RESUMEN
Diabetes mellitus is associated with increased prevalence of endothelial cell dysfunction and vascular diseases. Mechanisms leading to alterations in endothelial cell function are poorly understood. We report here that hyperglycaemia results in the expression of endothelial adhesion molecules involved in leukocyte adhesion and extravasation. Incubation of human umbilical cord endothelial cells (HUVEC) with 25 mM glucose induced the expression of P-selectin. This effect was reversed by the addition of 1 nM insulin. Moreover, increased ICAM-1 expression was observed upon HUVEC incubation with 25 mM glucose. Increased adhesion of U937 cells (a monocytic cell line) to endothelial cells cultured with 25 mM glucose was observed. High glucose-induced monocytes cell adhesion was inhibited by an anti-P-selectin monoclonal antibody (LYP20). These results show that high glucose concentration activates endothelial cells leading to monocytes adhesion providing further evidence that hyperglycaemia might be implicated in vessel wall lesions contributing to diabetic vascular disease.
Asunto(s)
Endotelio Vascular/metabolismo , Glucosa/farmacología , Insulina/farmacología , Selectina-P/biosíntesis , Adhesión Celular/efectos de los fármacos , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/efectos de los fármacos , Técnicas de Cocultivo , Relación Dosis-Respuesta a Droga , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Humanos , Monocitos/citología , Selectina-P/efectos de los fármacos , Células U937 , Venas UmbilicalesRESUMEN
This review presents the major animal models usually used for the study of the pathological processes related to insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) and to the main diabetic complications. These models can be observed spontaneously or can be obtained by selective cross-breeding or toxic exposure (chemical or viral), as well as genetically induced. They reproduce some aspects of the human pathology without combining them all in a single model. Consequently, a pertinent pharmacological approach may compare the results obtained with several models. The examination of the recent results obtained with transgenesis does not allow these animal models to replace more classical ones but they may constitute a future challenge for gene therapy despite the multifactorial aspect of diabetic disease.
Asunto(s)
Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Modelos Animales de Enfermedad , Animales , Animales Modificados Genéticamente , Humanos , Ratones , RatasRESUMEN
Diabetes produces dramatic changes in retinal microvasculature, triggering endothelial cell proliferation and microaneurysms. Capillaries become weakened, releasing blood into vitreal and retinal spaces. Photoreceptors become occluded and separated from the choriocapillaris, resulting in visual acuity decline, detachment and cell death. Several models have been developed that have proved useful for the study of this disease, resulting in a better understanding of the processes involved. Streptozotocin treatment affects the pancreatic beta cells, rapidly reducing them until insulin is no longer synthesized in sufficient amounts. The galactosemic model shifts metabolism away from glucose, increasing aldose reductase and retinal polyol metabolism. Finally, two weeks of cycled oxygen from high to low tension every 24 hours, followed by return to room air, triggers microangiogenesis in developing retinas. Use of these models, separately or in combination, as well as electroretinographic analysis, has begun to reveal the events taking place as diabetic retinopathy progresses. Endothelial cells become separated from pericytes as basement membranes thicken, and vascular endothelial growth factor increases, triggering their proliferation. Finally, early changes occurring within photoreceptors can now be studied.
