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.     

Sympathetic overactivity in active ulcerative colitis: effects of clonidine

Previous reports suggest that inflammatory bowel diseases may be accompanied by abnormalities in the neural autonomic profile. We tested the hypotheses that 1) an exaggerated sympathetic activity characterizes active ulcerative colitis (UC) and 2) a reduction of sympathetic activity by clonidine would be associated with clinical changes of UC. In 23 patients with UC and 20 controls, muscle sympathetic nerve activity (MSNA), ECG, blood pressure, and respiration were continuously recorded, and plasma catecholamine was evaluated both at rest and during a 75 degrees head-up tilt. Autonomic profile was assessed by MSNA, norepinephrine, epinephrine, spectral markers of low-frequency (LF) cardiac sympathetic (LF(RR); normalized units) and high-frequency (HF) parasympathetic (HF(RR); normalized units) modulation and sympathetic vasomotor control (LF systolic arterial pressure; LF(SAP)), obtained by spectrum analysis of the R-R interval and systolic pressure variability. Among UC patients, 16 agreed to be randomly assigned to 8-wk transdermal clonidine (15 mg/wk, 9 subjects), or placebo (7 patients). An autonomic profile, Disease Activity Index (DAI), and endoscopic pattern were compared before and after clonidine/placebo. At rest, MSNA, heart rate (HR), LF(RR), LF/HF, and LF(SAP) were higher and HF(RR) was lower in patients than in controls. Tilt decreased HF(RR) and increased MSNA and LF(RR) less in patients than in controls. Clonidine decreased HR, MSNA, epinephrine, LF(RR), and increased HF(RR), whereas placebo had no effects. Changes of the autonomic profile after clonidine were associated with reduction of DAI score. An overall increase of sympathetic activity characterized active UC. Normalization of the autonomic profile by clonidine was accompanied by an improvement of the disease.     

Clonidine increases food and protein consumption in rats

Rats were given clonidine or its diluent, and allowed to eat freely from two isocaloric diets that differred in protein or carbohydrate content. Low clonidine doses (25–50 μg/kg) significantly increased total food and protein intake by rats given access to a high and a low protein diet. Several pairs of diets, differing in protein contents, were tested; clonidine's effect was greatest when a diet containing 30–45% protein was paired with one that was very low (5%) in protein. Higher clonidine doses (200 μg/kg) failed to modify either total food or protein intake. Clonidine had no effects on food or nutrient intake among animals given access to diets that differed in carbohydrate content (25 or 70% carbohydrate, plus 25% protein). In rats given access to only one diet, clonidine administration decreased food consumption when the diet was low in protein (5%), but increased consumption when the diet contained 25 or 50% protein. These data suggest that central noradrenergic synapses participate in the mechanisms controlling appetites for proteins. Clonidine may enhance protein intake by stimulating presynaptic alpha receptors, thus diminishing central noradrenergic tone. This effect on noradrenergic transmission is probably partly overcome by protein consumption, which increases brain tyrosine levels and thus can accelerate norepinephrine synthesis. Clonidine or related drugs may be useful clinically in treating diseases characterized by impaired appetite or increased need for protein.     

Clonidine and the hormonal responses to graded exercise in healthy subjects

The aim of this study was to assess the acute effects of clonidine, an alpha 2-adrenergic agonist, on hormonal responses to graded exercise in 8 healthy young men. After fasting overnight, each subject was tested on 2 mornings, 1 week apart. On one occasion he was given 200 micrograms clonidine orally and on the other identical placebo tablets, the order being randomized in a double-blind fashion over the 2 days. Thereafter each subject performed 2 successive treadmill runs, equivalent to 60 and 100%, respectively, of maximal aerobic power. Clonidine pretreatment blunted the maximal increase in plasma catecholamines by more than 60% of the control response (p less than 0.01), without significantly altering the rise of plasma cortisol or ACTH. Furthermore, clonidine significantly reduced the exercise-induced maximal rise in plasma glucose, without modifying the slight decline in mean plasma insulin or increase in pancreatic glucagon levels. The drug did not affect the maximal increments in plasma growth hormone or prolactin occurring after exercise. It was concluded that a single dose of clonidine suppressed peripheral sympathetic responses, without altering central (pituitary) alpha-adrenergic-mediated hormonal responses, to short-term exercise in healthy men.     

