G.P. Levy

Salbutamol: a new, selective β-adrenoceptive receptor stimulant

1 Salbutamol is a β‐adrenoceptive receptor stimulant. Its pharmacological actions are reduced or abolished by β‐receptor antagonists. 2 In anaesthetized animals, salbutamol, given intravenously, was slightly less active than isoprenaline in preventing spasm of bronchial smooth muscle but was considerably less active as a cardiac stimulant and vasodepressor substance. Its duration of action was about 2 to 3 times that of isoprenaline. 3 Salbutamol given by mouth or aerosol to conscious guinea‐pigs, greatly diminished bronchospasm caused by inhalation of acetylcholine. By mouth, salbutamol was more active and had a longer duration than isoprenaline or orciprenaline without affecting heart rate. By aerosol, salbutamol was approximately 10 times as active as isoprenaline and 100 times as active as orciprenaline. Its duration of action was much longer than that of isoprenaline or orciprenaline. Only isoprenaline produced an increase in heart rate by the aerosol route. 4 On isolated guinea‐pig trachea salbutamol had about 1/10 the activity of isoprenaline, on isolated atria about 1/2000.

RECEPTORS FOR 5-HYDROXYTRYPTAMINE AND NORADRENALINE IN RABBIT ISOLATED EAR ARTERY AND AORTA

1 5‐Hydroxytryptamine (5‐HT) is thought to be implicated in the vascular disturbances of the external carotid artery bed associated with migraine. As part of a study of the pharmacology of some 5‐HT antagonists used in the treatment of migraine we have examined the interactions of these drugs with 5‐HT and noradrenaline in rabbit isolated ear artery and aortic strip. The results provide new information on the distribution of 5‐HT‐receptors and α‐receptors in these preparations. 2 In the aorta, 5‐HT and noradrenaline were of similar potency in producing contractions. Methysergide produced very small contractions and was about 1000 times less potent than the other two agonists. 3 In the ear artery noradrenaline produced monophasic vasoconstrictor responses, whereas 5‐HT and methysergide produced prolonged biphasic responses. 5‐HT was about 700 times less potent and methysergide about 4500 times less potent than noradrenaline. Methysergide was a better agonist in the ear artery than in the aorta. Biphasic responses to 5‐HT and methysergide were also obtained in ear arteries from reserpine‐treated rabbits indicating that neither agonist was acting by releasing endogenous noradrenaline. 4 Pizotifen, cyproheptadine and phentolamine had no agonistic actions in either the aorta or ear artery. 5 In the aorta methysergide, pizotifen and cyproheptadine were potent antagonists of 5‐HT and much weaker antagonists of noradrenaline. Phentolamine possessed the opposite profile of selectivity. These results show that there are distinct receptors for 5‐HT and noradrenaline in rabbit aorta. 6 In the ear artery the pA2 values for each of the four antagonists were virtually identical against 5‐HT and noradrenaline and similar to those obtained on α‐adrenoceptors in the aorta. We conclude that 5‐HT and noradrenaline act directly at α‐receptors to produce vasoconstriction in the ear artery and that this preparation does not contain specific 5‐HT‐receptors. 7 This insight into the distribution of 5‐HT‐receptors and α‐receptors allows interpretation of the various actions of methysergide. In the aorta, methysergide was a potent antagonist at 5‐HT‐receptors and a weak partial agonist at α‐receptors. In the ear artery, methysergide was a partial agonist at α‐receptors; it was only a weak antagonist of 5‐HT because this preparation does not contain specific 5‐HT‐receptors. 8 The cross‐reactivity demonstrated throughout these experiments indicates that 5‐HT‐receptors and α‐receptors, although distinct entities, have features in common. 9 These results are discussed in relation to the mode of action of methysergide, pizotifen and cyproheptadine in the treatment of migraine.

Evidence for two types of excitatory receptor for 5-hydroxytryptamine in dog isolated vasculature

