Hypotensive Effect Of Clonidine Research Articles

Cardiovascular Effects Mediated by Imidazoline Drugs: An Update.

Clonidine is a centrally acting antihypertensive drug. Hypotensive effect of clonidine is mediated mainly by central α2-adrenoceptors and/or imidazoline receptors located in a complex network of the brainstem. Unfortunately, clonidine produces side effects such as sedation, mouth dry, and depression. Moxonidine and rilmenidine, compounds of the second generation of imidazoline drugs, with fewer side effects, display a higher affinity for the imidazoline receptors compared with α2-adrenoceptors. The antihypertensive action of these drugs is due to inhibition of the sympathetic outflow primarily through central I1-imidazoline receptors in the RVLM, although others anatomical sites and mechanisms/receptors are involved. Agmatine is regarded as the endogenous ligand for imidazoline receptors. This amine modulates the cardiovascular function. Indeed, when administered in the RVLM mimics the hypotension of clonidine. Recent findings have shown that imidazoline drugs also exert biological response directly on the cardiovascular tissues, which can contribute to their antihypertensive response. Currently, new imidazoline receptors ligands are in development. In the present review, we provide a brief update on the cardiovascular effects of clonidine, moxonidine, rilmenidine, and the novel imidazoline agents since representing an important therapeutic target for some cardiovascular diseases.

Role of the Anesthetic Determine the Clonidine Effects Mediated by RVLM/-α2-Adrenoceptors on Blood Pressure and Heart Rate in Rats

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 involvement of I(1)-imidazole receptors in mediating the hypotensive effects of clonidine. It also indicates α2-/I(1)-receptors synergism in raising the urethane lowering of baseline of SBP to the levels of control or halothane group. In conclusion, the result suggests involvement both of the central and the peripheral α2-adrenoceptors in mediating urethane hypotensive effects.

Effects of chronic ethanol feeding on clonidine-evoked reductions in blood pressure, heart rate, and their variability: time-domain analyses.

The effects of chronic ethanol administration on the acute hemodynamic effects of clonidine were investigated in conscious radiotelemetered spontaneously hypertensive rats (SHRs). Changes evoked by clonidine (30 micro g/kg i.p.) in blood pressure, heart rate, and their variability were evaluated in ethanol [2.5 or 5% (w/v), 12 weeks] and pair-fed control rats. The blood pressure variability was determined as the standard deviation of the mean arterial pressure (SDMAP). Two heart rate variability indices were used, the standard deviation of beat-to-beat intervals (SDRR) and the root mean square of successive beat-to-beat differences in R-R interval durations (rMSSD). Compared with control rats, ethanol (2.5 and 5%)-fed rats exhibited concentration-related reductions in mean arterial pressure (MAP) and SDMAP versus no change in heart rate variability. In control rats, clonidine caused a significant reduction in MAP that continued for at least 5 h and was associated with significant reductions in SDMAP, SDRR, and rMSSD, responses that are consistent with the inhibition of central sympathetic tone. The hypotensive effect of clonidine was attenuated by ethanol in a concentration-related manner. The maximum reductions in MAP elicited by clonidine in ethanol (2.5 and 5%)-fed rats amounted to -23.4 +/- 2.8 and -15.1 +/- 1.5 mm Hg, respectively, compared with -35.4 +/- 1.2 mm Hg in control rats. The clonidine-induced reductions in SDMAP, SDRR, and rMSSD were also significantly attenuated by ethanol. These findings suggest that the attenuation of MAP and heart rate variability responses elicited by clonidine in ethanol-fed SHRs reflects alterations in the sympathovagal balance, which may be implicated in the antagonistic hemodynamic interaction between the two drugs.

Role of presympathetic C1 neurons in the sympatholytic and hypotensive effects of clonidine in rats.