Prospective double-blind trial of synthetic steroid (Org OD 14) for preventing postmenopausal osteoporosis.

A double-blind trial of Org OD 14, a synthetic steroid with an unusual endocrine profile, was conducted on 100 postmenopausal women; of these, 63 completed two years'' treatment (33 Org OD 14; 30 placebo). A dose of 2.5 mg/day successfully prevented bone loss over two years, whereas a significant reduction in bone mineral content occurred in women taking placebo, the rate being comparable to that in earlier studies (p less than 0.01). At the dosage used (2.5 mg/day) Org OD 14 also significantly reduced the severity of menopausal complaints (flushing, sweating, etc). Vabra aspiration curettage in 20 cases 6-18 months after starting active treatment showed no evidence of endometrial hyperplasia, though weak proliferation of the endometrium was seen in three. Org OD 14 may provide a new approach to hormonal prevention of bone loss in postmenopausal women without inducing appreciable endometrial stimulation; the potential value of Org OD 14 in osteoporosis and other post-climacteric complaints warrants further investigation.     

Effects of clonidine preemptive analgesia on acute postoperative pain in abdominal surgery

Preemptive analgesia refers to blockade of afferent nerve fibers before a painful stimulus, which prevents or reduces subsequent pain even beyond the effect of the block. The aim of the study was to compare the effect of clonidine used before and at the end of operation on pain control in abdominal surgery. A total of 77 patients admitted for colorectal surgery were randomly classified into three groups: epidural clonidine before operation, epidural clonidine at the end of operation, and control group. After the operation on patient demand, analgesia with boluses of epidural morphine was instituted. The parameters of postoperative pain level using VAS score (visual analog scale), sedation and analgesics consumption were determined as outcome measures at 1, 2, 6, and 24 h of the operation. Clonidine administered before operation provided lowest pain scores at 6 and 24 h (p < 0.05). Clonidine administered at the end of operation had low pain scores at 1 and 2 h, with a significant pain breakthrough thereafter (6.93 +/- 1.66 at 6 h and 4.04 +/- 2.39 at 24 h) compared with the group administered clonidine before operation (3.60 +/- 2.94 and 3.71 +/- 1.82). Clonidine administered before operation provided less sedation (p < 0.05) and a significantly lower use of analgesics (p < 0.05). Blockade of nociceptive stimulus using the centrally acting alpha2-adrenergic agonist clonidine before the onset of pain stimulus resulted in reduced pain levels, sedation and analgesic requirement.     

Pertussis toxin-sensitive pathway inhibits glucose-stimulated Ca2+ signals of rat islet beta-cells by affecting L-type Ca2+ channels and voltage-dependent K+ channels

A role of pertussis toxin (PTX)-sensitive pathway in regulation of glucose-stimulated Ca2+ signaling in rat islet beta-cells was investigated by using clonidine as a selective agonist to alpha2-adrenoceptors which link to the pathway. An elevation of extracellular glucose concentration from 5.5 to 22.2 mM (glucose stimulation) increased the levels of [Ca2+]i of beta-cells, and clonidine reversibly reduced the elevated levels of [Ca2+]i. This clonidine effect was antagonized by yohimbine, and abolished in beta-cells pre-treated with PTX. Clonidine showed little effect on membrane currents including those through ATP-sensitive K+ channels induced by voltage ramps from -90 to -50 mV. Clonidine showed little effect on the magnitude of whole-cell currents through L-type Ca2+ channels (ICa(L)), but increased the inactivation process of the currents. Clonidine increased the magnitude of the voltage-dependent K+ currents (IVK). These clonidine effects on ICa(L) and IVK were abolished in beta-cells treated with PTX or GDP-betaS. These results suggest that the PTX-sensitive pathway increases IVK activity and decreases ICa(L) activity of islet beta-cells, resulting in a decrease in the levels of [Ca2+]i elevated by depolarization-induced Ca2+ entry. This mechanism seems responsible at least in part for well-known inhibitory action of PTX-sensitive pathway on glucose-stimulated insulin secretion from islet beta-cells.     

