Central Sympathoinhibition Research Articles

A comparison of the effects of doxazosin and alfuzosin with those of urapidil on preganglionic symphathetic nerve activity in anaesthetised cats

Preganglionic sympathetic nerve activity, blood pressure, heart rate and femoral arterial conductance were recorded in anaesthetised, paralysed cats. Urapidil, doxazosin and alfuzosin were infused i.v. for 1 h into different animals at the rate of 2 mg kg −1 h −1. All three drugs caused a fall in thoracic preganglionic sympathetic nerve activity along with blood pressure. Although urapidil had a greater hypotensive action than doxazosin and alfuzosin its sympathoinhibitory action was delayed and weaker. Since all three drugs are α 1-adrenoceptor antagonists it appears that antagonism at this receptor type may cause central sympathoinhibition as well as a decrease in total peripheral resistance. However, the different effects of urapidil suggest that its action on central sympathetic tone and therefore its hypotensive action cannot be due entirely to its ability to block α 1-adrenoceptors.

A quantitative assessment of CNS sympatho-inhibition produced by psychotropic drugs

As one index of sympathetic reactivity, electrodermal responses (EDR) were evoked from central (hypothalamic) and peripheral (ulnar nerve) sites in pentobarbital-anesthetized cats. When compared with intravenous chlorpromazine (ED 50 ∼ 1.0 mg/kg), only thioridazine, trifluoperazine and pimozide were less potent than chlorpromazine in reducing the amplitude of these centrally-evoked sympathetic-cholinergic responses. Perphenazine and methotrimeprazine (a non-neuroleptic phenothiazine) were about twice as potent as chlorpromazine. Haloperidol and triflupromazine were about 5 times as potent and chlorprothixine was more than 10 times as potent. None of these agents reduced the peripherally-evoked electrodermal response, indicating a CNS mode of action. Diazepam was without effect at either site. In addition, pretreatment with yohimbine (0.5 mg/kg, i.v.) did not significantly alter the ED 50 for any of the above drugs. These results demonstrate that all of the phenothiazines and non-phenothiazine neuroleptics tested produced a dose-dependent central sympatho-inhibition and that diazepam does not. The results also suggest that there is no significant correlation between central symphatho-inhibition and the antipsychotic potency of these compounds and that their depression of central sympathetic outflow is independent of α-adrenergic mechanisms in the CNS.

Relation between central sympathoinhibitory and peripheral pre- and postsynaptic alpha-adrenoceptors as evaluated by different clonidine-like substances in rats.

A series of 8 clonidine-like substances were tested in rats on central sympathoinhibition (heart rate decrease in vagotomized rats, D50 = dose which decreased heart rate by 50 beats/min), peripheral postsynaptic activity (blood pressure increase in spinal rats, PD30 = dose which increased blood pressure 30 mm Hg) and peripheral presynaptic activity (inhibition of tachycardia as elicited by electrical stimulation in the spinal canal of pithed rats, ID50 = dose which inhibited for 50%). The D50, PD30 and ID50 were converted in moles/kg and the negative logarithms thereof were correlated. There was a good correlation between the central effect (D50) and both peripheral effects (PD30 and ID50, respectively; r = 0.89 and 0.91, respectively) provided one drug with low lipoid affinity was omitted from calculation (St 600). There was also good correlation between both peripheral effects (PD30 and ID50; r = 0.94) and this could be extended to other imidazolines which are not acting centrally as antihypertensives (oxymetazoline, naphazoline, St 91, tramazoline; r = 0.90). The results were interpreted by (1) the agonistic activity of the clonidine-like drugs mainly at alpha 2-adrenoceptors and (2) the presence of alpha 2-adrenoceptors at peripheral presynaptic, peripheral postsynaptic as well as central cardiovascular sites.