Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents.

Abstract

SUMMARY This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, hi addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate tbe release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic a-adrenoceptors reduces this release of transmitter and tbe reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic aradrenoceptors that mediate the responses of certain organs and the presynaptic aradrenoceptors that modulate the NE release during nerve stimulation. Therefore, subdassification of a-adrenoceptors into a, and a, subtypes is warranted but must be considered to be independent of the anatomical location of these receptors.Some noradrenergic nerve endings have also been shown to possess /3-adrenergic receptors, tbe stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinepbrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the Inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransraission and the subdassification of a-adrenoceptors to tbe treatment of hypertension is presented. Gonidtne, for example, appears to be a potent aradrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an a,-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic aradrenoceptors, which might contribute to its cardiovascular action.The antihypertensive effects of a-methyldopa are related to tbe formation of a-methylnorepinephrine, a preferential a r adrenoceptor agonist, which can stimulate peripheral presynaptic aradrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone.

Efeitos hemodinâmicos e renais da injeção de doses elevadas de clonidina no espaço peridural do cão

“…This may be explained by the activation of a 2 -pre-synaptic adrenoreceptors of peripheral nervous terminations with decreased norepinephrine exocytosis, and by clonidine sympatholytic effect on central nervous system 15 . Clonidine decreases discharges in splancnic nerve sympathetic pre-ganglionic fibers as well as in cardiac nerves post-ganglionic fibers 16 . On the other hand, it stimulates parasympathetic flow, which may contribute to decrease heart rate as a consequence of vagal tone increase, as well as to decrease sympathetic impulse 16 .…”

“…Clonidine decreases discharges in splancnic nerve sympathetic pre-ganglionic fibers as well as in cardiac nerves post-ganglionic fibers 16 . On the other hand, it stimulates parasympathetic flow, which may contribute to decrease heart rate as a consequence of vagal tone increase, as well as to decrease sympathetic impulse 16 . Clonidine-induced heart rate decrease seems to be also promoted by activation of imidazoline receptors located in the nucleus reticularis, probably in nucleus tractus solitarius 17 .…”

“…Esta ação pode ser explicada pela ativação dos adrenoceptores a 2 pré-sinápticos das terminações nervosas periféricas, com redução da exocitose da noradrenalina, e pelo efeito simpaticolítico da clonidina sobre o sistema nervoso central 15 . Aclonidina diminui as descargas nas fibras pré-ganglionares simpáticas do nervo esplâncnico, bem como nas fibras pós-ganglionares dos nervos cardíacos 16 . Por outro lado, estimula o fluxo parassimpático, o que pode contribuir para a redução da freqüência cardíaca, como conseqüência do aumento do tônus vagal, bem como para a redução do impulso simpático 16 .…”

“…Aclonidina diminui as descargas nas fibras pré-ganglionares simpáticas do nervo esplâncnico, bem como nas fibras pós-ganglionares dos nervos cardíacos 16 . Por outro lado, estimula o fluxo parassimpático, o que pode contribuir para a redução da freqüência cardíaca, como conseqüência do aumento do tônus vagal, bem como para a redução do impulso simpático 16 . A diminuição da freqüência cardíaca ocasionada pela clonidina parece ser causada também pela ativação dos receptores imidazolínicos situados no núcleo reticular, provavelmente no núcleo do trato solitário 17 .…”

Comparação dos efeitos do sufentanil e da clonidina administrados por via endovenosa para sedação em pacientes submetidos a cateterismo cardíaco

“…Após a administração da clonidina, observa-se uma redução das descargas pós-ganglionares nos nervos cardíacos e uma estimulação do fluxo parassimpático, com consequente aumento do tono vagal e redução da frequência cardíaca (LANGER et al, 1980).…”