The rostral ventrolateral medulla (RVLM) may play an important role in the sympatholytic and hypotensive effects of clonidine. The present study examined which type of presympathetic RVLM neuron is inhibited by clonidine, and whether the adrenergic presympathetic RVLM neurons are essential for clonidine-induced sympathoinhibition. In chloralose-anesthetized and ventilated rats, clonidine (10 microg/kg iv) decreased arterial pressure (116 +/- 6 to 84 +/- 2 mmHg) and splanchnic nerve activity (93 +/- 3% from baseline). Extracellular recording and juxtacellular labeling of barosensitive bulbospinal RVLM neurons revealed that most cells were inhibited by clonidine (26/28) regardless of phenotype [tyrosine hydroxylase (TH)-immunoreactive cells: 48 +/- 7%; non-TH-immunoreactive cells: 42 +/- 5%], although the inhibition of most neurons was modest compared with the observed sympathoinhibition. Depletion of most bulbospinal catecholaminergic neurons, including 76 +/- 5% of the rostral C1 cells, by microinjection of saporin anti-dopamine beta-hydroxylase into the thoracic spinal cord (levels T2 and T4, 42 ng. 200 nl(-1). side(-1)) did not alter the sympatholytic or hypotensive effects of clonidine. These data show that although clonidine inhibits presympathetic C1 neurons, bulbospinal catecholaminergic neurons do not appear to be essential for the sympatholytic and hypotensive effects of systemically administered clonidine. Instead, the sympatholytic effect of clonidine is likely the result of a combination of effects on multiple cell types both within and outside the RVLM.

Actions of L-NAME and methylene blue on the hypotensive effects of clonidine and rilmenidine in the anesthetized rat.

The antihypertensive mechanism of alpha2-adrenoceptor agonists, such as clonidine and rilmenidine, is not completely elucidated, although it is probably due to reduction of sympathetic tone mediated by stimulation of central alpha2-adrenoceptors. Because activation of alpha2-adrenoceptors on endothelial cells induces release of endothelium-derived relaxing factor (EDRF), we determined whether nitric oxide (NO) release is involved in the antihypertensive action of clonidine and rilmenidine. In chloralose-anesthetised Wistar rats, systolic and diastolic arterial blood pressures were recorded on a polygraph. Intravenous injection of clonidine or rilmenidine (control group) caused a rapid increase of arterial blood pressure. followed by a long-lasting hypotensive effect. The hypotensive effects, estimated as the area enclosed by the decrease in diastolic pressure during the 20 min after clonidine and rilmenidine injections, were 574+/-60 and 410+/-59 mm Hg/min, respectively. The delta decrease in diastolic arterial blood pressure observed 20 min after intravenous injections of clonidine and rilmenidine was 48+/-5 and 34+/-3 mm Hg, respectively. Clonidine and rilmenidine injected 5-10 min after intravenous pretreatment with L-NAME (2 and 1 mg/kg) or methylene blue (10 mg/kg) induced hypotensive effects that were significantly smaller than that observed for the control group. These results suggest that the antihypertensive effects of clonidine and rilmenidine also may be modulated by the NO-cyclic guanosine monophosphate (cGMP) pathway at the level of the central nervous system and/or at the vascular peripheral circulation.

Influence of sino-aortic barodenervation on the cardiovascular effects of imidazoline-like drugs

Earlier findings have shown that hypotensive effects of centrally acting drugs, such as clonidine, are enhanced in animals after denervation of arterial baroreceptors. The purpose of this study was to investigate the dynamic of changes in arterial pressure, heart rate and hypotensive effects of clonidine, rilmenidine and moxonidine in Wistar rats after sino-aortic denervation (SAD) using radio-telemetry. SAD was followed by significant elevation of arterial pressure lability (the standard deviation of the mean arterial pressure), while the baseline mean arterial pressure (MAP) and heart rate in barodenervated rats (12 days after SAD) was similar to intact rats. The hypotension produced by clonidine, rilmenidine and moxonidine was much greater in SAD rats than in intact rats. The study suggests that baroreflex mechanisms are not only important for maintaining levels of blood pressure in the very short term, but also for buffering the effects of centrally acting antihypertensive drugs.

Is the hypotensive effect of clonidine and related drugs due to imidazoline binding sites?

Clonidine and related alpha 2-adrenergic receptor (alpha 2AR) agonists lower arterial pressure primarily by an action within the central nervous system. These drugs also have varying degrees of affinity for other cellular components called nonadrenergic imidazoline binding sites (NAIBS). For over 20 years, the alpha 2AR agonist activity of clonidine-like drugs was thought to account for their therapeutic effects (alpha 2 theory). However, several groups have recently proposed a competing "imidazoline theory" according to which the hypotensive effect of clonidine-like drugs would in fact owe more to their affinity for one type of NAIBS, called I1 receptors. The alpha 2-theory is strongly supported by four main types of congruent data. First, the hypotensive effect of systemically administered clonidine is blocked by alpha 2AR antagonists that are without affinity for I1 NAIBs. Second, the hypotensive effect of intravenous clonidine is absent in genetically engineered mice in which a defective alpha 2AAR has been substituted for the normal one. Third, the sympatholytic effect of clonidine is consistent with the presence of conventional inhibitory alpha 2ARs on sympathetic preganglionic neurons and on their main excitatory inputs in the medulla oblongata. Fourth, the first I1 ligand without affinity for alpha 2ARs was found to be biologically inactive. The imidazoline theory is supported by a limited repertoire of whole animal "in vivo" pharmacological experiments that remain open to a wide range of interpretations. In conclusion, the bulk of the evidence strongly supports a largely predominant role of alpha 2AR mechanisms in the action of most clonidine-like agents at therapeutically relevant doses or concentrations. Even the small pharmacological differences between these agents cannot yet be linked with certainty to their relative affinity for I1 NAIBS.

