Adrenolytic action

In addition to its adrenergic neurone blocking activity (see p. 156) guanoxan has been shown [463] to have a protracted a-adrenolytic action in cats and dogs. Its resolution has been reported [464] and the two isomers were equipotent adren-... 

The activity spectrum of ergometrine (Fig. 7b) is quite different from that of ergotamine (Fig. 7a). It exerts a marked uterotonic effect, whereas its adrenolytic action is practically insignificant and the central nervous effects are only manifest after high doses. Ergometrine is therefore used mainly in obstetrics. In recent years it has been demonstrated that ergometrine exerts a pronounced antiserotonin effect. 

Levels of phenylethanolamine-N-methyltransferase (PNMT) have been found to be significantly raised in discrete brain stem regions in both SHR and DOCA-salt hypertensive rats.33 Administration of SKF 7698 (7), a PNMT inhibitor, normalized pressure in DOCA rats. The possibility that the effect was due to the adrenolytic action of (7) was not excluded. The best of a new series of PNMT inhibitors with much reduced a-blocking properties is SKF 6 139 (8).3 ... 

Many new phenylpiperazine derivatives with combined neurological and hypotensive properties have been described5 54 gf these, AP 1161 (24), a CNS depressant with weaker adrenolytic action than chlorpromazine but stronger antiserotonin activity has been recommended for clinical trial as a psychotropic drug ... 

Glaucine, bulbocapnine, corydine, and isocorydine all exhibited adrenolytic action in anesthetized cats and rabbits, glaucine having the highest activity. Unlike the other three bases, glaucine showed strong antitussive properties in tolerable doses, and did not cause catalepsy. ... 

The administration of low doses of PCP to rodents induces hyperactivity and stereotypy (Chen et al. 1959 ). The observation that neuroleptics such as chlorpromazine, haloperidol, and pimozide, and adrenolytics such as alpha-methyl paratyrosine antagonize these behavioral effects of PCP suggests that they are mediated by facilitation of central dopaminergic neurotransmission (Murray and Horita 1979). The actions of PCP on central dopaminergic neurotransmission may be similar to amphetamine. A dose of PCP (2.5 mg/kg) in rats, which has no effects when given alone, enhances the behavioral effects of 1 and 3 mg/kg of d-amphetamine (Balster and Chait 1978). PCP, like dopamine, has also been shown to suppress plasma prolactin (Bayorh et al. 1983). However, the firm establishment of an excl usive relationship between dopamine neuro-transmission and PCP effects is difficult because of the prominent interactions of this drug with other neurotransmitter systems. 

Hydrogenation of the double bond in position 9-10 of the lysergic acid moiety results in fundamental changes in the pharmacodynamic action, as a comparison of the activity spectra of ergotamine (Fig. 7a) and dihydroergotamine (Fig. 7c) makes evident. The vasoconstrictor and uterotonic effects of the dihydrogenated derivative have been markedly attenuated, as has the stimulation of central structures, so that these effects are hardly elicited by therapeutic doses. On the other hand the adrenolytic effect and the central inhibition of the vasomotor centers are markedly enhanced. This is manifested clinically in vasodilatation, hypotension, and a certain sedative action. 

Spector and Willoughby - have pointed out that the vascular changes in the acute inflammatory reaction may be due to the destruction of local vasoconstrictor substances such as adrenaline. Evidence in favour of this mechanism includes the observation that increased capillary permeability after thermal injury is suppressed by iproniazid and other monoamine oxidase inhibitors. Such inhibitors are known to inhibit the conversion of adrenaline, noradrenaline, 5-hydroxytryptamine and other amines to inactive metabolites. The authors provide evidence that the action of the monoamine oxidase inhibitors on capillary permeability is dependent on their anti-enzymic activity and not on some other unrelated property. Nevertheless, the evidence remains indirect an attempt to detect pressor amines in the plasma of burned animals was unsuccessful. The potentiating effect of bretylium and the antagonistic action of an adrenolytic substance, dibenamine, on the action of iproniazid suggest that it is local depots of adrenaline rather than noradrenaline or 5-hydroxytryptamine which are involved. Independent support for this suggested role of catecholamines... 

Rothlin and Hamet have studied the action of gambirine on the isolated rabbit uterus chiefly with respect to its adrenolytic activity. Gambirine (1 500,000) exerts a stimulating action on this preparation, augmenting tonus as well as frequency and amplitude of rhythmic contractions. This concentration of gambirine reverses the motor effect of epinephrine (209). 

Ketanserin a 5-HT2A antagonist with aj-adrenolytic activity is clinically used as an antihypertensive agent. The precise molecular mechanism of action is still a matter of debate. 

Substitutions in position 8 indicate that the benzene ring of phenylalanine required for pressor activity is not needed for inhibition of uptake. The relative importance of direct and indirect action for vascular smooth-muscle stimulation is not yet known. Indeed, either the pressor response or the vascular contraction in vitro evoked by angiotensin is not blocked by adrenolytic drugs. 

Kienlen (28 ) has stressed the likelihood of potentation with the central-acting analgesics, a loss of hypotensive action in the combination with a-adrenolytics and an antagonistic effect of the combination with neuroleptics. 

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