Controlled trial of budesonide given by the nebuhaler in preschool children with asthma.

OBJECTIVE--To determine whether the inhaled corticosteroid budesonide, given by a Nebuhaler spacing device, was effective in prophylaxis of asthma in preschool children. DESIGN--Double blind, placebo controlled, random order crossover trial with two week practice run in period. SETTING--Outpatient clinic referrals in secondary referral centre. PATIENTS--39 children aged 2-6 years selected for the following: able to use Nebuhaler; parents able to complete record card; poorly controlled asthma (defined); not already on systemic or inhaled steroids. Eleven withdrew for various reasons not connected with intolerance to budesonide. Age, sex, other atopies, and symptoms during run in period were similar in the 28 children who completed the trial and in the 11 who withdrew. INTERVENTIONS--Budesonide 200 micrograms or placebo (both one puff) given twice daily during 6-week treatment or control periods, using Nebuhaler after prior training. Three week "washout" at crossover. Compliance monitored by weighing canisters. Patients withdrawn if their acute attacks required treatment with systemic steroids. END POINT--Control of asthma. MEASUREMENTS AND MAIN RESULTS--Peak expiratory flow rate measured twice daily where cooperation allowed. Diary of symptoms and concomitant drug use kept daily. Results showed mean peak flow significantly higher (12% in mornings, 14% in evenings) in second three weeks of intervention compared with control period (95% confidence intervals 6.3-17.3% and 7.2-21.0%). Supplementary bronchodilator drugs reduced by 50% during intervention periods. CONCLUSIONS--Budesonide given by Nebuhaler is effective prophylaxis for preschool children with frequent asthma.     

Nifedipine in hypertensive emergencies.

The effects and safety of using oral nifedipine 10-20 mg as acute antihypertensive treatment were studied in a single-blind placebo-controlled study of 25 consecutive patients with very high blood pressure requiring emergency reduction. In addition the effect of this treatment on cerebral blood flow was investigated using xenon-133 in 10 patients randomly allocated to receive oral nifedipine or intravenous clonidine. Whereas placebo did not alter the blood pressure, oral nifedipine significantly reduced the systolic and diastolic blood pressures in all 25 patients (from 221 +/- 22/126 +/- 14 mm Hg to 152 +/- 20/89 +/- 12 mm Hg after 30 minutes, p less than 0.001). Heart rate increased from 74 +/- 11 to 84 +/- 11 beats/minute (p less than 0.01); this effect was inversely related to age (r = -0.65, p less than 0.01). The falls in systolic and diastolic blood pressures were closely related to the blood pressures before treatment ) r = 0.67, p less than 0.001 for systolic, and r = -0.58, p less than 0.01 for diastolic values). No serious unwanted effects were observed. Measurement of cerebral blood flow after nifedipine showed an increase in flow in four out of five patients. Clonidine, by contrast, reduced cerebral blood flow in all patients by up to 28%. Nifedipine is a simple, effective, and safe alternative drug for managing hypertensive emergencies, especially when continuous monitoring of the patient cannot be guaranteed.     

Effect of new beta-adrenergic blocking agent,Atenolol (Tenormin), on pain frequency,trinitrin consumption,and exercise ability.

In 11 patients with severe angina pectoris a new beta-blocking drug, atenolol (Tenormin; I.C.I.66082), was found in a double-blind randomized trial to reduce significantly the frequency of anginal attacks (P less than 0-001) and the amount of trinitrin consumed (P less than 0-03) in comparison with practolol and placebo. There was no significant improvement in the patients'' ability to exercise on the bicycle ergometer.     