Arterial pressure lability in hypotensive effects of clonidine in barodenervated spontaneously hypertensive rats

Hypotensive effect of clonidine and its effect on arterial pressure lability as the main index of stability of background blood pressure are studied in intact spontaneously hypertensive rats (SHR) and rats with chronic sinoaortic denervation. Barodenervation potentiates hypotensive and negative cardiochronotropic effects of clonidine, which is accompanied by reduced blood pressure lability. This indicates an increased sensitivity of central α2-and imidazoline receptors, which mediate the depressor effect of clonidine, against the background of chronic inhibition of the baroreceptor reflex.

Role of cardiac output in ethanol-evoked attenuation of centrally mediated hypotension in conscious rats.

Our previous studies have shown that ethanol selectively counteracts centrally mediated hypotensive responses. This study investigated the role of cardiac output and peripheral resistance in the antagonistic interaction between ethanol and antihypertensive drugs. Changes in blood pressure, heart rate, cardiac index, stroke volume, and peripheral resistance elicited by clonidine and subsequent ethanol or saline administration were evaluated in conscious rats. The aortic barodenervated rat was employed because it exhibits greater hypotensive responses to clonidine compared with the intact rat. Aortic barodenervation elicited acute rises in blood pressure, heart rate, and peripheral resistance, whereas cardiac index and stroke volume were not altered. The blood pressure of conscious aortic barodenervated rats returned to sham-operated levels by 48 hours due to concomitant reductions in cardiac index and stroke volume; the peripheral resistance, however, remained significantly elevated. Clonidine (30 microg/kg, I.V.) elicited greater decreases in blood pressure in aortic barodenervated compared with sham-operated rats. The hypotension was caused by decreases in cardiac index and stroke volume because peripheral resistance did not change. Ethanol (1 g/kg, I.V.) counteracted the hypotensive effect of clonidine and raised blood pressure to levels higher than preclonidine values. Significant (P<.05) increases in cardiac index and stroke volume and decreases in peripheral resistance accompanied the pressor effect of ethanol. Additional control groups were included in the study to determine the selectivity of the interaction. A dose of hydralazine (0.5 mg/kg, I.V.) was used that produced similar hypotension to that evoked by clonidine in aortic barodenervated rats. Hydralazine-evoked hypotension was similar in denervated and control rats and resulted from significant reductions in peripheral resistance. Reflex increases in heart rate and stroke volume and hence cardiac output were observed. Ethanol given after hydralazine produced a short-lived pressor effect (<5 minutes versus 40 minutes in the case of clonidine) and counteracted the sympathetically mediated increases in cardiac output, stroke volume, and heart rate. These findings support our hypothesis that ethanol selectively counteracts hypotensive responses of central origin by reversing the reduction in cardiac output elicited by clonidine.

Changes in cerebral hemodynamics after a single dose of clonidine in severely head-injured patients.

alpha 2-Adrenergic agonists induce cerebral vasoconstriction, reduce intracranial pressure (ICP) in experimental animals and may be useful in the hemodynamic management of head-injured patients. We studied the effects of the alpha 2 agonist clonidine on the cerebral circulation in 12 head-injured patients (Glasgow Coma Scale score < 8). Middle cerebral artery flow velocity (MCAV), ICP, mean arterial pressure (MAP), and cerebral perfusion pressure (CPP), were continuously recorded before (T0), at the end (T1), and 30 min after (T2) a 10-min intravenous (i.v.) infusion of 2.5 micrograms/kg clonidine. The cerebral arteriovenous oxygen content difference (AVDO2) and Paco2 were sequentially obtained. ICP, Paco2, AVDO2, and MCAV did not change after clonidine administration. In contrast, MAP and CPP decreased (P < 0.05 and P < 0.05, respectively, at T1 and T2). Three subjects displayed a transient increase in ICP (> 10 mm Hg) at T1; this increase was concomitant with the decrease in MAP. Clonidine administered as an i.v. infusion may induce a critical but transient increase in ICP in some severely head-injured patients. This effect may result from cerebral autoregulatory vasodilation and increased cerebral blood volume as a response to the hypotensive effects of clonidine.

