The effects of clonidine on the kidney function in the anesthetized dog

Studies were performed to determine the mechanism by which the antihypertensive agent clonidine increased urine flow. The response of the kidney has been examined in four combinations. The parameters of renal function have been compared during volume expansion by 1.5-2.0% body weight Ringer solution. In the control animals, volume expansion by 2% body weight, resulted in a slight increase in sodium excretion and urine flow. In 10 anesthetized dogs 1.0 microgram/kg/min of clonidine infused i.v. during 30 minutes (the total amount of clonidine infused was 30 micrograms/kg) decreased the arterial blood pressure from 136 +/- 13 mmHg to 127 +/- 12 mmHg and elevated urine flow from 2.95 +/- 1.65 ml/min to 4.34 +/- 1.77 ml/min while the urine osmolality diminished from 399 +/- 107 mosm/l to 265 +/- 90 mosm/l and the glomerular filtration remained constant. In 5 animals 0.1 microgram/kg/min of clonidine was infused into the left renal artery (this dose is corresponding to the renal fraction of the cardiac output) without any effects in the left kidney. 1.0 microgram/kg/min of clonidine infused directly into the left renal artery produced vasoconstriction in the ipsilateral kidney, decreased the glomerular filtration rate and the urine flow. By contrast in the right kidney the urine flow rose without hemodynamic changes, and the urine osmolality became hypoosmotic compared to the plasma. In ten dogs 1.0 microgram/kg/min of clonidine and 1 mU/kg/min of arginine-vasopressin were infused intravenously. The vasopressin infusion superimposed on the clonidine could not inhibit the increase of the urine excretion, and the fall of the urine osmolality. The results suggest that the clonidine increases the renal medullary blood flow possibly via a direct mechanism, decreases the sympathetic outflow to the kidney and via an indirect pathway, mediated by the renin-angiotensin system. The renal medullary flow increase produces a washout of the medullary osmotic gradient, and the water reabsorption diminishes.     

Evidence for antagonistic activity of endothelin for clonidine induced hypotension and bradycardia.

Effect of endothelin (ET) on clonidine induced cardiovascular effects was studied in male Sprague-Dawley rats. Clonidine (75 micrograms/kg, iv) produced significant decrease in blood pressure and heart rate. ET-1 (50 ng/kg, iv) pretreatment completely antagonized the hypotension and bradycardia induced by clonidine. ET-2 (50 ng/kg, iv) and ET-3 (50 ng/kg, iv) had similar antagonistic effect on clonidine induced hypotension and bradycardia. The antagonistic effect of ET lasted for several hours, however, 4 hours after ET pretreatment only partial blockade of clonidine induced hypotension and bradycardia was observed. This indicated that the antagonistic effect of ET was reversible. Initial hypertensive response induced by high dose of clonidine (750 micrograms/kg, iv) could not be antagonized by ET-1, ET-2 or ET-3, while phenoxybenzamine, an alpha adrenoceptor antagonist, blocked the hypertensive response of clonidine. Thus, ET has no antagonistic effect on the initial hypertensive response but antagonizes the hypotensive and bradycardic effect induced by clonidine. Clonidine induced hypotension and bradycardia are mediated through central alpha 2 adrenoceptors while hypertension is mediated through peripheral alpha 2 adrenoceptors. It is concluded that central alpha 2 adrenoceptors are different from peripheral alpha 2 adrenoceptors and ET antagonizes the effect of clonidine only on central alpha 2 adrenoceptors but has no antagonistic activity on peripheral alpha 2 adrenoceptors.     

Proceedings: The effects of hypothalamic and reflexogenic hypertension on renal and femoral circulation.

