Cardiovascular Changes Induced by Large Doses of Clonidine in Mice (original) (raw)
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American journal of physiology. Regulatory, integrative and comparative physiology, 2001
We examined the effects of clonidine injected unilaterally into the rostral ventrolateral medulla (RVLM) of conscious, unrestrained rats. We also examined whether the local alpha(2)-adrenoceptor mechanism contributed to the action of clonidine injected into the RVLM. Injection of clonidine but not vehicle solution significantly decreased the mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) in conscious, unrestrained rats as well as in propofol-anesthetized rats. The frequency of natural behavior was significantly lower after clonidine injection than after vehicle injection. The depressor and sympathoinhibitory responses were significantly larger in the propofol-anesthetized rats than in the conscious rats. Coinjection of a selective alpha(2)-adrenoceptor antagonist, 2-methoxyidazoxan, with clonidine into the RVLM significantly attenuated the depressor, bradycardiac, sympathoinhibitory, and sedative effects of clonidine injected alone. In con...
The central action of clonidine and its antagonism
British Journal of Pharmacology, 1972
1. We have examined the central actions of clonidine (2-(2-6-dichlorphenylamine)-2-imidazoline hydrochloride). It has been confirmed that when infused into the vertebral artery at 2 ug/min, it caused a decrease in blood pressure and a slight increase in heart rate. The same dose given intravenously or into the carotid artery had no effect. 2. Intravertebral clonidine also greatly reduced the reflex response to carotid occlusion and the effects of an intravertebral infusion of angiotensin (1 ng/kg)/ min. 3. This central action of clonidine was antagonized by the adrenergic neurone blocking drug bethanidine (4-5 mg/kg intravenously) even after the cervical cord had been transected at C4-C6 suggesting that bethanidine also has central actions. 4. Other drugs which also antagonized the central effects of clonidine were guanethidine (4-5 mg/kg intravenously), bretylium (10 mg/kg intravenously) and phentolamine (0-2 mg/kg intravenously). 5. It is suggested that there are central adrenergic neurones which inhibit cardiovascular autonomic reflexes and that the central autonomic effects of clonidine are due to stimulation of inhibitory adrenoceptors. The antagonism by adrenergic neurone blocking drugs of the effect of clonidine could therefore be due to blockade of these inhibitory pathways. 6. The central action of clonidine could only be demonstrated when a high concentration was infused into the vertebral artery and could not be shown with oral doses of (20 tg/kg)/day for seven days. It is concluded that the hypotensive action of therapeutic doses is unlikely to be due to the central action of clonidine.
Journal of Biotechnology Research Center
To examine the hypothesis of a role for α2-adrenoceptors in mediating the mechanism of urethane hypotensive effect whether it's peripheral or central, Wistar rats were anesthetized with urethane or (for comparison) with halothane, to study the influence of urethane that govern the mechanism of central and peripheral α2-adrenoceptors action, on basal BP & HR, and the rise in blood pressure (BP) to the stimulation of caudal pressor area (CPA), when these receptors were either centrally activated by bilateral rostral ventrolateral medulla (RVLM) microinjection of clonidine (30nM), and blockade with any of the clonidine antagonists, yohimbine (500pmol/50nl), and idazoxane (270nM) or yohimbine+idazoxane, or when peripherally activated (of urethane anesthetized rats) by i.v. clonidine (100nmol/kg), which also blockade with idazoxane or yohimbine+idazoxane. The results indicated presence of no anesthetic differences in a partial involvement of α2-receptors-RVLM, vs. a complete involve...
Site and Mode of Action of Clonidine in the Central Nervous System
Acta Medica Scandinavica, 1977
In urethaneanaesthetized rats clonidine was administered intravenously (i. v.J. intraearebroventricularly (i.c.v.) or onto the surface of the area postrema which protrudes into the fourth cerebnrl ventricle. In each instance clonidine induced a dose-dependent lowering of the blood pressure.
Ventrolateral medullary pressor area: site of hypotensive action of clonidine
Brain Research, 1987
Intravenous injections of clonidine produce an initial transient increase in blood pressure followed by a long-lasting hypotension and bradycardia. The initial pressor response is due to activation of vascular al-adrenergic receptors while the hypotcnsion and bradycardia are caused by the central actions of clonidine. Although, hypothalamus, nucleus tractus solitarius (NTS), ventrolateral medulla and the intermediolateral cell column of the thoracolumbar spinal cord (IML) have been implicated, the exact site of these actions of clonidine in the central nervous system is not established. The results of this investigation suggest that the pressor area in the ventrolateral medulla (VLPA) is the site of hypotensive and bradycardic actions of intravenously administered clonidine. This conclusion is based on the observation that microinjections of idazoxan, a specific a2-adrenergic receptor blocker, into the VLPA prevented and reversed the hypotension and bradycardia despite the fact that other proposed sites of these actions (NTS, hypothalamus and IML) were intact and accessible to intravenously administered clonidine.