Hypotensive effect of clonidine in aortic denervated rats instrumented with arterial catheters or radiotelemetric devices

Hypotensive effect of clonidine in aortic denervated rats instrumented with arterial catheters or radiotelemetric devices

Centrally Mediated Reduction in Cardiac Output Elicits the Enhanced Hypotensive Effect of Clonidine in Conscious Aortic Barodenervated Rats

In a previous study, we showed that centrally mediated hypotensive responses are enhanced in aortic barodenervated (ABD) rats as compared with sham-operated (SO) rats. In the present study, we tested the hypothesis that the high basal total peripheral resistance (TPR) of ABD rats accounts for enhanced hypotensive responses to clonidine in this rat model. Aortic barodenervation resulted in acute increases in blood pressure (BP) and heart rate (HR) in anesthetized rats, associated with significant increases in plasma norepinephrine (NE) levels and TPR; cardiac index (CI) and stroke volume (SV) were not affected. After recovery from anesthesia, conscious ABD rats had significantly increased BP at 3 h after barodenervation; BP returned to SO levels by 48 h even though plasma NE levels and TPR remained significantly increased. On the other hand, CI and SV showed significant reductions, beginning at 3 h, and remained low throughout the postdenervation period (48 h); the reduction in CI offset the increase in TRP and may therefore account for the restoration of BP of ABD rats to normal levels. Beginning at similar baseline BP values, cumulative intracisternal (i.c.) doses of clonidine (0.02-2.5 micrograms) elicited greater decreases in BP and plasma NE levels in conscious ABD as compared with SO rats. These responses were centrally mediated because systemic administration of 0.12 micrograms clonidine, a dose that elicited near maximal hypotensive response after i.c. administration, affected neither BP nor plasma NE levels. Contrary to the hypothesis, the hypotensive effect of clonidine in ABD rats resulted exclusively from a reduction in CO (owing to reductions in both HR and SV) because TPR was not affected. These findings suggest that (a) in ABD rats, a reduction in CO offsets a sustained sympathetically mediated elevation in TPR and restores BP to normal levels; and (b) an enhanced hypotensive response to clonidine in ABD as compared with SO rats cannot be accounted for by a higher basal TRP but rather by elicitation of greater reductions in CO through a centrally mediated sympathoinhibitory action.

Hypotensive effect of clonidine is not mediated by enhanced baroreflex gain in rats.

We wished to examine whether enhanced depressor baroreflexes contribute to the hypotensive effect of clonidine in rats. Clonidine's hypotensive effect and clonidine's effect on baroreflex gain mean heart rate/mean blood pressure, (delta HR/delta BP) were compared under two conditions: in conscious rats with intact baroreflex control of HR, and in pentobarbital-anesthetized (PA) rats in which baroreflex control of HR is obtunded. Clonidine produced greater hypotension and bradycardia in PA rats than in conscious rats, but this greater hypotension was not associated with enhancement of baroreflex gain. Instead, clonidine-induced hypotension in PA rats was associated with a further decrease in baroreflex gain, whereas hypotension in conscious rats was not associated with any change in baroreflex gain. Selective pharmacologic blockade of sympathetic (i.e., with atenolol treatment) or parasympathetic (i.e., with methyl-atropine treatment) control of HR showed that clonidine decreased baroreflex gain in PA rats through inhibition of sympathetic control of HR. This study suggests that clonidine's hypotensive effect is not associated with enhancement of reflex bradycardic responses in rats.

