The possibility that clonidine might exert some of its effects via opiate or histamine H2 receptors has been suggested from observations in animals and man. We undertook a double-blind, randomized study in six normal subjects, comparing the effects of 0.2 mg intravenous clonidine after pretreatment with 300 mg cimetidine, 0.8 mg naloxone, and saline. There was no attenuation of the hypotension, bradycardia, sedation, inhibition of salivary flow, or reduction in plasma catecholamines after cimetidine and naloxone, but the fall in plasma catecholamines ater clonidine correlated with blood pressure, sedation, and salivary flow, suggesting a central adrenergic mechanism for these effects. It is not known whether cimetidine can cross the blood-brain barrier after short-term dosing. We conclude that in normotensive subjects the short-term effects of intravenous clonidine are probably not mediated by an action at peripheral histamine H2 or central opiate receptors.

1 Changes in mean arterial pressure, heart rate and plasma noradrenaline after a-adrenoceptor blockade with several a-adrenoceptor antagonists have been studied in the conscious rabbit in order to investigate the possible role of presynaptic cx-adrenoceptors in cardiovascular regulation. 2 Prazosin (0.05-2 mg/kg) and phentolamine (0.5-20 mg/kg) produced dose-dependent falls in mean arterial pressure and rises in plasma noradrenaline. These changes were related to the degree of postsynaptic a-adrenoceptor blockade determined by the pressor response to intravenous phenylephrine. 3 Similar changes in mean arterial pressure and plasma noradrenaline were observed after administration of the direct vasodilators hydralazine (1-10 mg/kg) and nitroprusside (2.5 -55 g kg Imin ).4 After baroreceptor deafferentation by sinoaortic denervation the falls in mean arterial pressure were much greater and the rise in plasma noradrenaline was markedly attenuated. 5 Yohimbine (1 mg/kg) increased mean arterial pressure and plasma noradrenaline but it was not possible to exclude the possibility that central nervous effects of yohimbine underlay the increased sympathetic activity. 6 The magnitude of the baroreflex response to changes in pressure make it unlikely that the functional significance of the presynaptic a-adrenoceptor can be readily determined by measurement of plasma noradrenaline in intact animals.

1. Guanfacine (2-6 mg/day) a centrally acting antihypertensive drug, was effective in controlling blood pressure in 5 essential hypertensives and lowered plasma noradrenaline and urinary catecholamine excretion. 2. Withdrawal of guanfacine by blind substitution of identical placebo tablets under observation in hospital led to a gradual recovery of blood pressure over 2-4 days. 3. Salivary flow, which was reduced on guanfacine, returned to pretreatment levels by 2 days after withdrawal and significantly exceeded control for the next two days. 4. Urinary catecholamine excretion returned to pretreatment levels by 3 days but did not exceed control levels during the period of study. 5. Plasma noradrenaline returned gradually to pretreatment levels, and by day 4 significantly exceeded them. 6. No patient experienced symptoms suggesting catecholamine excess although four out of five reported a headache from the second day onwards. 7. Guanfacine, a centrally acting drug which pharmacologically resembles clonidine, has a slow offset of hypotensive effect over 2-3 days. Symptoms or biochemical evidence of catecholamine excess were not encountered within 48 h of withdrawal, possibly reflecting the longer duration of action and plasma half-life of guanfacine.

1Guanfacine 3-6 mg daily lowered blood pressure in five essential hypertensives and also reduced saliva production. 2 Plasma and urinary noradrenaline values were significantly reduced throughout the 8-10 weeks of treatment.3 On substitution of placebo tablets for guanfacine, blood pressure increased over a 2-4d period to reach but did not significantly exceed pretreatment levels. 4 After withdrawal of guanfacine plasma noradrenaline standing was significantly higher than the pretreatment level (P < 0.05) after 4 days. Saliva production was significantly higher than the pretreatment level on day 3 and day 4 of withdrawal. 5Guanfacine is an effective antihypertensive drug with a spectrum of actions similar to clonidine.However, in abrupt withdrawal blood pressure returned to the pretreatment level over a 2-4d period.