In anaesthetized dogs, electrical stimulation of the median posterior hypothalamus provoked hypertension accompanied by a decrease of renal blood flow and an increase of femoral blood flow. Similar hypothalamic reactions occurred after bilateral cervical vagotomy or after atropine, 2 mg/kg i.v. During reflexogenic hypertension induced by bilateral carotid occlusion in bivagotomized dogs, the renal and femoral blood flows were not significantly modified. The decrease of the renal blood flow and the increase of the femoral blood flow, during hypothalamic stimulation were greatly reduced or reversed after R 28935 equals erythro-1-(1--e12-(1,4-benzodioxan-2-yl)-2-OH-Et]-4-piperidyl)-2-benzimidaxolinone, 80 mug/kg i.v., but not after clonidine, 5 mug/kg i.v.     

Attenuating effects of intrathecal clonidine on the exercise pressor reflex

We tested the hypothesis that intrathecal injection of clonidine, an alpha 2-adrenergic agonist, attenuated the reflex cardiovascular and ventilatory responses to static muscular contraction in cats. Before clonidine (1 microgram in 0.2 ml), contraction-induced reflex increases (n = 10) in mean arterial pressure and ventilation averaged 25 +/- 3 mmHg and 359 +/- 105 ml/min, respectively, whereas after clonidine these increases averaged 8 +/- 4 mmHg and 200 +/- 114 ml/min, respectively (P less than 0.05). Clonidine had no effect on the heart rate response to contraction. Intrathecal injection of yohimbine (10 micrograms; n = 5), an alpha 2-adrenergic antagonist, but not prazosin (10 micrograms; n = 3), an alpha 1-adrenergic antagonist, prevented the attenuating effects of clonidine on the reflex pressor and ventilatory responses to contraction. Our findings were not due to the spread of clonidine to the medulla, because the reflex pressor and ventilatory responses to contraction were not attenuated by injection of clonidine (1 microgram) onto the medulla (n = 3). In addition, our findings were not due to a clonidine-induced withdrawal of sympathetic outflow, because intrathecal injection of clonidine (1 microgram) did not attenuate increases in arterial pressure and ventilation evoked by high-intensity electrical stimulation of the cut central end of the sciatic nerve (n = 5). Furthermore, our findings were not due to a local anesthetic action of clonidine, because application of this agent to the dorsal roots had no effect on the discharge of group IV muscle afferents. We conclude that stimulation of alpha 2-adrenergic receptors in the spinal cord attenuates the reflex pressor and ventilatory responses to static contraction.     

Influence of clonidine on the acute dependence response elicited in naive rats by naloxone

Clonidine has been used successfully in the treatment of opiate dependence. The discomforting effects of withdrawal are attenuated by the drug. The question of whether the more central process of dependence is affected by clonidine was tested in the present study. Change in plasma corticosterone was used as the indication of the stress of acute withdrawal from morphine. Conscious, unrestrained male rats showed a dose-related, though somewhat delayed, increase in plasma corticosterone after clonidine (0.01-0.1 mg/kg). The suggested mechanism for this effect involves presynaptic inhibition of noradrenergic neurons inhibiting CRF (corticotropin-releasing factor) release. Similar animals showed an elevation of plasma corticosterone after naloxone (0.4 mg/kg) was administered 3 hrs following a single morphine-priming (10 mg/kg). The naloxone-precipitated response was unaffected by clonidine (0.04 mg/kg). This dose of clonidine did not substitute for morphine-priming to produce the naloxone-precipitated response. The data suggests that clonidine elevated plasma corticosterone by an indirect mechanism. Further, the stress associated with acute withdrawal is unaffected by clonidine suggesting that the drug does not alter dependence development.     

Cholera toxin and pertussis toxin on opioid- and alpha 2-mediated supraspinal analgesia in mice.