An affinity label for alpha 2-adrenergic receptors in rat brain

Clonidine, a potent and highly selective alpha 2-adrenergic agonist of the central nervous system, was modified. Insertion of the strong alkylating isothiocyanate group (NCS) group, at its aromatic residue, makes clonidine a potential affinity label of the alpha 2-adrenergic receptors. In displacement of [3H]clonidine and p-[3H]aminoclonidine from rat brain membrane preparations, clonidine-NCS demonstrates high affinity for the alpha 2-adrenergic receptors (Kd = 50 mM). The covalent labelling of the central alpha 2-receptors requires higher concentrations of the irreversible ligand (1-70 microM), thus indicating possible non-productive interactions at the environment of the receptor site. Only partial protection of the receptors is observed with a reversible alpha 2-agonist. The new clonidine analog appears to be a general ligand for the alpha 2-adrenergic receptors and might serve as a potential affinity probe for these receptors.     

Ketanserin in the treatment of traumatic vasospastic disease.

The specific serotonin receptor blocker ketanserin was given orally to 12 patients with traumatic vasospastic disease in a double blind crossover study. The effect of treatment was assessed by measuring finger systolic pressure and rewarming time after cold provocation and by medical interview and diaries. Median (range) percentage change in finger systolic pressure after cooling was 50 (0-100)% after treatment with ketanserin compared with 0 (0-90)% after placebo. Median (range) rewarming time after cooling decreased from 320 (236-972)s with placebo to 160 (88-404)s after treatment with ketanserin. These changes were not significant. Ninety five percent confidence intervals for difference between the treatments, however, showed that finger systolic pressure may be 80% better and rewarming time 256 seconds faster after treatment with ketanserin than after placebo. The number of attacks did not differ significantly between the two treatments. Two patients had a feeling of warmth in their hands during treatment with ketanserin. The results suggest that orally administered ketanserin may improve digital circulation in patients with traumatic vasospastic disease, but larger numbers of patients are required to assess the true effect of treatment with ketanserin in this disease.     

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.     

High-dosage isosorbide dinitrate therapy for angina.

We investigated the possibility that high dosages (480 mg/d) of isosorbide dinitrate might reduce the frequency of angina attacks in selected patients who had not responded to low dosages of the drug (40 mg/d), and that the patients could tolerate the high levels of medication and maintain their responsiveness over the long term. In the single-blind phases of this trial 24 patients with grade 3 stable angina pectoris were given a placebo for 4 weeks and then increasing doses of isosorbide dinitrate for a further 6 weeks. The 19 patients who both responded to and tolerated high doses of the drug kept taking 480 mg/d for an average of 1 year. The average weekly rate of angina attacks fell by 74%, from 6.05 in the placebo phase to 1.6 during long-term active treatment (p less than 0.01). Nitroglycerin consumption decreased accordingly. The patients'' assessments of their levels of activity and well-being and their angina thresholds showed improvement among most of them. The trend of angina frequency was stable in 12 cases, downward in 6 and upward in only 1 case. Exercise performance as evaluated by a graded treadmill test showed a small but nonsignificant improvement of 18%. It was concluded that some patients who do not respond to the antianginal action of low-dosage isosorbide dinitrate and cannot be given beta-blockers may respond to high dosages and tolerate them for over a year. Isosorbide dinitrate may be clinically useful in patients with coronary heart disease even though their exercise performance is not significantly improved.     

Stimulation of 3H-norepinephrine release by trifluoperazine from rat pineal glands

Trifluoperazine (5-200 microM) stimulated the release of 3H-NE from isolated whole pineal glands in a dose dependent manner. Trifluoperazine-induced release was not dependent on extracellular Ca++, whereas 60 mM K+-evoked release was attenuated in the presence of EGTA and zero Ca++ Krebs. 60 mM K+ and 50 microM trifluoperazine produced an additive effect on 3H-NE release. Clonidine (5 microM) significantly reduced trifluoperazine-induced release by approximately 50% in the presence of Ca++, and in its absence, clonidine significantly attenuated the trifluoperazine response by 42%. Thus trifluoperazine may be acting upon the alpha 2 receptor or intracellular stores of Ca++. These intracellular interactions remain for further study.     

