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PubMed2004

Chronic treatment with rilmenidine in spontaneously hypertensive rats: differences between two schedules of administration.

Rilmenidine is one of the lead compounds of the second generation of centrally acting antihypertensive drugs. In the first part of this study, 2 routes of administration of chronic treatment (1 month) with rilmenidine were compared. In conscious and pentobarbital-anesthetized spontaneously hypertensive rats (SHR), rilmenidine was delivered intraperitoneally either 250 microg/kg b.i.d. or 500 microg/kg/d infusion by means of minipumps. The possibility of rilmenidine-induced desensitization of central (brain cortex) and/or peripheral (kidney) alpha2-adrenoreceptors was studied in saturation experiments with the classic alpha2-adrenergic antagonist [H]rauwolscine. In the second part of this study, the cardiovascular and cardiac antihypertrophic effects of the most efficient procedure were investigated. The discontinuous administration of the drug was more effective than infusion. In rats treated with rilmenidine b.i.d., mean blood pressure was reduced by nearly 15% when no reduction occurred in SHRs treated with minipumps. With the first schedule of administration, plasma concentration of the drug reached a maximum of approximately 30 ng/ml when it was only 12 ng/ml with the continuous infusion of the same dose. Anesthesia with pentobarbital potentiated the antihypertensive effect of rilmenidine in rats treated discontinuously and unmasked an antihypertensive action in rats receiving the drug with minipumps. In saturation binding experiments, no significant changes in adrenergic receptors were observed in kidney membrane preparations. In contrast, in brain cortical membranes a reduction by about 50% of the Bmax of [H]rauwolscine value was observed in rats treated discontinuously with rilmenidine. In contrast, a 400% increase of the Bmax was observed in the brain of rats treated with minipumps. Over the one-month period of the second study, the discontinuous treatment with the 500 microg/kg/d dose of rilmenidine was still able to reduce blood pressure, at least at the peak concentration time, but did not induce any significant reduction of the ventricular mass. In conclusion, rilmenidine has only weak antihypertensive effects in conscious SHRs, even at doses higher than those that are active in rabbits and humans. As a consequence, it lacks significant cardiac antihypertrophic effects in this species. Pharmacokinetic data show that the rapid plasma withdrawal of this drug may explain this particular feature in rats.

Analysis of Variance↗
PubMed1995

The effects of rilmenidine and atenolol on mental stress, dynamic exercise and autonomic function in mild to moderate hypertension.

1. The effects of 4 week treatment with rilmenidine or atenolol on tests of mental stress, dynamic exercise, autonomic function and psychometric tests were evaluated in a randomized, double-blind, placebo-controlled, cross-over study. 2. After a 4 week placebo run-in, 12 patients with essential hypertension (blood pressure [BP] 160/95 +/- 15/7 mmHg) received rilmenidine 1-2 mg day-1, and atenolol 50-100 mg day-1, each for 4 weeks, with a 4 week placebo wash-out between drug treatments. 3. Both agents produced a comparable reduction in supine and erect BP. During the mental arithmetic test, BP and heart rate (HR) responses were similar for rilmenidine and atenolol. 4. During bicycle exercise, the increase in HR was significantly greater after rilmenidine (+50 vs 41 beats min-1, P = 0.04). During recovery, the areas under the curve for diastolic BP (46,450 vs 51,400 mmHg s, P = 0.02) and HR (49,445 vs 63,597 beats min-1 s, P = 0.001) were significantly less with atenolol than rilmenidine. 5. Neither rilmenidine nor atenolol affected mental performance as judged by arithmetic and psychomotor tests. Physiological responses to autonomic function tests (deep breathing, facial immersion, isometric handgrip and cold pressor) were preserved with both drugs. The standing to lying ratio was higher on atenolol (P = 0.01) and Valsalva ratio was higher on rilmenidine (P = 0.03). 6. In conclusion, rilmenidine and atenolol exerted comparable antihypertensive effects both at rest and during mental and dynamic stress. Atenolol attenuated HR responses to dynamic exercise and the Valsalva manoeuvre; rilmenidine did not interfere with the physiological responses of BP and HR during autonomic function tests.

Adrenergic beta-Antagonists↗
PubMed1996

Interactions of the cardiac chronotropic effects of rilmenidine with the autonomic nervous system in conscious dogs: comparison with clonidine.