Asunto(s)
Retinopatía Diabética/etiología , Animales , Antibacterianos , Diabetes Mellitus Experimental , Retinopatía Diabética/inducido químicamente , Modelos Animales de Enfermedad , Galactosemias/complicaciones , Oxígeno/administración & dosificación , Oxígeno/farmacología , Estreptozocina/farmacologíaRESUMEN
OBJECTIVE: To focus on the cardioprotective role of angiotensin-converting enzyme (ACE) inhibitors in ischemic heart disease and to highlight some of the, as yet, unanswered questions about the relative merits of ACE inhibitors as cardioprotective drugs. DATA SOURCE: This review incorporates the data on this subject published in the available English literature up to June 1990. DATA SELECTION: The source material was analyzed and computed chronologically into two groups: experimental studies and clinical trials. DATA EXTRACTION: ACE inhibitors have gained access to the free world market for a variety of reasons. Their superiority in the management of hypertension and congestive heart failure is being recognized. Furthermore, recent experimental and limited clinical trials strongly indicate a role for ACE inhibitors in limiting myocardial ischemia-reperfusion-induced injury. Although the sulphydryl group (SH)-containing ACE inhibitor captopril has been extensively used for most studies, the cardioprotective role of non-SH-containing ACE inhibitors, particularly ramipril and enalapril, recently has been identified. ACE inhibitors reportedly limit infarct size, prevent ventricular remodelling and, more importantly, stabilize the electrical activity of the reperfused heart and prevent the occurrence of reperfusion arrhythmias. Preliminary clinical trials indicate an antianginal role for ACE inhibitors. ACE inhibition has also been reported to improve left ventricular performance in patients with long standing infarcts and ischemic failure. Although pharmacological effects of ACE inhibitors are well known, the mechanism of cardioprotection at the molecular and cellular levels is elusive. The role of ACE inhibitors in myocardial stunning and their free radical scavenging effects are still speculative. Furthermore, the effects of ACE inhibition during global myocardial ischemia-reperfusion are virtually unknown. CONCLUSIONS: The available data strongly indicates a role for ACE inhibitors in limiting myocardial ischemia-reperfusion-induced injury. However, more controlled studies, particularly multicentre clinical trials, are indicated to establish a therapeutic rationale for ACE inhibition in the management of ischemic heart disease.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Isquemia Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
1. To determine the site of action of rilmenidine, we examined its effets on arterial blood pressure (BP), heart rate (HR) and postganglionic renal sympathetic nerve activity (RSNA) after intracerebroventricular (i.c.v.) administration (300 micrograms kg-1), in groups (all n = 6) of conscious and freely moving, pentobarbitone-anaesthetized and pentobarbitone-anaesthetized and spinally transected, fifteen week-old male spontaneously hypertensive rats (SHRs). 2. In conscious SHRs, which exhibited a low sympathetic nerve activity (RSNA: 3.4 +/- 0.9 muV), rilmenidine was inactive on systolic BP (SBP), diastolic BP (DBP), HR and RSNA. 3. In intact pentobarbitone-anaesthetized SHRs, which exhibited an elevated sympathetic nerve activity (RSNA: 10.6 +/- 0.9 muV), rilmenidine exerted potent antihypertensive (delta SBP: -37 +/- 4%; delta DBP: -43 +/- 6%), bradycardic (delta HR: -32 +/- 3%) and sympathoinhibitory (delta RSNA: -68 +/- 9%) activities. 4. In pentobarbitone-anaesthetized SHRs with cervical spinal cord transection, BP was markedly decreased and sympathetic nerve activity (RSNA: 10.3 +/- 3.1 muV) returned to the level observed in conscious SHRs (RSNA: 3.6 +/- 0.5 muV). In these conditions, rilmenidine remained sympathoinhibitory (delta RSNA: -74 +/- 5%). 5. In conclusion, we have shown that pentobarbitone-anaesthesia enhances the peripheral sympathetic tone by a central action, as the spinal cord transection allows RSNA to return to normal levels and that, spinal or ganglionic structures could be a major site of the sympathoinhibitory action of rilmenidine.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Tronco Encefálico/fisiología , Oxazoles/farmacología , Simpaticolíticos/farmacología , Anestesia , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intraventriculares , Riñón/efectos de los fármacos , Riñón/inervación , Masculino , Pentobarbital , Ratas , Ratas Endogámicas SHR , Rilmenidina , Médula Espinal/fisiología , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
