Reversal of clonidine induced miosis by the alpha 2-adrenoreceptor antagonist RX 781094.

Clonidine given i.v. at a dose of 0.1 mg and 0.2 mg was found to cause miosis in a placebo controlled double-blind study in six healthy volunteers. In a further single-blind placebo controlled study in three of these volunteers, the alpha 2-adrenoreceptor antagonist RX 781094 at a dose of 0.1 mg/kg i.v. reversed the miosis induced by i.v. clonidine 0.2 mg. At a dose of 0.05 mg/kg the miosis was partially reversed.

Effects on blood pressure of noradrenaline and isoprenaline administered into the third ventricle of the brain of anaesthetized and conscious cats.

1 Noradrenaline administered into the third ventricle of the brain (IIIv) of both conscious and anaesthetized cats induced increases in blood pressure accompanied by small and variable heart rate effects. The pressor responses were reduced after autonomic ganglion blockade indicating their likely central origin. 2 Noradrenaline when administered either into a lateral cerebral ventricle (i.c.v.) in conscious and anaesthetized cats or into the cisterna magna (i.c.) in anaesthetized cats induced falls in blood pressure accompanied by bradycardia. 3 Pressor responses to IIIv noradrenaline in conscious cats were partly blocked by either propranolol or thymoxamine indicating a possible involvement in the responses of excitatory adrenoreceptors of both alpha and beta types. 4 Pressor responses induced by IIIv isoprenaline in conscious cats were blocked by propranolol but not by thymoxamine suggesting the effect is mediated solely via excitatory beta-adrenoreceptors. 5 In anaesthetized cats prior i.c. administration of noradrenaline reduced the pressor responses induced by IIIv noradrenaline. 6 In conscious cats i.v. clonidine reduced pressor responses to IIIv noradrenaline without depressing peripheral vascular noradrenaline sensitivity. 7 The results suggest the involvement of excitatory and inhibitory alpha-adrenoreceptors and of excitatory beta-adrenoreceptors in central blood pressure control. It is also concluded that activation of inhibitory alpha-adrenoreceptors in the hind brain region can suppress the cardiovascular effects of stimulating excitatory alpha- and beta-adrenoreceptors located in the region of the third ventricle.

Drug administration into the third ventricle of the brain of anesthetized and conscious cats.

A method is described for the administration of drugs into the third ventricle of the brain of conscious and anesthetized cats. Noradrenaline administered by this route produced cardiovascular stimulant effects as against depressor effects when administered into a lateral cerebral ventricle. The pressor responses evoked by third ventricular administration of noradrenaline were antagonized by spinal section in anesthetized cats and by hexamethonium in conscious animals. Conscious cats were more sensitive to the pressor effects of third ventricular noradrenaline than chloralose-anesthetized animals.

Recording of splanchnic (sympathetic) nerve activity in conscious and anaesthetised cats.

The method described allows of continuous recording of electrical activity from the splanchnic nerves of conscious unrestrained cats. The activity recorded was phasic and corresponded with respiration as reported by previous workers. Splanchnic nerve activity varied with the active state of the animal and, in general, closely paralleled changes in arterial blood pressure and heart rate. Noradrenaline administered intravenously raised arterial blood pressure but splanchnic nerve activity was depressed while acetylcholine produced the opposite effects.

Tissue levels of several radiolabelled beta-adrenoceptor antagonists after intravenous administration in rats.

The uptake of radioactively labelled propranolol, oxprenolol, metoprolol, acebutolol, practolol and atenolol into brain, liver and lung tissue was studied five min after intravenous administration (1.0 mg/kg) in normotensive Wistar rats anaesthetised with nitrous oxide and halothane. All of the beta-adrenoceptor antagonists including the least lipophilic compounds atenolol and practolol were detected in brain tissue five min after systemic administration. However, the level of propranolol (as measured by total radioactivity) in the bran was 40 and 67 times greater than the levels found for atenolol and practolol, respectively. Additionally, significantly more radioactivity was detected in lung tissue compared to that in liver tissue for the lipophilic, non-selective beta-adrenoceptor antagonists propranolol and oxprenolol. Levels of radioactivity in blood, brain, liver and lung were measured 5, 15, 30 and 60 min after administration of either propranolol or atenolol (1.0 mg/kg, i.v.) to both conscious and anaesthetised rats and a tendency towards high tissue levels of radioactivity was found in the animals which received the beta-adrenoceptor antagonists under anaesthesia. Pretreatment of groups of rats for 7, 14 and 21 days with unlabelled atenolol (1.0 mg/kg/day, i.p.) caused an increase in the subsequent central uptake of labelled atenolol whilst both the blood levels of radioactivity and the uptake into peripheral tissues were significantly lower in the 2 and 3 week pretreated rats compared to the control animals. These results are consistent with the hypothesis that a central action may contribute to the antihypertensive effect of beta-adrenoceptor antagonists.