1. The cardiac chronotropic effects of rilmenidine (10-100 micrograms kg-1) and clonidine (1-10 micrograms kg-1) were studied in conscious dogs with chronic atrioventricular block. 2. Rilmenidine and clonidine initially (< 3 min) decreased atrial rate, although the effect was not related to dose. More lastingly, ventricular rate was decreased in a dose-related manner (ratio, 1:21). Rilmenidine lowered mean blood pressure only at 100 micrograms kg-1, while clonidine had the same effect at doses of 5 micrograms kg-1 upward (ratio, 1:15). 3. When administered after atropine and pindolol, rilmenidine (50 micrograms kg-1) produced a decrease in atrial rate, with an identical intensity but longer duration than under basal conditions. When clonidine (2.5 micrograms kg-1) was given after atropine, no chronotropic atrial effect was observed. However, when clonidine (2.5 micrograms kg-1) was given after pindolol, it produced a decrease in atrial rate that was more marked, both in intensity and duration, than under basal conditions. After phenoxybenzamine, rilmenidine decreased atrial rate with a more marked and lasting effect than observed under basal conditions. Clonidine produced a bradycardic atrial effect identical to the basal effect. After yohimbine, rilmenidine and clonidine decreased atrial rate with an intensity similar to that under basal conditions, although the time course was totally different. 4. When given after atropine, rilmenidine (50 micrograms kg-1) and clonidine (2.5 micrograms kg-1) decreased ventricular rate as under basal conditions, whereas after pindolol and phenoxybenzamine, both drugs decreased ventricular rate less markedly than under basal conditions, both in intensity and duration. After yohimbine, rilmenidine and clonidine produced no chronotropic ventricular effect. 5. These results show that (a) the initial atrial bradycardia caused by rilmenidine results from both a decrease in sympathetic tone and an increase in cholinergic activity; while the effect of clonidine is caused mainly by the enhancement of cholinergic activity. For both drugs, alpha 2-adrenoceptors are involved at least in the initiation of the effect; (b) the very short duration of atrial bradycardia may result from reflex buffering in response to ventricular bradycardia. This buffering is less effective when heart rate was high; and (c) the ventricular bradycardia caused by both drugs is mainly the result of a decrease in sympathetic tone in response to the stimulation of alpha 2-adrenoceptors. The results also suggest that negative chronotropic postsynaptic alpha 2-adrenoceptors could be involved in the ventricular bradycardia.

Adrenergic beta-Antagonists↗
PubMed2000

Rilmenidine in the hypertensive type-2 diabetic: a controlled pilot study versus captopril.

BACKGROUND: Rilmenidine is an innovative antihypertensive agent that binds specifically to I1 imidazoline receptors. The antihypertensive efficacy of rilmenidine in treating type-2 diabetics has been demonstrated, and is associated with very good clinical and laboratory tolerance. DESIGN: This was a 6-month, double-blind, randomized, controlled study comparing the effects of rilmenidine and captopril on the progression of microalbuminuria in a population of patients with mild-to-moderate hypertension [90 mmHg < diastolic blood pressure (DBP) < 110 mmHg], type-2 diabetes, and microalbuminuria (30 mg/24 h < urine albumin excretion < or = 300 mg/24 h). RESULTS: Between month 0 and month 6, the mean supine blood pressure was reduced in a similar manner by rilmenidine (systolic blood pressure from 159 to 141 mmHg and diastolic blood pressure from 98 to 84 mmHg) and captopril (systolic blood pressure from 157 to 144 mmHg and diastolic blood pressure from 101 to 82 mmHg). The median value for microalbuminuria was reduced from 160 (90-260) to 56 (27-87) mg per 24 h by rilmenidine and from 144 (51-200) to 54 (41-123) mg per 24 h by captopril. Rate of clearance of creatinine was not significantly changed during the study by either treatment (with rilmenidine it varied from 95.2 to 95.6 ml/min; with captopril it varied from 86.2 to 90.4 ml/min). There was no statistical difference between the changes in levels of glycosylated hemoglobin for the groups treated with rilmenidine and captopril. Clinical and laboratory acceptabilities were good, and those for the two groups were comparable. CONCLUSION: Rilmenidine exerts similar antihypertensive effects to those of captopril on the hypertensive with type-2 diabetes. Decreases in microalbuminuria elicited by the two treatments do not differ. That administration of rilmenidine decreases microalbuminuria suggests that it could exert nephroprotective effects.

Aged↗
PubMed1993

Renal effects of rilmenidine in anesthetized rats: importance of renal nerves.