Cholera toxin, an agent that impairs the function of Gs transducer proteins, was injected (0.5 microgram/mouse, icv) and the antinociceptive activity of opioids and clonidine was studied 24h later in the tail-flick test. In these animals, an enhancement of the analgesic potency of morphine, beta-endorphin and clonidine could be observed. Cholera toxin did not modify the antinociception evoked by the enkephalin derivatives DAGO and DADLE. Pertussis toxin that catalyses the ADP ribosylation of alpha subunits of Gi/Go regulatory proteins was given icv (0.5 microgram/mouse). This treatment reduced the analgesic effect of opioids and clonidine. However, while the analgesia elicited by DAGO, DADLE and clonidine was greatly decreased, the effect of morphine and beta-endorphin was reduced to a moderate extent. It is concluded that Gi/Go regulatory proteins functionally coupled to opioid and alpha 2 receptors are implicated in the efficacy displayed by opioids and clonidine to produce supraspinal analgesia. Moreover, these two receptors are susceptible to regulation by a process that might involve a Gs protein.     

Differential cardiovascular effects of central clonidine and B-HT 920 in conscious rats

The effect of intracerebroventricular (i.c.v.) injection of the alpha 2-adrenoceptor agonists clonidine and B-HT 920 on mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of noradrenaline and adrenaline was examined in conscious unrestrained rats. The injection of 1.0 microgram clonidine significantly decreased MAP and slightly decreased HR. Plasma noradrenaline and adrenaline levels were slightly but not significantly decreased after the injection of 1 microgram clonidine. In contrast, the injection of 0.1-10.0 micrograms B-HT 920 increased MAP and decreased HR. Plasma noradrenaline and adrenaline levels were slightly increased after the injection of the 1- and 10-micrograms doses. The i.c.v. injection of the alpha 2-antagonist rauwolscine slightly but not significantly increased MAP and plasma noradrenaline and adrenaline levels. The responses to i.c.v. injection of clonidine and B-HT 920 were not changed by prior administration of rauwolscine. Neither the pressor response to B-HT 920 nor the depressor response to clonidine was abolished by rauwolscine, suggesting that neither response was mediated by alpha 2-adrenoceptors.     

The effect of single and chronic administration of imipramine on clonidine-induced hypothermia in the rat

The effect of imipramine (IMI) on the hypothermic action of clonidine, 50 μg/kg iv., was examined after a single dose and after 7, 14 and 21 days of IMI administration in doses of 2 and 10 mg/kg i.p. in rats. Single administration of IMI both in a dose of 2 and 10 mg/kg does not effect clonidine-induced hypothermia. IMI in a dose of 10 mg/kg given for one week significantly blocks the response to clonidine administration, but it has practically no effect in a dose of 2 mg/kg. After a three-week treatment also a dose of 2 mg/kg blocks clonidine-induced hypothermia. It has been demonstrated that the chronic administration of IMI in contrast to the single one significantly blocks clonidine hypothermia.     

Effects of long-term administration of clonidine on plasma renin activity.

Plasma renin activity (PRA) was studied before and during long-term treatment with moderate oral doses (0.2 or 0.3 mg/d) of clonidine. Nine outpatients with essential hypertension received clonidine for 12 weeks; a significant decrease in blood pressure was evident in all patients. Except for a nonsignificant increase after 12 weeks of treatment, PRA values were not notably changed by clonidine therapy. No correlation was found between individual blood pressure changes and PRA variation during the study. The absence of a net effect on PRA in this study does not exclude more complex interactions of clonidine with the renin-angiotensin system. Nonetheless, clonidine cannot generally be classified as a "renin-inhibiting" drug.     

