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AN INVESTIGATION OF THE ADRENERGIC BLOCKING ACTION OF CHLORPROMAZINE.

Antagonism by chlorpromazine of the responses of the rabbit aortic strip and the rat seminal vesicle to adrenaline and noradrenaline fulfils the conditions of competitive antagonism. Chlorpromazine was a remarkably potent antagonist (pA(2) approximately 14) of adrenaline and noradrenaline. In the cat anaesthetized with chloralose small doses (1.8 to 4.5 mg/kg) of chlorpromazine greatly reduced or reversed the pressor effect of adrenaline but the pressor effect of noradrenaline was unaffected. A larger dose (9 mg/kg) of chlorpromazine slightly reduced the pressor effect of noradrenaline but caused a spectacular reversal of the pressor effect of adrenaline. This difference was not observed in rabbits and in cats treated with dichloroisoprenaline. Chlorpromazine potentiated the depressor effect of isoprenaline. On the basis of these findings it is concluded that in the cat chlorpromazine in small doses (1.8 to 4.5 mg/kg) has no real adrenergic blocking action and that the selective block of adrenaline pressor effects by these doses is due to a potentiation of adrenergic vasodilatation. Large doses (7.2 to 28.8 mg/kg) of chlorpromazine reduced the pressor effect of noradrenaline; reciprocal analysis showed that this inhibition is competitive.

Adrenergic Agents↗

THE MECHANISM OF THE DEPRESSOR ACTION OF NORADRENALINE IN THE CAT.

In cats anaesthetized with pentobarbitone sodium or chloralose and injected with phenoxybenzamine or phentolamine, administration of (-)-noradrenaline (5 to 20 mug) produced a fall of blood pressure which resembled in onset and duration that produced by adrenaline under similar conditions. The depressor action of noradrenaline was due mainly to dilatation of the splanchnic blood vessels. This could be abolished by administration of pronethalol, a drug known to block sympathetic beta-receptors.

Blood Pressure↗

MODIFICATION OF THE EFFECTS OF GUANETHIDINE ON CARDIAC CATECHOL AMINES BY VARIOUS AGENTS.

A study has been made of the effect of injections of guanethidine in rats, in depleting catechol amines from the whole cardiac ventricles and from various subcellular fractions. Unlike reserpine, guanethidine first affected the concentration of the amines in the soluble fraction of the cell. Neither [2-(2,6-dimethylphenoxy)-propyl]trimethylammonium chloride monohydrate (beta-methyl xylocholine) nor hemicholinium affected the endogenous catechol amines or the uptake of injected noradrenaline, but each significantly reduced the action of guanethidine in depleting catechol amines. Administration of choline chloride after hemicholinium reversed its influence on guanethidine depletion. In cats, cocaine potentiated the pressor response to noradrenaline, but antagonized the response to tyramine and guanethidine, while bretylium and N-o-chlorobenzyl-N'N"-dimethylguanidine sulphate (BW392C60) potentiated the responses to noradrenaline, tyramine and guanethidine.

Amines↗

SOME PHARMACOLOGICAL PROPERTIES OF THIOPROPERAZINE AND THEIR MODIFICATION BY ANTI-PARKINSONIAN DRUGS.

The pharmacological properties of a phenothiazine derivative thioproperazine have been compared with those of chlorpromazine, and the modifications by some anti-Parkinsonian drugs of its actions on the central nervous system have been studied. Thioproperazine was less potent than chlorpromazine in lowering blood pressure and antagonizing adrenaline in the cat, in depressing respiratory rate in the rabbit, in producing hypothermia and analgesia and in reducing the minimum anaesthetic dose of hexobarbitone in mice, and in protecting rats from convulsions induced by tryptamine. It was roughly equipotent to chlorpromazine in reducing locomotor activity of mice. Thioproperazine was more potent than chlorpromazine in protecting grouped mice from the acute toxicity of dexamphetamine, in preventing the acute behavioural disturbances produced by dexamphetamine in the rat, in producing a state of experimental catatonia in the rat and in preventing the emetic action of apomorphine in the dog. Hyoscine, benztropine or promethazine greatly reduced the ability of thioproperazine to prevent behavioural changes due to dexamphetamine in the rat and also abolished symptoms of experimental catatonia produced by thioproperazine. In contrast, the antiapomorphine activity of thioproperazine in the dog was not reduced to any extent by hyoscine or benztropine.

Anesthetics↗

THE PRESERVATION OF BRADYKININ BY PHENOTHIAZINES IN VITRO.

Chlorpromazine and phenoxybenzamine have been shown to potentiate the actions of bradykinin in vivo. To test whether this phenomenon could be due to inhibition of the enzymatic destruction of bradykinin, bradykinin was incubated with either tissue extracts or with carboxypeptidase B. Bradykinin was rapidly destroyed by acetonedried powders of brain and serum of various animals as well as by purified carboxypeptidase B. The rate of disappearance of bradykinin activity was decreased in the presence of phenothiazine derivatives, phenoxybenzamine and hydroxyzine, but not by compounds of a larger group including other psychotropic drugs, tranquillizers and ganglionic and adrenergic blocking agents. Spectrophotometric studies of the hydrolysis of hippuryl-L-arginine confirmed the presence of a carboxypeptidase B-like activity in brain. The substances that acted as inhibitors of bradykinin destruction were also enzyme inhibitors as measured by this technique. Previous incubation of carboxypeptidase B with phenothiazines and zinc ions greatly reduced the enzymatic inhibition by the phenothiazines, which indicated a possible chelating action by these inhibitors on the metalo-enzyme carboxypeptidase B.

Animals↗

COMPARISON OF THE EFFECTS OF BRETYLIUM, GUANETHIDINE AND BETHANIDINE ON SMOOTH MUSCLE RESPONSES TO DIFFERENT RATES OF SYMPATHETIC NERVE STIMULATION.

The relative effects of bretylium, guanethidine and bethanidine on smooth muscle responses to different rates of sympathetic nerve stimulation have been compared. The responses studied were vasoconstriction in the femoral vascular bed and contraction of the spleen in anaesthetized cats, vasoconstriction in perfused ears of rabbits and inhibition of pendular movements in rabbit isolated ileum preparations. Except in the isolated ileum, the action of bretylium on curves relating the frequency of nerve stimulation and the effect on response was different from that of guanethidine. Whereas bretylium caused relatively greater inhibition of responses to high stimulus frequencies and depressed the slopes of the curves, guanethidine preferentially suppressed responses to low stimulus frequencies and caused roughly parallel shifts of the curves. In each situation tested bethanidine was the most potent of the three blocking agents and in general its effect on frequency/response curves was intermediate between those of bretylium and guanethidine.

Animals↗