraluminal pressure of 1-25 mm Hg, and typical doseresponse curves were obtained for these spasmogens. PA, values for atropine against acetylcholine and mepyramine against histamine were determined by the method of Arunlakshana & Schild (1959). Increasing doses of atropine caused successive shifts to the right of the acetylcholine dose-response curve and a PA, (30 min) of 8.46 -l-0.768 (n = 3) was obtained. A PA, value for mepyramine could not be obtained as the shifts in the histamine dose-response curves were not parallel. This is surprising as the antagonism of histamine by mepyramine on the guinea-pig ileum was shown by Arunlakshana & Schild (1959) to be competitive. The small residual intraluminal pressure of the intact trachea preparation is reduced by 8-adrenoceptor stimulants and doses producing maximal responses lowered the intraluminal pressure to just below atmospheric pressure. On washing, the intraluminal pressure rose to its previous level in about 10 min. The responses to /3-stimulants were reproducible but pressure changes involved were too small to allow satisfactory quantitative evaluation. These results are similar to those previously described by Jamieson (1962), Wellens (1966) and Guirgis (1969). However, we have found that a suitably high intraluminal pressure could be developed if the tracheal lumen was momentarily exposed to atmospheric pressure immediately after the /3-stimulant was washed from the bath. The tone then recovered quickly but to a level higher than before. Repetition of this procedure resulted in successive increases in the level of the intraluminal pressure until equilibrium was reached usually after the fourth or fifth cycle. At this time the intraluminal pressure varied from 14-22 mm Hg and sometimes exceeded 30 mm Hg. Very occasionally the intraluminal pressure failed to

The effect of isoprenaline on the contraction of smooth muscle produced by histamine, acetylcholine or other agents.

Isoprenaline given intravenously is a more potent antagonist of bronchospasm produced by histamine than of that produced by acetylcholine in the anaesthetised guinea‐pig. This greater activity of isoprenaline against histamine was also observed on isolated tracheal muscle and ileum of the guinea‐pig. It was also found in isolated guinea‐pig ileum that stimulation of the periarterial sympathetic nerves produced a greater inhibition of contractions produced by histamine or 5‐hydroxy‐tryptamine than of those produced by acetylcholine or bradykinin. The inhibitory actions of isoprenaline were absent in tissues without β‐receptors and tissues in which the β‐receptors were blocked by pronethalol.

The pharmacology of 5-(2-t-butylamino-1-hydroxyethyl) salicylamide (AH 3474), a β-adrenoreceptor blocking agent

AH 3474 is a specific β‐adrenoreceptor antagonist, devoid of stimulant activity. When given by mouth to conscious guinea‐pigs and dogs, AH3474 and propranolol are equiactive in antagonizing isoprenaline‐induced tachycardia. In anaesthetized animals AH 3474 was 2–4 times less active than propranolol when given intravenously. A similar potency ratio was found in volunteer studies in which the drug was taken orally. On isolated tissues AH 3474 was much less active than propranolol. AH 3474 had 1/10th the activity of propranolol in blocking the inhibitory action of isoprenaline on the rat uterus and was at least 100 times less active in antagonizing the tachycardia induced by adrenaline on the guinea‐pig atria. In vitro, equilibrium conditions for AH 3474 were obtained in 15 min, whereas 45 min were required for propranolol. AH 3474 antagonized the cardiac arrhythmias induced by ouabain in the anaesthetized dog. The amount required far exceeded the β‐adrenoreceptor blocking dose. AH 3474 possessed no “quinidine‐like” actions on cardiac muscle of dog or guinea‐pig. The local anaesthetic activity of AH 3474 was 400 times less than that of propranolol.

The response of an isolated artery to sympathomimetic amines

The rabbit ear central artery preparation responded with contractions to noradrenaline, dopamine, tyramine, octopamine, phenylethylamine, β‐phenylethanolamine and periarterial sympathetic nerve stimulation. Noradrenaline, dopamine and nervous stimulation gave monophasic responses. Tyramine and octopamine gave biphasic responses consisting of an initial fast contraction followed by a second contraction of slow onset and long duration. Phenylethylamine and phenylethanolamine also gave biphasic responses, but the second contraction was of quick onset and short duration of action and often merged with the first contraction. Cocaine, superior cervical ganglionectomy and reserpinization reduced the second phase of the contraction to tyramine, octopamine and phenylethylamine. The second phase of the response to phenylethanolamine was reduced by reserpine but not by cocaine or denervation.