Modulation of Norepinephrine Release in Blood Vessels

Summary: Various imidazoline and guanidine derivatives with agonistic or antagonistic properties at α2-adrenoceptors may modulate norepinephrine release not only via classic α2-autoreceptors but also via presynaptic imidazoline receptors. This possibility was examined in rabbit pulmonary artery and aorta preincubated with [3H]norepinephrine (NE) and superfused with a physiological salt solution. The release of [3H]NE from the sympathetic nerves contained in the preparations was stimulated by electrical impulses (2 Hz, unless stated otherwise). α2-Adrenoceptor-blocking imidazolines such as phentolamine, tolazoline, idazoxan, and 4-chloro-2-(2-imidazoline-2-ylamino)-isoindoline (BDF 6143) increased the electrically evoked [3H]NE release. Their concentration-response curves were bell-shaped, and the maximum increase obtainable was less than that obtained with rauwolscine, a nonimidazoline α2-adrenoceptor antagonist. When the frequency of stimulation was decreased from 2 to 0.66 Hz (leading to a decreased concentration of NE in the biophase of the α2-autoreceptors and therefore a decreased degree of autoreceptor activation), BDF 6143 no longer facilitated but instead concentration-dependently inhibited [3H]NE release. An inhibition of release without any facilitatory component could also be observed at 2 Hz with all imidazoline derivatives mentioned above when the presynaptic α2-adrenoceptors had been blocked by rauwolscine and/or preexposure to the irreversible α-adrenoceptor antagonist phenoxybenzamine. Clonidine and moxonidine, two imidazolines with α2-adrenoceptor agonistic properties, and cirazoline, an imidazoline devoid of intrinsic activity at α2-adrenoceptors, inhibited [3H]NE release. Rauwolscine apparently was antagonistic not only at presynaptic α2-adrenoceptors but also at presynaptic imidazoline receptors because it antagonized the inhibitory response to BDF 6143 at 0.66 Hz. The pA2 values of rauwolscine for α2-adrenoceptor antagonism in various tissues of several species (reported in the literature) were, as a rule, in the range of 8.0. In the rabbit pulmonary artery and aorta, pA2 values of rauwolscine in this range could be found only for the antagonism against the moxonidine-induced inhibition of [3H]NE release, whereas the pA2 values against clonidine and other putative imidazole receptor agonists were between 6.37 and 6.77. Taken together, the present data suggest that in addition to the classic α2-adrenoceptors, imidazoline receptors are involved in modulation of NE release in the rabbit pulmonary artery and aorta. Comparison of the potencies of all putative imidazoline receptor-ligands investigated in these blood vessels with their potencies in other tissues (including those in the rostral ventrolateral medulla of the brainstem involved in the hypotensive effect of clonidine and moxonidine) revealed that the imidazoline sites are heterogeneous. In the rabbit pulmonary artery and aorta, moxonidine activates predominantly α2-adrenoceptors (but not the coexisting presynaptic imidazoline receptors subtype), whereas it possesses particularly high affinity for the imidazoline receptors in the rat rostral ventrolateral medulla. Thus. moxonidine may be particularly selective for the imidazoline receptor of the brainstem.

An enhanced hypotensive response to clonidine can still be found in panic patients despite psychological treatment

Investigation of “biological markers” in panic disorder and other neurotic conditions is limited by the fact that appropriate subjects are either disturbed by the ongoing effects of the disorder, or corrupted by the effects of medication. The advent of an empirically effective psychological treatment makes it possible to circumvent these difficulties. The hypotensive effect of clonidine has been studied in eight Panic Disorder patients who has been successfully treated with a psychological intervention. In comparison with an age- and sex-matched group of normal subjects they showed an enhanced fall in systolic blood pressure that could not be explained by differences in conventional indices of physiological arousal. It is possible that the previously reported enhanced sensitivity to alpha-2-adrenoceptor ligands found in patients with Panic Disorder is part of an abnormality of autonomic function that can be found in these subjects irrespective of their clinical state.

Effect of Naloxone on Blood Pressure Responses and Plasma Catecholamine Levels Following Clonidine Injection in Conscious, Unrestrained Rats

Intravenous injection of clonidine produces a biphasic blood pressure response, a transient increase followed by a prolonged decrease. Significant increases in plasma norepinephrine (NE), epinephrine (EPI), and dopamine (DA) levels occur 5 min following injection, corresponding to the hypertensive phase. Thirty minutes after clonidine injection, blood pressure, NE, EPI, and DA levels had returned to control levels. However, at 60 min, when the blood pressure had decreased to below control levels, a significant decrease in plasma NE was found. This finding confirms that clonidine decreases blood pressure, in part, by reducing sympathetic nerve activity. Naloxone, an opiate antagonist, when given prior to clonidine, abolished the hypotensive phase as well as preventing the decrease in plasma NE levels. The hypertensive phase was potentiated. Naloxone, when given alone, increased plasma NE levels at 15, 40, and 70 min following injection, indicating that naloxone increases sympathetic nerve activity peripherally, and may prevent clonidine's hypotensive phase by also increasing sympathetic activity in the central nervous system through blockade of opiate receptors. Therefore, the hypotensive effect of clonidine may involve interactions with endogenous opiate peptides.