Factors affecting angiotensin II-induced hypothermia in rats

Systemic administration of angiotensin II (AII) to the rat has previously been shown to induce a dose-dependent, hypothermic response manifested by a fall in colonic temperature (CT), a decrease in heat production and an increase in tail skin temperature (TST). The factors mediating AII-induced hypothermia and their site of action were the subjects of the present investigation. To this end, intracerebroventricular administration of 1 microgram of AII induced a 0.4 degrees C reduction in CT and a 2.4 degrees C increase in TST. In contrast, SC administration of 200 micrograms angiotensin III/kg induced a slight increase in CT but had no affect on TST. Pretreatment with the AII-receptor antagonist, saralasin, at either 1 or 10 micrograms/kg, SC did not affect either the fall in CT or the increase in TST induced by administration of 200 micrograms AII/kg, SC. However, the administration of 100 micrograms saralasin/kg, SC attenuated both the fall in CT and the increase in TST induced by either 100 or 200 micrograms AII/kg. Since both the presynaptic alpha adrenoceptor agonist, clonidine, and the opioid antagonist, naloxone, modulate the pressor and dipsogenic responses to AII, their effects on AII-induced hypothermia were tested. Both clonidine (25 micrograms/kg, SC) and naloxone (1 mg/kg, IP) enhanced the fall in CT. Clonidine lengthened the duration of the increase in TST while naloxone had no effect. Pretreatment with the presynaptic adrenoceptor antagonist, yohimbine (300 micrograms/kg, SC), did not alter the hypothermic response to administration of AII. To determine whether vasodilation of the tail of the rat was mediated by AII-induced prostaglandin release, indomethacin (4 and 6 mg/kg) was administered.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of alpha 1 and alpha 2 activation of adrenergic receptors on aqueous humor dynamics

Effects of phenylephrine (alpha 1-adrenergic agonist), prazosin (alpha 1-adrenergic antagonist), clonidine (alpha 2-adrenergic agonist), and yohimbine (alpha 2-adrenergic antagonist) on aqueous humor (AH) dynamics were studied with a cat eye model. Phenylephrine (130 microgram/ml) inhibited AH outflow (67% at 90 min. period) more than AH formation (26% at the same period) indicating the intraocular pressure (IOP) might be raised by the administration of phenylephrine. Prazosin (0.1 microgram/ml) produced effects opposite to those of phenylephrine (55% reduction of AH formation and 25% reduction of AH outflow at 3 hr. period) suggesting the alpha 1-adrenergic receptor is responsible for increases rather than decreases of IOP. Both clonidine (10 microgram/ml) and yohimbine (0.1-1.0 microgram/ml) inhibited AH formation (60% inhibition) more than AH outflow (no inhibition for clonidine and 40% inhibition for yohimbine) to lower IOP. The conventional theory of receptor antagonism does not seem to function at alpha 2-receptor sites.     

延髓弧束核微量注射可乐宁对自发性高血压大鼠...

In order to study whether atrial natriuretic factor (ANF) is involved in the depressor effect of clonidine, microinjection of the latter into nucleus tractus solitarii (NTS) was carried out in anesthetized stroke-prone spontaneously hypertensive rats (SHRsp) and normotensive Wistar-Kyoto (WKY) rats. Each strain was randomly divided into three groups by injecting: (1) clonidine (1.0 microgram/0.2 microliter); (2) yohimbine (3.3 micrograms/0.2 microliter) followed by (1); (3) artificial cerebral spinal fluid (ACSF, 0.2 microliter) as control. A decrease of blood pressure and heart rate and a suppression of ANF release elicited by clonidine were significantly greater in SHRsp than in WKY rats. After blockade of alpha 2-receptor with yohimbine, the hypotensive effect of clonidine was blocked completely in WKY rats, but only partially in SHRsp, while the suppression effect on ANF release was eliminated in both strains. In addition, the decrease of plasma catecholamine produced by clonidine could also be blocked after yohimbine. The results suggest that ANF probably does not contribute to the depressor effect of centrally administered clonidine, while in SHRsp the decrease of plasma ANF might be a blood pressure-dependent compensatory response.     

Intracerebroventricular injection of antibodies directed against Gs alpha enhances the supraspinal antinociception induced by morphine, beta-endorphin and clonidine in mice.