1. The acute cardiovascular effects of two alpha 2-adrenoceptor agonists, rilmenidine and clonidine, were studied in 15-week-old male spontaneously hypertensive rats (SHRs). The effects of these drugs were compared with intravenous (i.v.) and intracerebroventricular (i.c.v.) administration in conscious and pentobarbitone-anaesthetized SHRs, in which aortic blood pressure (BP) was continuously recorded. 2. In conscious SHRs, i.v. doses of either rilmenidine (30, 100, 300 micrograms kg-1) or clonidine (3, 10, 30 micrograms kg-1) induced dose-dependent short-lasting increases in BP followed by moderate decreases associated with bradycardia, while the same three doses of both drugs given i.c.v. were devoid of BP and heart rate (HR) effects. 3. Pentobarbitone-anaesthesia increased the sympathetic control of BP and suppressed the cardiac baroreflex sensitivity. 4. In anaesthetized SHRs, i.v. injections of the same 3 doses of rilmenidine and clonidine induced a slight increase in BP, rapidly followed by profound and long-lasting BP and HR decreases. Surprisingly, when given i.c.v., these 3 doses lowered BP and HR to the same extent but in a more progressive manner. 5. The lack of efficacy of both drugs in conscious SHRs after the i.c.v. administration of i.v. active doses and the lack of more marked and rapid effects in anaesthetized SHRs, after i.c.v. than after i.v. injections, question the involvement of a major central site of action for these antihypertensive alpha 2-adrenoceptor agonists. Moreover, these results show that the cardiovascular effects of these drugs are profoundly influenced by baseline sympathetic nervous system activity which is enhanced by pentobarbitone-anaesthesia.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Anestesia , Clonidina/farmacología , Hemodinámica/efectos de los fármacos , Oxazoles/farmacología , Agonistas alfa-Adrenérgicos/administración & dosificación , Animales , Presión Sanguínea/efectos de los fármacos , Clonidina/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intravenosas , Inyecciones Intraventriculares , Masculino , Oxazoles/administración & dosificación , Pentobarbital , Ratas , Ratas Endogámicas SHR , Reflejo/efectos de los fármacos , Rilmenidina , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Nitrates and other nitrosovasodilators are locally acting agents. Their efficacy is reported to depend upon the availability of sulfhydryl groups in vascular smooth muscle. Long term nitrosovasodilator therapy has limited effectiveness, and development of nitrate tolerance has been recognized to be due to exhaustion of the tissue sulfhydryl pool, in addition to vasodilation-induced reflex activation of the neurohumoral system. Under both experimental and clinical conditions it has been demonstrated that N-acetylcysteine and other exogenously introduced sulfhydryl donors potentiate hemodynamic responses to nitrates and reverse nitrate tolerance. The newer group of angiotensin-converting enzyme (ACE) inhibitor drugs has been reported to be effective in reducing afterload and preload in a variety of experimental and clinical trials. Captopril, the first developed ACE inhibitor, and its analogs contain sulfhydryl groups. Although the sulfhydryl group of captopril is not thought to be responsible for its vasodilator action, it can act as a sulfhydryl donor to promote nitrate effectiveness and prevent development of tolerance. Limited experimental and clinical trials on combined therapy with nitrates and captopril have produced promising results. An ingenious prototype compound, S-nitrosocaptopril, has recently been synthesized. This is an exciting new development in vasodilator therapy, but clinical application must await full experimental characterization of this and other identical compounds.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Músculo Liso Vascular/efectos de los fármacos , Nitratos/uso terapéutico , Vasodilatadores/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/química , Animales , Quimioterapia Combinada , Tolerancia a Medicamentos , Humanos , Nitratos/química , Compuestos de Sulfhidrilo , Vasodilatadores/químicaRESUMEN
1. The acute and chronic effects of rilmenidine, a partial agonist of alpha 1- and alpha 2-adrenoceptors with antihypertensive properties, were compared to those of clonidine on blood pressure (BP), heart rate (HR) and the urinary excretion of catecholamines, which was used as an index of sympathetic activity. 2. As these drugs are known to interfere centrally and peripherally with the sympathetic nervous system, long-term arterial blood pressure recordings in freely moving unstressed adult spontaneously hypertensive rats (SHR) were used. 3. Acute i.v. administrations of rilmenidine (0.3 mg/kg at 1200 h, 1.2 mg/kg at 1700 and 2200 h) and clonidine (12 micrograms/kg at 1200 h, 50 micrograms/kg at 1700 and 2200 h) induced short-lasting increases in BP associated with a decrease in HR, which were followed by prolonged, dose-dependent decreases in BP without bradycardia. The pressor effect was less marked and the associated bradycardia was more marked in active SHR with physiologically high sympathetic activity than in resting SHR. 4. A 12-day oral treatment with rilmenidine (6.0 mg/kg daily) or clonidine (150 micrograms/kg daily) induced moderate decreases in BP without change in HR. Rilmenidine but not clonidine decreased normetanephrine (NMN) excretion in active but not in resting SHR. 5. Finally, during the 24 h following the cessation of the treatments, BP returned to normal, without significantly exceeding that of untreated controls. However, upswings in BP or HR were observed, more markedly and frequently after clonidine than after rilmenidine. 6. In conclusion the effects of alpha 2-adrenoceptor agonists appear to be influenced by the pre-existing sympathetic tone. The general agreement between these data and those observed in patients demonstrates that the use of conscious unstressed animals is of value to determine the cardiovascular effects of drugs which act on the sympathetic nervous system.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Clonidina/farmacología , Hemodinámica/efectos de los fármacos , Oxazoles/farmacología , Administración Oral , Animales , Presión Sanguínea/efectos de los fármacos , Catecolaminas/orina , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intravenosas , Masculino , Ratas , Ratas Endogámicas SHR , RilmenidinaRESUMEN