Renal function studies using standard clearance techniques were done in control and rilmenidine-infused (20 micrograms/Kg/min i.v. for 80 min) Wistar rats anesthetized with Inactin. The role of renal sympathetic nerves in the action of rilmenidine was assessed using rats in which the left kidney was denervated 7 to 10 days before the experiment. In other experiments, renal sympathetic nerve activity was recorded during infusion of rilmenidine. Arterial pressure and heart rate were decreased significantly by rilmenidine but changes in arterial pressure were limited to 10 to 12 mm Hg by ligating the proximal aorta during infusion of rilmenidine. Under these conditions, rilmenidine did not alter glomerular filtration rate significantly, but renal blood flow increased significantly in both innervated and denervated kidneys. Urine flow, total and fractional sodium excretion, and clearance of osmoles increased significantly in innervated kidneys but not in denervated kidneys. Free water clearance was decreased significantly, but only in the innervated kidney. Potassium excretion and fractional potassium excretion were increased significantly in both kidneys, although the change was larger in the innervated kidneys. Rilmenidine decreased renal sympathetic nerve activity progressively until by 80 min nerve activity was essentially absent. The data indicate that rilmenidine increases renal blood flow and potassium excretion by a mechanism independent of renal nerves, whereas the natriuresis and diuresis is dependent upon intact renal nerves. The increase in fractional excretion of sodium was associated with a marked decrease in renal sympathetic nerve activity suggesting that the natriuresis is caused by decreased tubular reabsorption of sodium subsequent to a central action of rilmenidine.

Adrenergic alpha-Agonists↗
PubMed1995

Effects of rilmenidine and clonidine on the electroencephalogram, saccadic eye movements, and psychomotor function.

Rilmenidine is a novel oxazoline derivative that is effective in the treatment of hypertension. Studies in animals have indicated that rilmenidine may reduce blood pressure without the associated central alpha 2 side effects of clonidine. The aim of this double-blind, crossover, placebo-controlled study was to evaluate the hypotensive and central sedative effects of single oral doses of rilmenidine (1 or 2 mg), clonidine (150 or 300 micrograms), and lorazepam (2.5 mg) in 12 healthy male volunteers. Drug effects were assessed with a test battery composed of resting electroencephalogram, auditory evoked responses (AERs), saccadic eye movements, psychomotor performance, and subjective ratings as well as blood pressure and heart rate. Rilmenidine and clonidine produced similar dose-dependent reductions in blood pressure without an effect on heart rate. Saccadic eye movements were not significantly impaired after rilmenidine (1 mg) treatment in contrast to after clonidine (150 micrograms) treatment. Peak saccadic velocity was impaired by all drugs except rilmenidine (1 mg), which was indistinguishable from placebo. The electroencephalographic spectral analysis also demonstrated greater sedation with lorazepam than with the other drugs and greater vigilance with placebo and rilmenidine (1 mg) than with lorazepam. AERs showed a differentiation in sedative effects between lorazepam and clonidine (300 micrograms) relative to placebo, rilmenidine (1 mg), and clonidine (150 micrograms). These results are consistent with the hypothesis that at lower doses, rilmenidine may act preferentially through imidazoline receptors, whereas at higher doses, alpha 2-adrenoceptors may become activated.

Adult↗
PubMed1998

Regression of left ventricular hypertrophy in hypertensive patients after 1 year of treatment with rilmenidine: a double-blind, randomized, controlled (versus nifedipine) study.

