Disease relevance of C11120

• Rilmenidine is a novel antihypertensive agent related to alpha 2-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once a day or 1 mg twice a day [1].
• It showed stable plasma concentrations of rilmenidine during a six-month treatment in hypertensive patients with renal insufficiency, reflecting the absence of accumulation of the drug [2].
• In conclusion, this study confirmed the good acceptability of rilmenidine in hypertensive patients with chronic renal insufficiency [2].
• METHODS AND RESULTS: Rilmenidine micro-injected into the rostral ventrolateral medulla produced hypotension and inhibition of renal sympathetic nerve activity with doses an order of magnitude lower than those required in the nucleus tractus solitarius [3].
• CONCLUSIONS: These results suggest that the hypotension and bradycardia induced by intravenous administration of moxonidine and rilmenidine were mediated mainly by actions on central imidazoline receptors whereas clonidine appears to act predominantly on central alpha 2-adrenoceptors [4].

Psychiatry related information on C11120

• 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 [5].
• Nevertheless, although it binds to alpha 2-adrenoceptors, rilmenidine did not cause sedation in animal models: at doses up to 10 mg/kg in mice and rats, it did not prolong the barbiturate-induced sleeping time and did not modify the spontaneous locomotor activity in rats at doses up to 2.5 mg/kg [6].
• Cessation of rilmenidine infusion resulted in somewhat similar cardiovascular and behavioral disturbances, but unlike clonidine there was a return to normal rapid eye movement sleep without rebound [7].

High impact information on C11120

• Administered as single-drug therapy, rilmenidine rapidly normalized blood pressure (systolic blood pressure, less than 160 mmHg; diastolic blood pressure, no more than 90 mmHg--supine) in 17 patients; this persisted throughout the trial period [8].
• In a second group of 10 patients with moderate hypertension (diastolic blood pressure, 105 to 115 mmHg), rilmenidine 1 mg was administered in order to evaluate its efficacy and hemodynamic effects (bioimpedance and radionuclide ventriculography), at rest and during a lying cycloergometer effort test [9].
• In this respect, several findings resulting from fundamental pharmacology, clinical pharmacology, and therapeutics differentiate rilmenidine from clonidine and related drugs [10].
• Antihypertensive drugs and baroreflex sensitivity. Effects of rilmenidine [11].
• In conscious sino-aortic denervated dogs, rilmenidine (1 mg/kg orally for two weeks) significantly reduced blood pressure and heart rate [6].

Chemical compound and disease context of C11120

• In conclusion, rilmenidine offers an effective and safe treatment for mild-to-moderate hypertension in diabetic patients treated with insulin and does not interfere with their blood glucose control [8].
• Acceptability and plasma concentrations of rilmenidine, a new antihypertensive agent mainly eliminated via the kidney, were evaluated in 17 hypertensive patients (supine diastolic blood pressure, 104 +/- 3 mmHg) with renal insufficiency (creatinine clearance, 35 +/- 4 ml.minute-1/1.73 m2; range, 12 to 58) [2].
• This review focuses on the main pharmacological and clinical properties of rilmenidine and moxonidine, paying particular attention not only to their efficacy in hypertension but also to other potential cardiovascular indications [12].
• Alpha-methylnoradrenaline, however, was similarly potent at producing hypotension when it was injected into the rostral ventrolateral medulla or nucleus tractus solitarius but, unlike rilmenidine, did not lower renal sympathetic nerve activity when it was injected into the nucleus tractus solitarius [3].
• The effects of rilmenidine [(N-dicyclopropylmethyl) amino-2-oxazoline; S 3341], an alpha 2 agonist, on the hypertensive rat heart have been compared with those of propranolol, using a model of deoxycorticosterone acetate (DOCA)-salt hypertension [13].

Biological context of C11120

• The evidence for rilmenidine binding on central sites named "imidazoline sites" involved in blood pressure regulation could possibly provide further insight into its mechanism of action and explain the duality of its effects [6].
• Pharmacokinetics of rilmenidine [1].
• This effect was due to a reduction in cardiac output (bioimpedance method) significant (p = 0.05) only for rilmenidine [9].
• Rilmenidine was rapidly and extensively absorbed, with an absolute bioavailability close to one and a time to peak plasma concentration of two hours [1].
• Rilmenidine (1 mg) did not affect water and electrolyte balance [14].