The antihypertensive properties of rilmenidine, an oxazoline derivative, have been demonstrated in several experimental models of hypertension after short- or long-term administration. In pentobarbitone-anesthetized spontaneously hypertensive rats, intravenous rilmenidine (0.1 to 1 mg/kg) dose-dependently reduced blood pressure and heart rate. Upon long-term subcutaneous infusion (5 to 15 mg/kg per day) in conscious spontaneously hypertensive rats, rilmenidine induced a dose-dependent decrease in both cardiovascular parameters. In conscious sino-aortic denervated dogs, rilmenidine (1 mg/kg orally for two weeks) significantly reduced blood pressure and heart rate. The hypotensive action of rilmenidine is mediated through a reduction in peripheral sympathetic tone, resulting from a central action and possibly a peripheral action. Rilmenidine also decreases catecholamine release from the adrenal medulla which might contribute to the antihypertensive effect. Therefore, rilmenidine acts similarly to clonidine and related compounds in order to lower blood pressure, i.e., reduction of sympathetic tone. 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. These results demonstrate a dissociation between sedative and antihypertensive effects of rilmenidine. Three hypotheses have been proposed to explain why this drug is almost devoid of sedative activity in animal experimental models: (1) unknown properties counteracting the alpha 2-adrenoceptor-mediated sedation; (2) a preferential action at the peripheral level; (3) central receptors involved in sedation and hypotension may be different. The intimate mechanism underlying the hypotensive effects of rilmenidine is currently under investigation. 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.
Asunto(s)
Antihipertensivos/farmacología , Oxazoles/farmacología , Agonistas alfa-Adrenérgicos/farmacología , Animales , Encéfalo/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Nervios Periféricos/efectos de los fármacos , Rilmenidina , SimpaticolíticosRESUMEN
In several blood vessels, the influence of the alpha 2-adrenoceptor agonists rilmenidine and clonidine was compared. In aortas of rat and rabbit and in the rabbit pulmonary artery, both compounds evoked contractions due to stimulation of postjunctional alpha 1-adrenoceptors. In the aorta of the rat, but not in that of the rabbit, removal of the endothelium markedly enhanced the contractions to rilmenidine and clonidine. At the alpha 1-adrenoceptors, clonidine was about 135 times more potent than rilmenidine. The activity of both substances at post- and prejunctional alpha 2-adrenoceptors was compared in the rabbit saphenous vein. Rilmenidine and clonidine evoked contractions of the vein by stimulating postjunctional alpha 2-adrenoceptors and decreased the stimulation-induced overflow of [3H]-noradrenaline by activating the prejunctional alpha 2-adrenoceptors. At the post- and prejunctional alpha 2-adrenoceptors, clonidine was about 30 times more potent than rilmenidine. These data illustrate that, although less potent than clonidine, rilmenidine is 5 times more specific for the alpha 2-adrenoceptors. In the isolated perfused rat kidney, rilmenidine and clonidine antagonized the vasoconstrictions induced by noradrenaline. Although the exact mechanism of this inhibitory response remains to be elucidated, our results indicate that rilmenidine may possess some interesting properties at the level of the renal circulation.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Clonidina/farmacología , Riñón/metabolismo , Músculo Liso Vascular/metabolismo , Oxazoles/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Antagonistas Adrenérgicos alfa/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Interacciones Farmacológicas , Técnicas In Vitro , Riñón/efectos de los fármacos , Masculino , Músculo Liso Vascular/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Conejos , Ratas , Ratas Endogámicas , Circulación Renal/efectos de los fármacos , Rilmenidina , Vena Safena/efectos de los fármacosRESUMEN
Evidence gathered over the past ten years supports the existence of subtypes of alpha 2-adrenoceptors. A receptor which resembles the alpha 2-adrenoceptor, called the imidazoline-preferring receptor (IPR), is virtually insensitive to catecholamines but binds selectively imidazolines and oxazolines such as idazoxan and rilmenidine. In contrast, the catecholamine-preferring alpha 2-adrenoceptor is preferentially activated by catecholamines including alpha-methylnorepinephrine and epinephrine and is antagonized selectively by rauwolscine. In addition to different pharmacological profiles to agonists and antagonists, the IPR and alpha 2-adrenoceptors show differences in anatomical distribution and molecular properties. The evidence has been drawn primarily from in vitro physiological and radioligand binding studies, but is gradually extending into in vivo and even clinical studies.