OBJECTIVE: To assess the effect of 1-year treatment with rilmenidine, an oxazoline compound that exerts its antihypertensive effects through binding to imidazoline receptors in the brainstem, on left ventricular hypertrophy (LVH) secondary to essential, mild-to-moderate hypertension [supine diastolic blood pressure (DBP)95-115 mmHg]. METHODS: We performed a double-blind, randomized, controlled (versus slow-release nifedipine) trial. Adjustment of treatment took place every month (M) between inclusion (MO) and an evaluation after 6 months (M6), then during M9 and after 1 year (M12) to achieve supine DBP values < or = 90 mmHg. Patients were dropped from our study if they had DBP> 95mmHg during two consecutive visits or DBP>115 mmHg on one occasion. The daily dosage of rilmenidine was 1 mg, and could be increased to 2 mg/day. The daily dosage of slow-release nifedipine was started from the beginning at the maximum dosage of 40 mg/day, so that there was no true adjustment of treatment despite the allocation of patients to a different unit in the case of DBP> 95 mmHg. The primary criterion was the change in left ventricular mass index (LVMI, g/m2), assessed by echocardiography, between MO and M12 for patients who completed the trial. RESULTS: After a 1-month placebo run-in period, 76 patients were selected and 73 were included (35 treated with rilmenidine and 38 treated with nifedipine). Fifteen patients withdrew from the study and two completed the study with a major deviation from protocol, leaving 56 patients (24 treated with rilmenidine and 32 treated with nifedipine) for a per-protocol analysis. Baseline demographic characteristics and history of arterial hypertension for the rilmenidine and nifedipine groups were similar, for included patients and for those taken into account for the per-protocol analysis. Between MO and M12, DBP in members of the per-protocol population was adequately controlled for those in the rilmenidine group (102.7+/-4.6 versus 88.5+/-7.1 mmHg, respectively) and for those in the nifedipine group (102.7+/-5.1 versus 85.6+/-79 mmHg, respectively). During MO, LVMI of patients in the rilmenidine group (176.9+/-41.3 g/m2) was slightly higher than that of patients in the nifedipine group (172.6+/-35.1 g/m2). During M12, LVMI was observed to have decreased both for patients in the rilmenidine group (to 154.8+/-40.2 g/m2, a decrease of 22.1+/-23.3 g/m2, P< 0.001) and for those in the nifedipine group (to 145.6+/-36.4 g/m2, a decrease of 26.9+/-29.5 g/m2, P< 0.001) but the difference between these two groups was not significant (P= 0.5). CONCLUSION: One-year treatment with a daily dosage of 1 or 2 mg rilmenidine achieves a significant reduction of left ventricular mass, which is not statistically different than that occurring with a daily dosage of 40 mg of slow-release nifedipine.

Adult↗
PubMed1999

[Essential arterial hypertension treated with rilmenidin : what dose for what patient?].

OBJECTIVE: To study the therapeutic interest of dose adaptation from 1 mg to 2 mg daily when treating essential hypertension with rilmenidine in monotherapy, in terms of normalisation of blood pressure, of clinical tolerance and of laboratory parameters. METHODS: In a non-comparative multicentre study conducted in France in patients with essential hypertension, rilmenidine was started at 1 mg daily. When the target blood pressure was not achieved (supine diastolic blood pressure (DBP) < or = 90 mm Hg) after 6 weeks, the dose was adapted to 2 mg daily. For persistent non-responders, a second antihypertensive was added from 3 months and a third from 6 months as necessary. Total follow up was for 12 months. RESULTS: Eighteen thousand two hundred and thirty five (18,235) patients of either sex, average age 61.2 years and 90 mm Hg < supine DBP < 115 mm Hg were included. Sixteen thousand four hundred and ninety six (16,496) patients were followed for 12 months with complete data being available for 15,963 of them., 13,565 (84.9%) were treated with rilmenidine in monotherapy, 9,626 (60.3%) at 1 mg daily, and 3,939 (24.6%) at 2 mg daily. For patients who were treated with rilmenidine 1 mg daily throughout the study, mean reduction of blood pressure between D0 and M12 was -27.5/-18.9 mm Hg. Mean reduction was -30.0/-20.3 mm Hg for those who completed the study on 2 mg per day. 82.8% of the analysed population were normalised with rilmenidine in monotherapy, 59.1% with 1 mg daily. Dose adaptation to 2 mg normalised an additional 23.7% of patients. Rilmenidine monotherapy was associated with good clinical and laboratory acceptability. CONCLUSION: The step-wise adaptation of rilmenidine dose in the treatment of essential hypertension is justified by the superior normalisation rate achieved by increasing the dose from 1 mg to 2 mg daily. This adaptation neither increases side effects nor changes laboratory parameters. These data support dose adaptation of rilmenidine monotherapy before association with another antihypertensive. However, neither ther blood pressure level nor associated risk factors predict the type of patients who will be normalised by 1 mg daily or those who require 2 mg. The practice of always starting rilmenidine at 1 mg daily in essential hypertension is therefore supported.

Antihypertensive Agents↗
PubMed2006

Reduced hemodynamic responses to physical and mental stress under low-dose rilmenidine in healthy subjects.