The intracerebroventricular (i.c.v.) injection of antisera directed against different sequences of Gs alpha to mice enhanced the antinociceptive potency of the opioids morphine, beta h-endorphin-(1-31) and of the alpha 2-agonist clonidine when studied 24 h later in the tail-flick test. The activity of DAGO, DADLE, DPDPE and [D-Ala2]-Deltorphin II remained unchanged after that treatment. Cholera toxin (0.5 microgram/mouse, i.c.v.), agent that impairs the receptor regulation of Gs transducer proteins promoted comparable changes in the supraspinal analgesia induced by these substances. Six days after a single i.c.v. injection (0.5 microgram/mouse) of pertussis toxin the antinociceptive activity of all the opioids and clonidine appeared diminished. It is concluded that opioids and clonidine promote analgesia after binding to receptors functionally coupled to Gi/G(o) proteins, moreover, the activity of morphine, beta-endorphin and clonidine in this test seems to be counteracted by a process involving activation of Gs alpha transducer proteins.     

Variations in the effect of clonidine on arterial pressure in rats in the presence of various anesthetics]

The central hypotensive agent, clonidine (30 microgram/kg i.v.) has been injected in normotensive rats anesthetized with various agents. This dose of clonidine elicits usually a biphasic blood pressure response, i.e. a transient increase due to peripheral vasoconstriction, followed by a long lasting decrease. This has been observed in the animals anesthetized with pentobarbitone as well as with urethane. The hypotensive effect is abolished during chloralose, ketamine or Alfatésine anesthesia. These data emphasize that some anesthetics mays particularly modify the effects of centrally acting cardiovascular drugs.     

Hypotensive action of prolactin in rats with spontaneous hypertension

Rats (SHR) weighing 240 +/- 10 g with spontaneous hypertension were given intraperitoneally porcine prolactin in doses from 0.2 to 2000 micrograms/kg of body weight. The systolic pressure was measured before hormone administration and 2 hours after it. It was found that prolactin in doses of 200 to 2000 micrograms/kg caused a decrease of the systolic pressure by 22%. The dose of 20 micrograms/kg decreased this pressure by 9% and the dose of 0.2 microgram/kg by 7.9%.     

Chronic growth hormone administration does not suppress endogenous growth hormone secretion in patients with neurosecretory growth hormone dysfunction.

Short children who respond normally to growth hormone (GH) stimulation, but have a subnormal spontaneous secretion of GH (neurosecretory GH dysfunction, NSD) are treated with exogenous GH which might suppress their endogenous GH secretion. The effect of chronic administration of GH (8-24 months) on plasma GH responses to GHRH, clonidine and spontaneous GH secretion were studied in 17 NSD patients. The diagnosis of NSD was based on a normal GH response to clonidine (greater than 10 micrograms/l) and an integrated concentration of (IC-GH) GH less than 3.2 micrograms/l. The GH dose used in this study was 0.25 IU/kg three times a week in 10 patients and 0.05 IU/kg daily in 7 patients. Insulin-like growth factor I levels (nmol) increased significantly on therapy from 9.3 +/- 3.8 to 24.4 +/- 22.4 (p less than 0.001). The GH response (microgram/l) to GHRH was 20.4 +/- 5.5 before treatment and 22.4 +/- 6.2 on GH. Peak GH after clonidine was 22.4 +/- 8.9 and 22.8 +/- 8.1, respectively. There was no significant decrease in the number of GH spontaneous peaks (1.8 +/- 0.7 vs. 2.0 +/- 0.7, respectively) or in the area under the curve. A subcutaneous GH bolus of 0.25 IU/kg in 4 patients resulted in a GH peak of 55-82 micrograms/l at 3-5 h and a gradual return to basal levels at 15-20 h after GH administration. The first spontaneous GH peak appeared 26-28 h after GH injection, peak amplitude was 10-15 micrograms/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serotonin mediation of the protective effect of clonidine against pentylenetetrazol-induced seizures in rats