Different alpha-receptor subtypes are involved in clonidine-produced analgesia in different pain tests

Dose-response curves for clonidine-produced analgesia in rats were constructed using the tail-flick and formalin tests. Subsequently, the relative role of alpha 1 and alpha 2 receptors in clonidine analgesia in each of these tests was determined using systemic administration of vehicle controls, tolazoline, yohimbine and prazosin prior to injection of an ED50 dose of clonidine. Clonidine was found to be significantly more potent in the formalin test than in the tail-flick test. Furthermore, clonidine analgesia in the tail-flick test was completely antagonized by tolazoline and yohimbine, but not by prazosin, whereas clonidine was antagonized by tolazoline and prazosin, but not by yohimbine in the formalin test. The implications of these findings with regard to the contributions of different alpha-receptor subtypes to clonidine-produced analgesia in different pain tests are discussed.     

Alpha-2 adrenergic and opioid receptor-mediated gastroprotection.

Clonidine inhibited the development of gastric mucosal lesions induced by either acidified ethanol or indomethacin. The ED50 values were: 7.1 and 5.2 microg x kg(-1) orally, respectively. The gastroprotective effect was antagonised by the pre-synaptic alpha-2 antagonist yohimbine, the more selective alpha-2 antagonist Ch-38083 and the pre-synaptic alpha-2B antagonist prazosin. Moreover, the non-selective opioid receptor antagonist naloxone, the delta receptor selective naltrindole also reversed the clonidine-induced mucosal protective action. Clonidine was also effective following intracerebroventricular administration with the ED50 of 37 ng/rat against ethanol-induced mucosal damage. Our results suggest that: 1) the gastroprotective effect of clonidine is likely to be mediated by alpha-2B adrenoceptor subtype; 2) there is an interaction between pre-synaptic alpha-2 adrenoceptors and opioid system; and 3) clonidine can induce gastroprotection by central mechanism.     

Combined oral and nasal beclomethasone diproprionate in children with atopic eczema: a randomised controlled trial.

In a double blind, placebo controlled, crossover trial in 26 children with severe atopic eczema those receiving four weeks'' treatment with combined oral plus nasal beclomethasone diproprionate improved significantly more than those receiving placebo. No adverse effects were observed, but 24 hour urinary cortisol excretion was slightly reduced. This combination may provide effective treatment in refractory atopic eczema with relatively little of the danger associated with systemic administration of prednisolone and other traditional corticosteroids.     

Effect of clonidine on three types of experimental hypertension and on plasma renin activity in dogs]

Intra-cisternal clonidine (3 microgram/kg) reduced hypertension and cardiac acceleration after defrenation in dogs, but did not act in intra-venous infusion (10 microgram/kg). The renin activity was not modified. Clonidine was always inactive on hypertension after stimulation of visceral afferences or after injection of potassium cyanidine. These results show that a central mechanism was implied in the anti-hypertensive action of clonidine.     

Effects of "natural oestrogen" replacement therapy on menopausal symptoms and blood clotting.

In a double-blind study on the value of equine ("natural") oestrogens 30 patients presenting with menopausal symptoms in a group practice were monitored for possible adverse effects on blood clotting, weight, and blood pressure. The women were randomly allocated to two groups and given either three months'' hormone treatment followed by three months'' placebo or vice versa. An appreciable amelioration of all symptoms on placebo made it difficult to asses the genuine value of oestrogen treatment during the period of study. Both groups made a dramatic clinical improvement during the first three months. Nevertheless, the symptoms of the 15 women who received oestrogen first returned after the cross-over to placebo without any suggestion of a placebo response. In contrast, the other group who took placebo first did not deteriorate after changing to oestrogen. The menopausal index and the karyopyknotic index were not reliable guides to the need for oestrogen treatment. Hot flushes, however, were proportionately reduced on oestrogen and they seemed to be more readily eliminated in individual cases by oestrogen. The results of blood clotting studies indicated that natural oestrogen administration raised the levels of the extrinsic clotting factors VII and X and accelerated the prothrombin time. The findings were similar to those observed after three months synthetic oestrogen administration with oral contraception. Long-term studies and epidemiological surveys of the clinical incidence of thrombotic and other sequelae are needed before large-scale oestrogen replacement treatment can be recommended.