1 As part of an investigation into the mode of action of anti‐migraine drugs, a study of the excitatory receptors for 5‐hydroxytryptamine (5‐HT) has been carried out in a range of isolated vascular preparations from the dog. 2 5‐HT contracted the dog isolated femoral artery and saphenous vein over the concentration‐range 1.0 × 10−8to 5.0 × 10−6mol/l. 3 In the femoral artery methysergide and cyproheptadine were potent, competitive and specific antagonists of the contractile responses to 5‐HT, with pA2 values of 8.52 and 8.55 respectively. 4 In the saphenous vein, methysergide was only a weak antagonist of 5‐HT. In addition, it was an agonist over the concentration‐range 5.0 × 10−8to 1.0 × 10−5mol/l. Cyproheptadine was a weak and unsurmountable antagonist of contractile responses to 5‐HT and methysergide. 5 Contractile responses to 5‐HT and methysergide in the saphenous vein were not antagonized by morphine (3.0 × 10−5mol/l), indomethacin (5.0 × 10−5mol/l), phentolamine (5.0 × 10−7mol/l), propranolol (1.0 × 10−6mol/l), atropine (1.0 × 10−6mol/l), mepyramine (1.0 × 10−6mol/l) or cimetidine (1.0 × 10−5mol/l). 6 In the external carotid and lingual arteries the pattern of activity obtained with methysergide and cyproheptadine was the same as that in the femoral artery, while in the auricular artery the pattern of activity was the same as that in the saphenous vein. 7 The results are consistent with the hypothesis that there are two types of receptor mediating 5‐HT‐induced vasoconstriction in dog vasculature. One type, characterized by the pattern of activity obtained in the femoral artery, is like the previously described ‘D‐receptor’. The other type, characterized by the pattern of activity obtained in the saphenous vein, has not been described before. The verification of this hypothesis requires the identification of a specific antagonist of 5‐HT and methysergide in the saphenous vein.

A non-adrenergic inhibitory nervous pathway in guinea-pig trachea.

1 Electrical stimulation of the guinea‐pig isolated tracheal tube causes a biphasic response, initially excitatory and then inhibitory. The excitatory response was abolished by atropine leaving the inhibitory response unaffected. 2 The inhibitory response was greatly reduced but not abolished by propranolol or guanethidine. A residual inhibitory response was still present in tracheas in which sympathetic nerve function had been abolished by pretreatment with syrosingopine or 6‐hydroxydopamine. These results show that the inhibitory response is predominantly adrenergic but that a small non‐adrenergic component is also present. 3 The non‐adrenergic inhibitory response was abolished by lignocaine and tetrodotoxin suggesting that it is nervous in origin. 4 Optimal stimulation parameters for the predominantly adrenergic inhibitory response were a pulse width of 0.7–2 ms, a stimulation period of 7 s and a frequency of 20 Hz. For the non‐adrenergic inhibitory response, optimal stimulation parameters were a pulse width of 2 ms, a stimulation period of 12 s and a frequency of 20 Hz. 5 Evidence obtained with pharmacological antagonists, enzyme inhibitors and activators suggested that the transmitter mediating the non‐adrenergic inhibitory nervous response is unlikely to be: acetylcholine, histamine, 5‐hydroxytryptamine, cyclic 3′,5′‐adenosine monophosphate or a prostaglandin. 6 The adenosine uptake blocking drugs dipyridamole, hexobendine and Dilazep potentiated the non‐adrenergic inhibitory nervous response and unmasked inhibitory responses to adenosine and adenosine 5′‐triphosphate. 7 It is concluded that electrical stimulation of the guinea‐pig trachea, in addition to activating cholinergic and adrenergic nervous pathways, may activate a separate and distinct inhibitory nervous pathway. This pathway has some features in common with the non‐adrenergic non‐cholinergic inhibitory pathways in gastro‐intestinal muscle.

THE α‐ AND β‐ADRENOCEPTOR BLOCKING POTENCIES OF LABETALOL AND ITS INDIVIDUAL STEREOISOMERS IN ANAESTHETIZED DOGS AND IN ISOLATED TISSUES

1 The antagonist potencies of labetalol and each of its four stereoisomers have been compared at α1‐, β1‐ and β2‐adrenoceptors in anaesthetized dogs and in isolated tissues. 2 The RR stereoisomer is a potent, non‐selective antagonist at β‐adrenoceptors but has only weak α1‐adrenoceptor blocking activity. 3 The SR stereoisomer was the most potent antagonist at α1‐adrenoceptors, and it also had similar potency as an antagonist at β‐adrenoceptors. 4 The α‐ and β‐adrenoceptor blocking profile of the RS stereoisomer is intermediate between that of the RR and SR, but the SS stereoisomer is a relatively weak antagonist at both α‐ and β‐adrenoceptors. 5 It is concluded that, although most of the α1‐adrenoceptor blocking activity of labetalol is attributable to the SR stereoisomer and nearly all of its β‐adrenoceptor blocking activity resides in the RR stereoisomer, each of the stereoisomers contributes to the overall pharmacological profile of labetalol.