An intraperitoneal injection of 0.5 mg/kg clonidine significantly increased the latency to the first convulsion and reduced tonic seizures and mortality caused by pentylenetetrazol (PTZ), 90 mg/kg, administered subcutaneously to rats. 1 mg/kg clonidine produced similar effects except that tonic seizures were not significantly affected. No effect was observed with 0.01 or 0.1 mg/kg clonidine. Metergoline (1 mg/kg) and methysergide (10 mg/kg), administered intraperitoneally, completely prevented the effect of 0.5 mg/kg clonidine on PTZ-induced seizures. An intraperitoneal injection of 5 mg/kg of d-fenfluramine, a releaser of 5HT from nerve terminals, significantly reduced tonic seizures and completely blocked mortality caused by PTZ but did not significantly modify the latency to the first convulsion. The results suggest that serotonin plays an important role in the protective effect of 0.5 mg/kg clonidine against PTZ-induced seizures. Possible reasons for the different effects of clonidine on different experimental seizures are discussed.     

Effects of oral clonidine on plasma 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) in man: Preliminary report

Repeated (N=15) administration of clonidine (0,1,5 μg/kg,p.o.) to three normotensive male subjects resulted in significant decreases in plasma free 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) at three hours for both the 1 μg/kg dose (p < .05) and the 5 μg/kg dose (p < .01) when compared to concentrations following placebo. The mean decrement in plasma free MHPG following a 5 μg/kg dose was 36%. Systolic blood pressure fell a mean of 17 mmHg after 1 μg/kg and 37 mmHg after 5 μg/kg of clonidine. The application of a clonidine challenge test to assess noradrenergic receptor sensitivity $\text{in}$$\text{vivo}$ is discussed.     

A comparison of the inhibitory effects of clonidine and guanfacine on the behavioral and autonomic components of morphine withdrawal in rats

Intravenous administration of naloxone (0.5 mg/kg) to morphine dependent rats elicited classical autonomic and behavioral symptoms of narcotic abstinence including hypertension, tachycardia, withdrawal body shakes, escape attempts, diarrhea, etc. Pretreatment of dependent rats with either clonidine (3–90 μg/kg) or guanfacine (3–900 μg/kg) produced a dose-dependent reduction in the hypertensive response to subsequent injection of naloxone. Clonidine was about 12 times more potent than guanfacine in inhibiting this autonamic symptom of withdrawal. Both drugs were less effective at blocking body shakes and escapes, however, when all symptoms were combined in a ranked score, guanfacine was less effective than clonidine at reducing the ranked abstinence intensity score. Since clonidine blocked the autonomic component of withdrawal at doses more consistent with its clinical anti-withdrawal actions, it is possible that 1) measurement of behavioral signs of withdrawal in rats is a less sensitive index than is measurement of autonomic changes associated with withdrawal, or, 2) a reduction in autonomic outflow in general is most relevant to suppressing the apparent intensity of the abstinence syndrome.     

Clonidine reduces elevated cerebrospinal fluid catecholamine levels in patients with essential hypertension

Cerebrospinal fluid (CSF) catecholamines were measured in normotensive patients and in patients with mild to moderate essential hypertension. CSF-norepinephrine (NE) concentrations were 50% lower in the normotensive individuals (127 ± 28 vs. 240 ± 23 pg/m1) (P<0.01). In hypertensive patients, CSF-NE was inversely related to age (r =-0.68; P<0.01) and directly related to plasma NE (r = 0.61; P<0.05). Clonidine (450 mcg/day for 2 weeks) significantly reduced CSF-NE (?40%) in hypertensive patients. In addition, it decreased blood pressure, plasma and urinary NE. Urinary VMA was not affected by clonidine. No correlation was observed between clonidine effects on BP and on plasma or CSF catecholamines. This study indicates that patients with essential hypertension have elevated levels of CSF-NE which are reduced after treatment with clonidine. The elevation of CSF-NE suggests that central (spinal?) noradrenergic activity may be increased in patients with mild to moderate essential hypertension, and that can be reduced by treatment with clonidine.