Possible involvement of brain opioid peptides in clonidine-induced hypotension in spontaneously hypertensive rats.

The effect of intracisternal pretreatment with opiate antagonists or antisera against various opioid peptides on the hypotension and bradycardia induced by cumulative intracisternal administration of clonidine (0.02-2.5 microgram) was studied in conscious Wistar-Kyoto rats and in spontaneously hypertensive rats. No effect of any pretreatment on basal values of blood pressure and heart rate was detected in either of these strains. In spontaneously hypertensive rats intracisternal pretreatment with naltrexone resulted in a dose-dependent inhibition of clonidine-induced hypotension and bradycardia. DL-naloxone also antagonized the hypotension but not influence the hypotensive and bradycardic response to clonidine. In Wistar-Kyoto rats naltrexone and the beta-endorphin antiserum B4 failed to affect the cardiovascular effects of clonidine. B4 and an antiserum against dynorphin(1-13) inhibited clonidine-induced hypotension in spontaneously hypertensive rats, whereas a [Met5]enkephalin antiserum had no effect. Use of antisera specifically recognizing the C-terminus of beta-, alpha-, and gamma-endorphin, respectively, revealed that only the beta-endorphin antiserum inhibited the fall in blood pressure in spontaneously hypertensive rats after cumulative administration of clonidine. None of the antisera used affected clonidine-induced bradycardia. These results indicate that activation of stereospecific opiate receptors in spontaneously hypertensive, but not in Wistar-Kyoto rats, plays a role in the central hypotensive effect of clonidine. beta-Endorphin(1-31) and dynorphin(1-13) might be the endogenous ligands for these receptors.

Growth hormone response to clonidine after recovery in patients with endogenous depression.

The growth hormone response to clonidine was measured in ten drug-free recovered patients, seven of whom had previously been tested when endogenously depressed, and compared with the response in ten individually matched controls. In eight of the patients there was an impairment of the growth hormone response, despite clinical recovery, although the hypotensive effect of clonidine in these patients was normal. This is suggestive of a persisting abnormal alpha2-adrenoceptor function in forebrain regions after recovery from an episode of endogenous depression, and may represent a trait marker for this condition.

Central Cardiovascular Effects of a Noncatecholamine Endogenous Ligand for Clonidine Receptors

Cats and rats anaesthetized with pentobarbital were used to study the central cardiovascular effects of the clonidine displacing substance (CDS). The potential influence of centrally applied CDS on the cardiovascular effects of clonidine was also investigated in both species. CDS is a brain substance which is not a catecholamine (CA) and which displaces completely the binding of tritiated clonidine to brain membranes. It was observed that direct application of CDS unilaterally to the nucleus reticularis lateralis (NRL), a privileged site of action for clonidine in the cat, increases markedly the mean arterial pressure (MAP) and does not affect the heart rate (HR). CDS also causes hypertension when infused into the left vertebral artery in the cat. When MAP reverted to baseline, the hypotensive effect of clonidine given by the same route is significantly prevented. In rats, the intracisternal administration of CDS increased MAP without affecting HR. Here also, the CDS pretreatment antagonized the hypotensive effect of i.v. clonidine as compared with control animals. It is concluded that CDS is an endogenous non-catecholamine ligand for receptors involved in the hypotensive effect of clonidine. This substance interferes with clonidine on these receptors. It is a candidate as a neuromodulator or a neurotransmitter involved in the blood pressure regulation at least in the NRL region.

EFFECT OF CLONIDINE ON ADRENAL MEDULLA CATECHOLAMINE LEVELS IN RATS

The effects of clonidine on adrenal medulla catecholamines levels were studied in normotensive rats. Intraperitoneal injections (50,100 micrograms/kg) of clonidine caused a dose-dependent decrease in adrenaline content of the gland. This effect was suppressed by denervation of the adrenal medulla, i.e. unilateral section of splanchnic fibers performed 5 days before. These results demonstrate that clonidine decreases the catecholamine content of the adrenal medulla only through a central action. They suggest that the adrenal medulla is involved in the hypotensive effect of clonidine.