The hypotensive effect of 2-(5-chloro-2-phenoxyanilino)-2-imidazoline (FR35447)

The hypotensive effect of FR35447 was comparable to that of prazosin and was more potent than that of hydralazine, but its duration of action was shorter. Repeated administration of FR35447 or prazosin to hypertensive rats for 5 consecutive days induced no significant difference in the intensity or duration of the hypotensive effect. In contrast, marked tachyphylaxis to hydralazine or phentolamine was observed. FR35447 as well as prazosin induced only a transient increase in cardiac output in anesthetized dogs, whereas hydralazine induced a longlasting increase. This difference may contribute to no development of tolerance to FR35447 or prazosin. FR35447 decreased the pressor response to noradrenaline, but not that to angiotensin II or vasopressin in pithed rats, which indicates that FR35447 is an alpha-adrenoceptor antagonist. FR35447 has some selectivity for alpha 2-adrenoceptors, but the selectivity was far less than that of yohimbine. Since FR35447 induced only slight hypotension following intracerebroventricular injection in anesthetized cats, the hypotensive effect of the drug does not appear to be mediated through the central nervous system. Whereas prazosin induced a dose-dependent increase in blood glucose in rats, FR35447 showed no significant effect.     

Sleep produced by clonidine (2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride)

1. The dose of clonidine (given intravenously) required to elicit sleep in the young chick is 1/25th to 1/50th of an equiactive dose of noradrenaline. The approximate ED50 is 0.01 mumol/kg. Phentolamine (10-15 mg/kg, but not 5 mg/kg) antagonizes the action of both clonidine and noradrenaline.2. Intensive treatment with p-chlorophenylalnine (700 mg/kg for 3-4 days) does not prevent the hypnotic effect of clonidine in the chick, although brain 5-HT is reduced to 15% of normal. Neither is natural sleep modified.3. Sleep after clonidine is not affected by methysergide (0.1-1 mumol/kg, i.m.), but prevented by LSD (0.1-0.3 mumol/kg). The effect of LSD is interpreted as a physiological antagonism.4. Clonidine (50 mg/kg) injected intravenously into adult rats causes sleep which is not abolished by phentolamine (5 mg/kg) or by p-chlorophenylalanine in doses which interfere with natural sleep.5. When, per kg body weight, the same dose of clonidine is injected into the lateral cerebral ventricle of rats, sleep ensues in more than half the animals, and persistent eating in about a third; only one of seventeen rats showed no change in behaviour. Eating and sleeping remained unaltered after p-chlorophenylalanine. The actual dose of clonidine injected into the lateral ventricle was 0.037 mumol, amounting to about 0.15 mumol/kg or 15 times the dose required intravenously in the chick. Noradrenaline 0.15 mumol per (intraventricular) injection caused eating but no sleep, whereas higher doses produced ataxia and paresis.6. The work suggests that clonidine does not elicit sleep by an action requiring the integrity of the 5-HT-containing neurones arising in the raphé nuclei, and that its action is not on tryptamine receptors. In the chick, sleep appears to be produced by a central sympathomimetic effect; it is possible, but not certain, that this also holds for the rat.7. The intravenous hypnotic dose of clonidine for the cat is about the same as that for the rat, but injection is not accompanied by signs of peripheral sympathetic stimulation.     

Central effects of clonidine 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride in fowls.

1 The effects of clonidine infused into the IIIrd cerebral ventricle, the hypothalamus or intravenously were studied on behaviour, electrocortical activity, body, comb and leg temperatures, respiration and carbon dioxide elimination in adult and young fowls (Gallus domesticus). 2 Behavioural and electrocortical slow wave sleep were induced by clonidine infused into IIIrd cerebral ventricle, the hypothalamus or intravenously. Suprisingly, sleep elicited by intravenous clonidine was much longer-lasting than that induced by an identical dose given intraventricularly. 3 Body temperature was lowered by clonidine given intraventricularly or infused into the hypothalamus. Depending on initial comb temperature and ambient temperature, comb temperature was elevated, unaffected or lowered as body temperature fell; temperature of the unfeathered legs also rose as body temperature declined after clonidine. 4 Following clonidine, but before any considerable decline of body temperature, tachypnoea and wing abduction developed; during recovery of body temperature, the wings were lowered and applied closely to the trunk and the feathers partly erected. 5 CO2 elimination fell more swiftly than body temperature following intrahypothalamic clonidine in young chicks; initial recovery developed sooner than that of body temperature, but eventual recovery was delayed compared to that for body temperature. The effects of clonidine were much more marked in young chicks studied at an ambient temperature below thermoneutrality as compared to thermoneutrality. 6 The soporific effects of clonidine were attenuated by intraventricular phentolamine; its hypothermic effects were prevented by phenoxybenzamine and prevented or attenuated by phentolamine. Intraventricular atropine, haloperidol, methysergide and propranolol were ineffective. 7 Larger doses of intraventricular phentolamine elicited shivering, tachypnoea and wing abduction; body temperature was elevated, to the extent even of lethal hyperthermia. Intraventricular atropine also elevated body temperature. 8 Clonidine infused intravenously, intraventricularly or into the hypothalamus, replaced the behavioural and electrocortical arousal evoked with dexamphetamine, by sleep associated with slow wave electrocortical activity.     

Influence of 2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride on cardio-inhibitory vagal fibres

Neural activity of cardio-inhibitory vagal fibres was recorded in anaesthetized cats. The discharges increased when the blood pressure rose after injection of an alpha-adrenergic substance such a norepinephrine or 2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride (St 91). After transection of the afferent baroreceptor nerves neither norepinephrine nor St 91 influenced neural activity. These findings show that the increase in neural activity is of reflex origin. An influence of St 91 on central parasympathetic structures could not be demonstrated.     

The influence of 2-(2,6-dichlorphenylamino)-2-imidazoline hydrichloride (clonidine) and some related compounds on gastric secretion in the anaesthetized rat

Drugs tested on the anesthetized rat were: clonidine, naphazoline, xylometazoline, tolazoline, and phentolamine. Clonidine, naphazoline, xylometazoline and tolazoline produced a dose dependent stimulation of gastric acid secretion. The effect was probably not related to the influence of these drugs on haemodynamics. Phentolamine did not increase gastric acid secretion.

The increased production of gastric acid was hardly affected by atropine but was considerably reduced after pretreatment with hexamethonium. Only the effect of tolazoline was completely blocked by atropine.

Clonidine was less effective in the anaesthetized guinea pig than in the rat.

Clinidine did not affect gastric secretion in the despinalized (pithed rat). The response to histamine was also markedly reduced.

The stimulatory effect of clonidine and related drugs in the anaesthetized rats is possibly caused by a histamine-like action or by the liberation of histamine. Ganglionic stimulation may also contribute. In conscious animals the decreased gastric secretion resulting from treatment with clonidine is probably of central origin.     

Crystal and molecular structure of 2-[N-allyl-N-(2,6-dichlorophenyl)amino]-2-imidazoline hydrobromide

The structure of 2-[N-Allyl-N-(2,6-dichlorophenyl)amino]-2-imidazoline hydrobromide was determined by X-ray analysis. Compared to clonidine, the introduction of the allyl group does not affect the overall conformation.