Asunto(s)
Receptores de Droga , Agonistas alfa-Adrenérgicos/metabolismo , Antagonistas Adrenérgicos alfa/metabolismo , Animales , Encéfalo/metabolismo , Predicción , Humanos , Receptores de Imidazolina , Riñón/metabolismo , Receptores Adrenérgicos alfa/clasificación , Receptores Adrenérgicos alfa/metabolismo , Receptores de Droga/metabolismoRESUMEN
1. The effects of rilmenidine, a new alpha 2-adrenoreceptor agonist with antihypertensive properties, were investigated on plasma catecholamines, blood cell adrenoreceptors and adrenal medullary function. 2. In conscious sino-aortic denervated (SAD) dogs, rilmenidine (1 mg kg-1 orally for 2 weeks) significantly reduced both blood pressure and heart rate when compared with placebo treatment. The drug decreased plasma noradrenaline and adrenaline levels and corrected the decrease in leucocyte beta-adrenoreceptors observed in placebo-treated SAD dogs. There was no change in platelet alpha 2-adrenoreceptors. 3. In anaesthetized normotensive dogs, rilmenidine (0.1 and 0.3 mg kg-1 i.v.) induced a dose-dependent decrease in both cardiovascular parameters (blood pressure and heart rate) and catecholamine release from the adrenal medulla. 4. The present study shows that rilmenidine decreases sympathetic tone mainly by an action on the adrenal medulla. In addition, its ability to lower blood pressure in SAD dogs, i.e. a model of hypertension in which high sympathetic tone is present, indicates that rilmenidine may also depress other parts of the sympathetic nervous system.
Asunto(s)
Médula Suprarrenal/efectos de los fármacos , Agonistas alfa-Adrenérgicos/farmacología , Catecolaminas/metabolismo , Oxazoles/farmacología , Sistema Nervioso Simpático/efectos de los fármacos , Médula Suprarrenal/metabolismo , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Plaquetas/metabolismo , Presión Sanguínea/efectos de los fármacos , Perros , Frecuencia Cardíaca/efectos de los fármacos , Leucocitos/metabolismo , RilmenidinaRESUMEN
Rilmenidine (S 3341) is a new alpha 2 agonist, with antihypertensive properties. Pharmacologic data concerning its hemodynamic and central nervous system effects in the rat are described in this report. In the anesthetized or conscious spontaneously hypertensive rat, rilmenidine was found effective and potent as an antihypertensive agent, lowering blood pressure in a dose-dependent manner after intravenous and oral administration. These effects are related to a reduction in sympathetic tone as seen by the decrease in plasma catecholamines induced by rilmenidine in the spontaneously hypertensive rat. Studies in the normotensive pithed rat (electrical stimulation and adrenalectomization) confirmed the presynaptic alpha 2-stimulating properties of rilmenidine and suggested that a component of the antihypertensive activity of rilmenidine could be exerted through these peripheral receptors. A study of the central effects of rilmenidine was performed using classic neuropharmacologic tests. No effect was observed on the pentobarbitone-induced sleeping time in the rat. Rilmenidine caused only a minimal and non-dose-dependent inhibition of the righting reflex in the chick. In the rat, rilmenidine did not decrease the motor activity at concentrations up to 50 times higher than the antihypertensive dose. These results confirmed the contrast between rilmenidine and clonidine and suggest that a dissociation between sedative and antihypertensive effects could occur with rilmenidine.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Sistema Nervioso Central/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Oxazoles/farmacología , Adrenalectomía , Agonistas alfa-Adrenérgicos/administración & dosificación , Anestesia , Animales , Presión Sanguínea/efectos de los fármacos , Catecolaminas/sangre , Pollos , Clonidina/farmacología , Estado de Descerebración , Estimulación Eléctrica , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Oxazoles/administración & dosificación , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas , Reflejo/efectos de los fármacos , Rilmenidina , Sueño/efectos de los fármacosRESUMEN
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)