Activation of the sympathetic nervous system plays a major role in the pathogenesis and prognosis of cardiovascular diseases. Rilmenidine is an I(1)-imidazoline receptor agonist that reduces blood pressure by modulation of central sympathetic activity, but the effects of low-dose rilmenidine on the hemodynamic responses to physiological maneuvers that increase adrenergic drive is not known. To assess the effects of low-dose rilmenidine on the hemodynamic responses to stress, 32 healthy subjects (20-56 years old) underwent acute physical exercise (n = 15, individualized ramp protocol on treadmill) and mental stress (n = 17, word color Stroop and mental arithmetics tests) two hours after the oral administration of 0.5 mg of rilmenidine (RIL) or placebo (PLA) following a randomized, double-blind, placebo controlled crossover study. No subject complained of any side effect. Rilmenidine reduced peak exercise heart rate (PLA: 187 +/- 7; RIL: 181 +/- 9 bpm; P = 0.003), but did not modify peak aerobic power (VO(2max) - PLA: 41.7 +/- 6.2; RIL: 42.3 +/- 6.7 ml/kg/min; P = 0.26). During mental stress, rilmenidine inhibited the peak systolic (PLA: 123 +/- 10; RIL: 114 +/- 8 mmHg; P = 0.02) and diastolic (PLA: 86 +/- 7; RIL: 81 +/- 7 mmHg; P <0.05) blood pressure responses. In conclusion, rilmenidine reduced the hemodynamic response to physical and mental stress stimuli without limiting exercise capacity. These results support the concept that rilmenidine, at a dose lower than the ones recommended to treat hypertension, reduced the myocardial oxygen demand to stress and may carry potential clinical impact.

Administration, Oral↗
PubMed1988

Effects of two alpha 2 agonists, rilmenidine and clonidine, on the morphine withdrawal syndrome and their potential addictive properties in rats.

The interaction between adrenergic systems and opiate receptors or neuronal systems linked to these receptors has been previously demonstrated. For this reason, clonidine can be used to reduce withdrawal syndrome to opiates. Rilmenidine (S 3341) is a new agonist of alpha 2 adrenoceptors. The purpose of these experiments was to compare the effects of rilmenidine and clonidine on morphine withdrawal syndrome and their potential addictive properties in the rat. Rats were made morphine-dependent by repeated intraperitoneal (i.p.) administration of increasing doses of morphine. Withdrawal was precipitated by injecting naloxone subcutaneously. Withdrawal scores were evaluated for 10 minutes. Clonidine (0.05, 0.1 and 0.2 mg/kg, i.p.) and rilmenidine (5 and 10 mg/kg, i.p.) significantly reduced overall withdrawal scores. Addictive potential was evaluated in the rat by a place preference test after the following treatments (mg/kg, i.p.): rilmenidine 0.1 to 5, clonidine 0.01 to 0.5, heroin 0.12, and d-amphetamine 1.5. Rilmenidine did not modify the time spent in the conditioned side at doses of 0.1 to 1 and 5 mg/kg, but increased it at 2.5 mg/kg (+25%). In contrast, a reinforcing effect was induced by clonidine (+21%, +43%, +34% at 0.1, 0.25, 0.5 mg/kg), heroin (+39%) and amphetamine (+52%). In conclusion, rilmenidine as well as clonidine reduced the morphine withdrawal syndrome. However, rilmenidine was 100 times less active than clonidine. Clonidine, heroin and d-amphetamine have clear reinforcing properties. Rilmenidine did not exhibit dose-dependent reinforcing properties and the isolated effect noted after 2.5 mg/kg is difficult to interpret because it is minor and is not observed with a higher dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1988

Pharmacokinetics of rilmenidine in healthy subjects.

Rilmenidine is a novel alpha 2-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once or twice daily. The pharmacokinetic parameters were investigated after single or repeated administration in healthy subjects, using labeled and unlabeled compounds. Rilmenidine was rapidly and extensively absorbed, with an absolute bioavailability factor close to 1 and a maximal plasma concentration achieved within 2 hours. Rilmenidine was not subject to presystemic metabolism. Distribution was independent of the free fraction because rilmenidine was weakly bound to plasma proteins (less than 10%). The volume of distribution was approximately 5 l.kg-1 (315 liters). Elimination was rapid with a total body plasma clearance of approximately 450 ml.min-1 and an elimination half-life of approximately 8 hours. Renal excretion was the major elimination process (two-thirds of the total clearance). Metabolism was very poor, with a renal elimination of rilmenidine as the parent drug (urinary fraction of rilmenidine was about 65% and no metabolite plasma levels were detected). Linear pharmacokinetics were demonstrated for rilmenidine from 0.5 to 2 mg but, at 3 mg, a slight deviation from linearity was observed. In repeated administration, the linear disposition of rilmenidine with dose was confirmed.