Cardiovascular effects of carbachol and other cholinomimetics administered into the cerebral ventricles of conscious cats.

1. The cholinomimetic substances acetylcholine, nicotine, tetramethylammonium chloride and carbachol were infused intracerebroventricularly (i.c.v.) into conscious, normotensive cats and their effects on behaviour, blood pressure and heart rate recorded. 2. Intracerebroventricular acetylcholine, nicotine and tetramethylammonium chloride each produced small, mainly stimulant, effects on the cardiovascular system which were not accompanied by any marked behavioural effects. 3. Intracerebroventricular carbachol at a dose of 30 microgram produced marked and persistent cardiovascular stimulant effects accompanied by a striking rage/fear reaction. When the dose of carbachol was reduced to 7.5 microgram the behavioural effects were no longer seen but marked cardiovascular stimulant effects remained. 4. The cardiovascular stimulant effects of i.c.v. carbachol were apparently mediated via the peripheral sympathetic system since they were abolished by peripheral adrenergic neurone blockade. 5. The blood pressure and heart rate increases produced by i.c.v. carbachol were blocked by prior i.c.v. treatment with atropine, hexamethonium, guanethidine, bethanidine or propranolol. 6. The data are consistent with an interaction between central cholinergic and catecholaminergic neural pathways involved in central regulation of blood pressure and further suggest the involvement of beta-adrenoreceptors in the responses to centrally-administered cholinomimetics.

Cardiovascular effects of dopamine after central administration into conscious cats.

Dopamine (30 and 45 mug) administered intracerebroventricular (i.c.v.) to a group of 10 conscious normotensive cats caused dose-related increases in blood pressure and heart rate. In 4 of these animals the initial cardiovascular stimulant effects of i.c.v. dopamine were followed by hypotension and bradycardia. 2 alpha-Methyldopamine (30 and 45 mug i.c.v.) produced qualitatively similar responses to dopamine except that the cardiovascular stimulant effects were smaller and the secondary depressant effects somewhat more prolonged. 3 Both stimulant and depressant effects of i.c.v. dopamine and alpha-methyldopamine were greatly inhibited by autonomic ganglion blockade or by adrenergic neurone blockade. 4 The cardiovascular stimulant effects of both i.c.v. dopamine and i.c.v. alpha-methyldopamine were selectively inhibited by beta-adrenoceptor blocking agents whilst the cardiovascular depressant effects of these substances were abolished by the alpha-adrenoceptor blocker phentolamine or by the dopamine-beta-hydroxylase inhibitor disulfiram. 5 Haloperidol by either i.c.v. or the intravenous route abolished both cardiovascular stimulant and depressant effects of i.c.v. dopamine, whilst pimozide by either route inhibited only the cardiovascular stimulant effects. 6 In 2 cats, injection of dopamine into the cisterna magna produced predominantly depressant effects on the cardiovascular system except with a higher dose which induced biphasic responses.

Interaction of angiotensin II with noradrenaline and other spasmogens on rabbit isolated aortic strips.

Angiotensin II in sub-contractor concentrations enhanced the contractions of rabbit isolated aortic strips to noradrenaline, potassium chloride, histamine, acetylcholine, isoprenaline and 5HT. The potentiation of noradrenaline responses by angiotensin II was independent of any effect of angiotensin II on neuronal uptake of noradrenaline. The sensitization of this tissue to spasmogens induced by angiotensin II occurred in reserpine-treated preparations and in normal tissues suspended in calcium-free bathing medium. Procedures which abolished the transfer of sodium ions across membranes such as substitution of fructose for glucose in the bathing medium, absence of potassium ions or treatment with ouabain each abolished the non-specific sensitization. The evidence suggests that angiotensin II may cause a non-specific sensitization of this tissue by inhibiting sodium transfer across the cell membrane.

The brain as a possible site for the cardiovascular effects of beta-adrenoceptor blocking agents in cats.

1. DL-Propranolol, L-propranolol, DL-alprenolol, pindolol (LB46), practolol, ICI 66082, sotalol and oxprenolol all produced prolonged falls in blood pressure and heart rate after intracerebroventricular administration in conscious normotensive cats. 2. Transient initial pressor responses and tachycardias were observed after intracerebroventricular infusions of all the beta-adrenoceptor antagonists used, except ICI 66082. 3. D-Propranolol, D-alphrenolol, procaine and lignocaine all produced initial increases in blood pressure and heart rate but did not subsequently cause any reduction in either blood pressure or heart rate. 4. The time of maximum hypotension and bradycardia after intracerebroventricular infusion of beta-adrenoceptor antagonists coincided with the maximum inhibition of the centrally mediated tachycardia observed after intracerebroventricular isoprenaline.