A comparison of some cardiovascular properties of propranolol, MJ 1999 and quinidine in relation to their effects in hypertensive animals

1 A comparison of some cardiovascular effects of propranolol, MJ 1999 and quinidine has been made in rats and dogs. 2 After intravenous, subcutaneous or oral administration to rats and dogs, propranolol was found to be 2–4 times more potent than MJ 1999 in blocking the chronotropic and vasodepressor responses to intravenously administered isoprenaline. 3 Propranolol and quinidine affected the e.c.g. of rats and dogs in a similar manner. 4 At dose‐levels causing effective blockade of β‐receptors propranolol and MJ 1999 had no hypotensive effect after short‐ or long‐term administration to conscious hypertensive rats and dogs. 5 At very high dose‐levels propranolol and quinidine, but not MJ 1999, lowered blood pressure in the hypertensive rat. This effect of propranolol is probably related to one or more of the properties that propranolol and quinidine have in common rather than to a blockade of β‐receptors. 6 The possible relevance of these results to the use of propranolol as a hypotensive agent in man is discussed.

COMBINED α‐ AND β‐ADRENOCEPTOR BLOCKING DRUG AH 5158: FURTHER STUDIES ON α‐ADRENOCEPTOR BLOCKADE IN ANAESTHETIZED ANIMALS

1 AH 5158, 5‐[1‐hydroxy‐2‐[(1‐methyl‐3‐phenylpropyl)amino]ethyl]salicylamide, competitively antagonised phenylephrine‐induced vasopressor responses in anaesthetized dogs, thus confirming that the drug possesses α‐adrenoceptor blocking activity. 2 In contrast, AH 5158 was a relatively ineffective antagonist of vasopressor responses to noradrenaline in anaesthetized dogs. Thus, at the lowest dose‐level tested (1 mg/kg) AH 5158 abolished the increase in pulse width caused by noradrenaline, but otherwise had little or no blocking effect in doses as high as 10 mg/kg. Propranolol (0.1 mg/kg) also abolished the increase in pulse width caused by noradrenaline. With both drugs this effect is thought to be a consequence of blockade of the β‐adrenoceptor‐mediated cardiac stimulant action of noradrenaline. 3 The interaction between AH 5158 and noradrenaline in spinal dogs, anaesthetized cats and pithed rats was very similar to that seen in anaesthetized dogs. 4 Noradrenaline pressor responses were effectively antagonized by AH 5158 in anaesthetized dogs pretreated with cocaine. The degree of block was similar to that obtained when phenylephrine was the agonist in untreated dogs. 5 These results are consistent with the hypothesis that AH 5158 blocks a cocaine‐sensitive inactivation process for noradrenaline in addition to blocking α‐ and β‐adrenoceptors. The resultant increase in the level of circulating noradrenaline would tend to counteract the adrenoceptor blocking action of the drug. 6 The implications of these findings are discussed.

Effect of labetalol on the uptake of [3H]-(-)-noradrenaline into the isolated vas deferens of the rat.

1 The effects of the combined a‐ and, B‐adrenoceptor blocking drug, labetalol, on the uptake of [3H]4‐)‐noradrenaline into the isolated vas deferens of the rat have been determined and compared with those of some other ca‐adrenoceptor blocking drugs and cocaine. 2 Labetalol, like cocaine, produced a simple competitive inhibition of [3H]‐(‐)‐noradrenaline uptake and was about 4 times less potent than cocaine. It is concluded that labetalol is a potent inhibitor of uptake1. Phentolamine and thymoxamine also inhibited [3H]‐(‐)‐noradrenaline uptake, and were respectively 8 and 14 times less potent than cocaine. Tolazoline, piperoxan and yohimbine were inactive in concentrations up to 30 ig/ml. 3 The uptake1 blocking action of labetalol could explain, at least in part, the previously reported difference in its ability to block noradrenaline and phenylephrine vasopressor responses in the anaesthetized dog. 4 The possibility that uptake1 inhibitory concentrations of labetalol could be present in the blood of subjects receiving normal antihypertensive doses of the drug is discussed.

The Relationships Between the Cardiovascular Effects, α- and β-Adrenoceptor Blocking Actions and Plasma Concentration of Labetalol in Doca Hypertensive Rats

The relationships between the cardiovascular effects, alpha- and beta-adrenoceptor blocking actions and plasma concentration of labetalol have been examined in conscious DOCA hypertensive rats. Labetalol (10, 30 and 100 mg/kg p.o.) reduced resting heart rate; blood pressure was reduced only by the two higher doses. The effects lasted 5-24 hours. There was a highly significant correlation between the plasma labetalol concentration and its cardiovascular effects. During the labetalol-induced hypotension and bradycardia the vasopressor responses to intra-arterial injections of phenylephrine were reduced; the tachycardia and vasodepressor responses produced by intra-arterial injections of isoprenaline were also reduced. It is concluded that alpha- and beta-adrenoceptor blockade probably account for the labetalol-induced decreases in resting blood pressure and heart rate respectively.