Absorption↗
PubMed1994

Pharmacokinetics of rilmenidine in patients with chronic renal insufficiency and in hemodialysis patients.

The pharmacokinetics of rilmenidine (1 mg orally) was studied in 3 groups of patients with stable chronic renal insufficiency. This was an open, single-blind study following a single administration, and after 15 days of treatment. Group 1 included 11 patients with a creatinine clearance between 15 and 80 mL/min. Group 2 included 17 patients with a creatinine clearance < 15 mL/min. Group III included 10 hemodialysis patients. In patients with chronic renal failure, total plasma clearance and renal clearance of rilmenidine decreased; terminal half-life was 30-42 hours, which is clearly longer than previous values achieved in healthy volunteers. After repeated administration (1 mg daily in group 1, 1 mg every other day in group 2, 1 mg at the end of each dialysis session in group 3), the area under the curve was significantly increased, corresponding to drug accumulation. The steady state was reached after 6 days in patients in group 1 and after 8 days in patients in group 2. The pharmacokinetics of rilmenidine was linear since the terminal elimination half-life and renal clearance were not significantly different after single and repeated administration of rilmenidine. A positive correlation was found between rilmenidine total plasma clearance and creatinine clearance, and between rilmenidine renal clearance and creatinine clearance. Mean rilmenidine hemodialysance was 85 mL/min, that is, 26% of the rilmenidine renal clearance value achieved in healthy volunteers (330 mL/min). Thus, the following dosage schedule can be proposed. In patients whose creatinine clearance ranges between 15 and 80 mL/min, a 1 mg dose every day can be recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Rilmenidine and vigilance. Review of clinical studies.

In this study, the possible effects of rilmenidine on vigilance are evaluated. Sedation is the most disturbing side effect of alpha 2-agonists, especially during the first weeks of treatment. The level of vigilance was first determined by assessing drowsiness using visual analogue scales and/or by several psychometric tests in four pharmacoclinical studies in healthy subjects or in hypertensive patients: three studies with single administration of rilmenidine (0.5 to 3.0 mg) and one study with repeated administration for three days. These studies were double-blind, Latin-square designed, and controlled versus placebo (in all studies) and versus clonidine (in three studies). Analysis of these results illustrated that after short-term and repeated administration: (1) the effects on vigilance observed with rilmenidine 1 mg did not differ statistically from data observed with placebo; and (2) sedative effects observed with clonidine were significantly greater than with rilmenidine, at equihypotensive doses. Daytime drowsiness was systematically assessed and graded by inciting questioning at each visit in five clinical studies. Ambulatory hypertensive patients were treated with rilmenidine (1 mg per day or 1 mg twice a day). These studies were controlled versus placebo (one study for two weeks, 120 patients; and one study for one month, 126 patients), hydrochlorothiazide (six weeks, 56 patients), clonidine (six weeks, 333 patients), and methyldopa (three months, 157 patients). The results showed that: (1) drowsiness observed with rilmenidine did not differ statistically from that observed with placebo or diuretic; and (2) drowsiness occurred less frequently with rilmenidine than with reference alpha 2-agonists at equihypotensive doses. In conclusion, these results confirm in current clinical use the dissociation already observed in laboratory animals between the antihypertensive effects and the sedative effects and may distinguish rilmenidine among alpha 2-agonists.

Adrenergic alpha-Agonists↗
PubMed1991

Rilmenidine lowers arterial pressure via imidazole receptors in brainstem C1 area.

We sought to determine the site of action and receptor type responsible for the antihypertensive actions of rilmenidine, an oxazoline analogue of clonidine. In anesthetized paralyzed rats decerebration did not alter the dose dependent reductions in arterial pressure and heart rate elicited by i.v. drug. Rilmenidine microinjected bilaterally into the C1 area of the rostral ventrolateral medulla (RVL), but not nucleus tractus solitarii (NTS) nor caudal ventrolateral medulla (CVL), elicited dose-dependent falls in arterial pressure and heart rate at doses an order of magnitude less than required systemically. Prior microinjection into the C1 area of the selective alpha 2-adrenoceptor antagonist SKF-86466, even at high doses, failed to modify the hypotension to i.v. rilmenidine. However, microinjection of 3- to 10-fold lower doses of idazoxan, a ligand for imidazole as well as alpha 2-adrenoceptors, blocked the effects. Rilmenidine also competed with the clonidine analogue [3H]p-aminoclonidine ([3H]PAC) at specific binding sites in membranes of bovine ventrolateral medulla and frontal cortex. In RVL rilmenidine competed with binding to imidazole and alpha 2-adrenergic binding sites with a 30-fold selectivity for the imidazole binding sites. In frontal cortex binding was of lower affinity and restricted to alpha 2-adrenergic sites. We conclude that rilmenidine, like clonidine, acts to lower arterial pressure by an action on imidazole receptors in the C1 area of RVL. The higher selectivity of rilmenidine for imidazole to alpha 2-adrenoceptors as compared to clonidine may explain the lower sedative effects of rilmenidine.