Anatomical context of C11120

• Rilmenidine also decreases catecholamine release from the adrenal medulla which might contribute to the antihypertensive effect [6].
• Protective effects of rilmenidine and AGN 192403 on oxidative cytotoxicity and mitochondrial inhibitor-induced cytotoxicity in astrocytes [15].
• In contrast, injection of rilmenidine into the nucleus tractus solitarius had no effect on basal renal sympathetic nerve activity and renal sympathetic baroreflex parameters [3].
• In vivo, rilmenidine may enhance uptake of Ca2+ from the extracellular fluid by astrocytes, a process that may contribute to the neuroprotective effects of this agent [16].
• Pretreatment with thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, abolished the response to rilmenidine, confirming the involvement of intracellular stores and suggesting that rilmenidine and thapsigargin activate a common Ca2+ influx pathway [16].

Associations of C11120 with other chemical compounds

• In conclusion, rilmenidine increases baroreflex sensitivity to increases in blood pressure with phenylephrine; during tests of autonomic function, the lower blood pressures that occur with rilmenidine are associated with correspondingly greater R-R intervals; this may also indicate enhanced baroreflex sensitivity [11].
• Because rilmenidine and captopril lower blood pressure, studies were also performed in sinoaortically denervated (SAD) rabbits to determine the role of the baroreflex in the renal hemodynamic response [17].
• Other putative imidazoline receptor agonists, including cimetidine, rilmenidine, and imidazole-4-acetic acid, likewise enhance PNMT mRNA production showing relative potencies that correlate with their binding affinities at chromaffin cell I1-imidazoline binding sites [18].
• Effects of a single intravenous dose of rilmenidine (445 mug/kg) on the renal sympathetic nerve activity (RSNA) baroreflex were examined before and after microinjection into the RVLM of the mixed imidazoline/alpha2-adrenoceptor antagonist idazoxan and the alpha2-adrenoceptor antagonist 2-methoxyidazoxan (2-MI) [19].
• 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) [20].

Gene context of C11120

• In a host-cell-specific manner, transfection of IRAS cDNA into Chinese hamster ovary cells led to high-affinity I1 binding sites by criteria of nanomolar affinity for moxonidine and rilmenidine [21].
• The hypotensive action of rilmenidine is dependent on functional N-methyl-D-aspartate receptor in the rostral ventrolateral medulla of conscious spontaneously hypertensive rats [22].
• The correlation between the localization of [3H]rilmenidine-labelled I-RBS and [3H]RO19-6327-labelled MAO-B in rabbit kidney (r = 0.87, P = 0.057) suggest that [3H]rilmenidine may label a binding site co-existent with MAO-B, but not MAO-A (n.s.), in this tissue, but rilmenidine did not inhibit [3H]RO41-1049 or [3H]RO19-6327 binding [23].
• Cells treated with rilmenidine or moxonidine showed an increased level of extracellular signal-regulated kinase (ERK) phosphorylation in a concentration-dependent manner, which could be reversed by efaroxan or D609, a selective PC-PLC inhibitor [24].
• The antihypertensive properties of rilmenidine, an oxazoline derivative, have been demonstrated in several experimental models of hypertension after short- or long-term administration [6].

Analytical, diagnostic and therapeutic context of C11120

• Plasma concentrations of rilmenidine were measured by gas chromatography combined with mass spectrometry at Days 0, 1, 5, 7, 9, and 11, and Months 1.5, 3, 4.5, and 6 before administration [2].
• DESIGN AND METHODS: We used a randomized, double-blind, 6-week cross-over study, with a 1-week placebo run-in period, two 2-week active treatment intervals (rilmenidine 1 mg twice daily or placebo) and intervening 1-week placebo washout [25].
• 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) [26].
• Renal denervation altered the hemodynamic and renal effects following intracerebroventricular administration of the I1-imidazoline receptor agonist, rilmenidine, in pentobarbital anaesthetized rats [27].
• Systemic rilmenidine (600 microg/kg i.v.) elicited hypotension and bradycardia along with significant elevation in MAPK(p42/44), detected by immunohistochemistry, in RVLM neurons [28].

References