On the mode of action of chlorpromazine on peripheral adrenergic mechanisms

Thoenen, H.; Hürlimann, A.; Haefely, W.

doi:10.1016/0028-3908(65)90031-6

Cited by 26 publications

(10 citation statements)

References 14 publications

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“…Several anecdotal studies reported improved survival of patients with septic shock treated with chlorpromazine in addition to conventional therapy [41][42][43][44][45][46][47]. The beneficial effect of chlorpromazine was attributed to a-adrenergic blockade resulting in improved peripheral perfusion [43,44,48]. The 201 exacerbation of hypotension in patients with septic shock was effectively reversed by fluid-loading and administration of an a-adrenergic agonist [42,44,49].…”

Section: Discussionmentioning

confidence: 99%

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

1986

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Soluble phospholipase A2 has been implicated in the pathogenesis of local and systemic inflammatory reactions. Elevated levels of circulating phospholipase A2 (PLA2) correlate with the severity of circulatory collapse and pulmonary dysfunction in gram-negative septic shock. Characterization of septic shock serum PLA2 revealed a calcium-dependent enzyme with absolute 2-acyl specificity with a pH optimum of 7.5. We tested a number of therapeutic agents for their ability to inhibit PLA2 from human septic shock serum. Chloroquine, chlorpromazine, dexamethasone base, dexamethasone sodium phosphate, indomethacin, lidocaine, oleic acid, palmitic acid, promethazine, trans-retinoic acid, rutin and dl-alpha-tocopherol were all studied over the range of 10(-2) to 10(-7) M. All agents, with the sole exception of dexamethasone base, inhibited PLA2 activity at concentrations greater than 10(-3) M. PLA2 inhibition by dexamethasone sodium phosphate was factitious, due to the formation of calcium-phosphate complexes. Of the 11 agents studied, chlorpromazine was the most effective, with an IC50 of 7.5 X 10(-5) M, a membrane concentration achievable within its therapeutic range. Inhibition was non-competitive with an apparent Ki of 5 nM. Since serum PLA2 levels correlate with mortality in both experimental endotoxemia and clinical gram-negative septic shock, and chlorpromazine was previously shown to improve survival in these conditions, we postulate that its therapeutic efficacy resides at least in part in its PLA2-inhibitory activity.

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Section: Discussionmentioning

confidence: 99%

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

1986

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“…In our experiments with anaesthetized rats the chlorpromazine-induced blockade of the pressor response to hypothalamic stimulation, which has also been reported by Schmitt (1966), paralleled a marked inhibition of the noradrenaline pressor effect. An adrenergic blocking activity of chlorpromazine has been demonstrated in the cat by the inhibition of the nictitating membrane contraction following cervical sympathetic stimulation (Thoenen, Hurlimann & Haefely, 1965), whereas it had been denied by Jourdan, Duchene-Marullaz & Boissier (1955) because it lacks activity against the responses to cervical sympathetic stimulation in dogs and rabbits. In the rat also we failed to obtain consistent inhibition of the eyelid response to stimulation of the superior cervical sympathetic nerve, in contrast to the inhibition of the response to hypothalamic stimulation.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological modifications of sympathetic responses elicited by hypothalamic stimulation in the rat

C¹

1968

British J Pharmacology

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1. The rise in blood pressure and the eyelid contractions elicited by electrical stimulation of the posterior hypothalamus in anaesthetized rats were studied for the assessment of drug effects on the sympathetic system. They were compared with the noradrenaline pressor effect and eyelid responses to cervical sympathetic nerve stimulation. 2. Phentolamine caused a similar reduction of the pressor responses induced by hypothalamic stimulation and by noradrenaline. It also reduced the eyelid contractions elicited by central and by peripheral electrical stimulation. 3. Guanethidine caused an immediate inhibition of the pressor response to hypothalamic stimulation, while it potentiated noradrenaline effects. Eyelid contractions elicited both by central and by peripheral electrical stimulation were inhibited. 4. Chlorpromazine inhibited the pressor responses both to hypothalamic stimulation and to noradrenaline, but it caused a much greater reduction in the centrally evoked eyelid responses than in those due to peripheral stimulation. 5. Diazepam caused a reduction of sympathetic responses to central stimulation but not to peripherally elicited responses. 6. In unanaesthetized rats the rise in blood pressure induced by hypothalamic stimulation was accompanied by increased locomotor activity culminating in a flight reaction. In contrast to the pressor effect, which was reduced by all four of the above-mentioned drugs, the flight reaction was not affected by phentolamine and guanethidine and only delayed by chlorpromazine and diazepam at dose levels which impaired the spontaneous locomotor activity.In a preliminary paper (Morpurgo & Morillo, 1962) we suggested that the simultaneous recording of different sympathetic responses elicited by hypothalamic sLimulation would provide a better procedure for the evaluation of drugs acting on the autonomic nervous system than procedures involving the stimulation of single organs.

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“…However, in a recent study, Feigenbaum & Yanai (1985) (Arbilla et al, 1978;Bartholini et al, 1976) and peripheral nervous system (Thoenen et al, 1965;Hope et al 1978). This antagonistic action of neuroleptics could induce hypothermia by promoting vasodilatation.…”

Section: Discussionmentioning

confidence: 99%

“…Some neuroleptics possess adrenoceptor blocking properties (Thoenen et al, 1965;Bartholini et al, 1976) which could be responsible for the induction of the hypothermia. Hence, the effects of an ac-adrenoceptor agonist on this hypothermia were investigated.…”

Section: Introductionmentioning

confidence: 99%

Neuroleptic‐induced hypothermia in mice: lack of evidence for a central mechanism

Boschi

Launay

Rips

1987

British J Pharmacology

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1 The present study investigated the ability of neuroleptic drugs to induce hypothermia in mice when they were administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.). 2 Twelve neuroleptics belonging to five chemical classes including phenothiazines, butyrophenones, benzamides, thioxanthenes and diphenylbutylpiperidines were injected i.p. All of them, except benzamides, induced a dose-dependent decrease in rectal temperature. 3 Neuroleptics were administered i.c.v. via cannulae previously implanted in mice to determine whether this response might have a central origin. None of the drugs tested induced hypothermia at doses which did not produce toxic effects. These negative results suggest that neuroleptics act to elicit hypothermia via a peripheral, rather than a central mechanism. 4 Since some neuroleptics possess a-adrenolytic properties which could induce hypothermia by promoting vasodilatation, we attempted to antagonize the hypothermia produced by peripheral administration of two neuroleptics with phenylephrine, an a-adrenoceptor agonist that does not cross the blood-brain barrier. The hypothermia induced by both chlorpromazine and haloperidol was attenuated by phenylephrine, supporting the view that peripheral a-adrenoceptors may mediate neuroleptic-induced hypothermia.

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On the mode of action of chlorpromazine on peripheral adrenergic mechanisms

Cited by 26 publications

References 14 publications

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

Pharmacological modifications of sympathetic responses elicited by hypothalamic stimulation in the rat

Neuroleptic‐induced hypothermia in mice: lack of evidence for a central mechanism

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