Animals↗
PubMed2004

Moxonidine and rilmenidine injected into the medial septal area reduces the salivation induced by pilocarpine.

We determined the effects of moxonidine and rilmenidine 20 nmol (alpha(2)-adrenergic and imidazoline receptor agonists) injected into the medial septal area (MSA) on the pilocarpine-induced salivation, when injected intraperitoneally (i.p.), of male Holtzman rats weighing 250-300 g, with stainless-steel cannula implanted into the MSA. The rats were anesthetized with zoletil 50 mg kg(-1) b.wt. (tiletamine chloridrate 125.0 mg and zolazepan chloridrate 125.0 mg) into quadriceps muscle intramuscularly (IM), saliva was collected using pre-weighed small cotton balls inserted in the animal's mouth. The pre-treatment with moxonidine injected into the MSA reduced the salivation induced by pilocarpine (1 mg kg(-1)) injected i.p. (12+/-3 mg min(-1)) vs. control (99+/-9 mg min(-1)). The pre-treatment with rilmenidine 40 nmol also reduced the salivation induce by pilocarpine injected i.p. (20+/-5 mg min(-1)) vs. control (94+/-7 mg min(-1)). Idazoxan 40 nmol (imidazoline receptor antagonist) injected into the MSA previous to moxonidine and rilmenidine partially blocked the effect of moxonidine and totally blocked the rilmenidine effect in pilocarpine-induced salivation injected i.p. (60+/-8 and 95+/-10 mg min(-1), respectively). Yohimbine 40 nmol (alpha(2)-adrenergic receptor antagonist) injected into the MSA previously to moxonidine and rilmenidine partially blocked the moxonidine effect but produced no change on the rilmenidine effect on i.p. pilocarpine-induced salivation (70+/-6 and 24+/-6 mg min(-1), respectively). Injection of these alpha(2)-adrenergic and imidazoline agonists and antagonists agents i.p. produced no change on i.p. pilocarpine-induced salivation. These results show that central, but not peripheral, injection of alpha(2)-adrenergic and imidazoline agonists' agents inhibit pilocarpine-induced salivation. Idazoxan, an imidazoline receptor antagonist, totally inhibits the rilmenidine effect and partially inhibits the moxonidine effect on pilocarpine-induced salivation. Yohimbine produced no change on rilmenidine effect but partially inhibited the moxonidine effect. Both of these antagonists when injected into the MSA previous to pilocarpine i.p. potentiated the sialogogue effect of pilocarpine. The results suggest that alpha(2)-adrenergic/imidazoline receptor of the MSA when stimulated blocked pilocarpine-induced salivation in rats when injected intraperitonially. These receptors of the medial septal area have an inhibitory mechanism on salivary secretion.

Adrenergic alpha-Agonists↗
PubMed2006

How can we block sympathetic overactivity? Effects of rilmenidine and atenolol in overweight hypertensive patients.

The aim of the present study was to evaluate effects of long-term treatment with rilmenidine compared with atenolol on lipid and glucose metabolism and cardiovascular remodelling in hypertension. In total, 37 patients with hypertension were randomised to rilmenidine 1-2 mg/day or atenolol 50-100 mg/day for 26 weeks. Standard oral glucose tolerance test with a parallel measurement of insulin and glucose levels was performed. The 'areas under the curve' (AUC) for insulin and glucose were calculated. Plasma lipids, left ventricular mass index (LVMI), and intima-media thickness (IMT) were measured. Brachial artery diameter during reactive hyperaemia was used to test endothelium-dependent vasodilatation (EDVD). Blood pressure reduction was equally achieved in both treatment arms. The fasting glucose level increased in the atenolol group from 4.8+/-0.6 to 5.2+/-0.7 mmol/l (P<0.01). The AUC of glucose in rilmenidine group decreased from 860+/-93 to 737+/-66 mmol/min/l (P<0.05), and in the atenolol group it increased from 937+/-86 to 989+/-88 mmol/min/l (P<0.05). Rilmenidine showed a positive effect on lipid levels, whereas in the atenolol group a significant decrease of high-density lipoprotein cholesterol was observed. Left ventricular mass index decreased with rilmenidine by 9.6% and by 6.9% with atenolol (P<0.05). Intima-media thickness significantly decreased in the rilmenidine group. Endothelium-dependent vasodilatation slightly increased on in the rilmenidine group, while on in the atenolol group it remained unchanged. Our data suggest that in hypertensive patients central inhibition of sympathetic drive can produce favourable effects on glucose and lipid metabolism compared with standard beta-blockade with a similar antihypertensive efficacy. Rilmenidine also provides beneficial effects on cardiovascular remodelling and altered endothelial function in hypertension.