Circulation, 1984
The effects of clonidine, naloxone, and their combination on arterial blood pressure (BP), heart rate (HR), and hemodynamic and biochemical parameters were examined.in 29 patients with essential hypertension. Treatment for 3 days with 0.3 mg/day clonidine reduced BP and HR, and these effects were quickly reversed by a single injection of 0.4 mg iv naloxone in 17 of the patients (responders), but not in the remaining 12 (nonresponders). Responders had higher control values for cardiac output, stroke index, plasma renin activity (PRA), and plasma epinephrine levels than did nonresponders. Basal BP was similar in the two groups, but clonidine decreased BP, PRA, and plasma epinephrine more in responders than in nonresponders. Naloxone given during placebo treatment had no significant effects. During clonidine treatment naloxone increased BP, HR, total peripheral resistance, PRA, and plasma epinephrine and norepinephrine, and decreased stroke volume in responders, whereas in nonresponders its only effect was a small increase in HR. It is concluded that in a subset of hyperadrenergic, hypertensive patients the antihypertensive effect of clonidine involves a naloxonereversible inhibition of central sympathetic outflow, probably mediated by the release of an endogenous opioid. Circulation 69, No. 3, 461-467, 1984. THE ANTIHYPERTENSIVE AGENTS clonidine and a-methyldopa are believed to produce their cardiovascular effects through a central mechanism. They stimulate a2-adrenergic receptors in the pontomedullary region, which results in a reduction of sympathetic and increase in parasympathetic tone. 1 Recent reports have demonstrated that in hypertensive rats the antihypertensive action of these drugs is inhibited by the opiate antagonists naloxone and naltrexone,24 or by central administration of an antiserum to /3-endorphin.t5 Furthermore, clonidine and 1-a-methylnorepinephrine increase the release of immunoreactive /3-endorphin from the superfused brain stem of spontaneously hypertensive rats in vitro.6 These findings have been interpreted to indicate that the antihypertensive effect of
Brain Research, 1987
In vivo electrochemistry allowed recording of a catechol oxidation current in the ventrolateral medulla, caudal to the obex, in anesthetized rats whose ventilatory, metabolic and hemodynamic parameters were rigorously controlled. Hemorrhage or controlled hypotension induced an increase in the metabolism of catecholamines in the A 1 noradrenergic group, which remained activated after full hemodynamic recovery. Clonidine (200/,g. kg-1 i.p.) given 30 min prior to hemorrhage or immediately before controlled hypotension suppressed partially the increased metabolism of catecholamines especially during the recovery period. This suggests that clonidine preserved phasic reactivity upon circulatory disturbances and decreased tonic hyperactivity following circulatory recovery.
Antihypertensive Effects of Clonidine in Tetraplegic Subjects Devoid of Central Sympathetic Control
Clinical Science, 1979
1. The effects of 300 μg of oral clonidine on blood pressure, heart rate, plasma noradrenaline and adrenaline concentrations were studied in seven tetraplegic subjects with physiologically complete cervical spinal cord transections. 2. Clonidine did not significantly change resting blood pressure during the 8 h of the study. Resting heart rate fell. Resting plasma noradrenaline and adrenaline concentrations, when measured 2 h after clonidine, were not significantly lower. 3. Urinary bladder stimulation resulted in a marked rise in blood pressure accompanied by an elevation in plasma noradrenaline but not adrenaline. The hypertensive response to bladder stimulation was substantially reduced by clonidine, the maximum suppression occurring 2–4 h after administration of the drug. The plasma noradrenaline response to bladder stimulation, when measured 2 h after clonidine, was significantly lower than the response before clonidine. In two tetraplegic subjects with indwelling catheters the...
Brain Research, 1978
To localize the central site and mechanism of clonidine induced hypotension, the drug was applied by the technique of microiontophoresis to neurons of the bulbar cardiovascular center in decerebrate cats. The excitatory and inhibitory cardiovascular neurons (CVN) were identified by their response to an increase in the arterial blood pressure induced by intravenous injections of small doses of norepinephrine (NE). Clonidine had an inhibitory effect on the spontaneous firing rate of excitatory CVN but had no effect on the firing rate of inhibitory CVN. At the same doses, it had no effect on the firing rate of NCVN recorded from the same area. Furthermore, clonidine had a blocking action on the excitatory response of CVN induced by microiontophoretic application of NE. It is concluded that clonidine produces its hypotensive response by acting on a-adrenergic receptors of bulbar CVN.