Adult↗
PubMed2000

Haemodynamic and metabolic effects of rilmenidine in hypertensive patients with metabolic syndrome X. A double-blind parallel study versus amlodipine.

OBJECTIVE: To compare the effects of rilmenidine with those of amlodipine on blood pressure, glucose metabolism, plasma lipid concentration and fibrinolysis parameters. DESIGN: A four-month randomized double-blind, parallel group study. PATIENTS AND METHODS: Obese hypertensive patients with hypertriglyceridaemia (> or = 2.3 mmol/l) and impaired glucose tolerance (OMS-ADA) were included (n = 52). A placebo run-in period of 2 weeks was followed by 4 months of double-blind treatment with either rilmenidine or amlodipine. Blood pressure was recorded using a mercury sphygmomanometer. Glucose metabolism was evaluated by an oral glucose tolerance test RESULTS: Of the 52 patients recruited, 47 (21 rilmenidine and 26 amlodipine) completed the 4-month treatment period. The intention-to-treat analysis showed a comparable reduction in systolic and diastolic blood pressure (SBP, DBP) with the two anti-hypertensive treatments (rilmenidine -13.9/-13.5 mmHg; amlodipine - 17.6/-15.0 mmHg). Insulin concentrations under basal conditions and 2 h after a standard oral glucose load did not change significantly after treatment in both groups. Plasma glucose under basal conditions and 2 h after a standard oral glucose load as well as the area under the plasma glucose concentration curve tended to decrease in the rilmenidine group and to increase in the amlodipine group so that the changes in these parameters were significantly different between the two study groups (P= 0.041, P = 0.042 and P = 0.015, respectively). Plasminogen activator inhibitor type 1 (PAI-1) antigen and PAI-1 activity were only decreased in the rilmenidine group (not statistically significant). CONCLUSION: Our results demonstrate that rilmenidine and amlodipine have a comparable anti-hypertensive effect but only rilmenidine is able to improve glucose metabolism.

Adult↗
PubMed2006

Effects of rilmenidine on 24-h rhythmicity of blood pressure and spontaneous baroreflex sensitivity in essential hypertensive subjects.

OBJECTIVE: To study the effects of the centrally acting imidazoline-like compound rilmenidine on the circadian and short-term cardiovascular rhythms derived from continuous blood pressure (BP) recordings in patients with mild essential hypertension. METHODS: This was a single-center, open study. Recordings were obtained from eight subjects, using a Portapres during two 24-h hospitalizations: the first after the inclusion visit and the second 4 weeks after starting rilmenidine treatment (1 or 2 mg/day). For circadian analysis of cardiovascular variables, 10 min were selected every hour to obtain 24 periods per subject for each session. Spontaneous baroreflex sensitivity (BRS) was estimated using the sequence technique and the cross-spectral analysis between systolic BP and interbeat intervals. RESULTS: Rilmenidine significantly reduced the overall systolic and diastolic BP and heart rate (P < 0.001). The effects of rilmenidine on BP and heart rhythm were marked during the daytime. Rilmenidine reduced the low-frequency (LF) component of systolic BP variability throughout the 24 h. The highest values of spontaneous BRS were observed at night. Rilmenidine increased the BRS obtained by the slope of the sequence method throughout the 24-h period (P < 0.001). The LF gain was significantly increased with rilmenidine during the day and the night. CONCLUSIONS: Rilmenidine may differentially affect the baroreflex-dependent (phasic or reflex) and the baroreflex-independent (tonic) autonomic outflow. The 24-h approach reinforced this concept, since indexes of BRS were increased throughout the 24-h period while BP was reduced during the daytime.

Adult↗