Impact of the COVID-19 pandemic on clinical research in hospitals: observational study in the first epicenter of the epidemic during the general lockdown in France.

OBJECTIVE: The COVID-19 epidemic has had a strong impact on the entire healthcare sector in France with priority being given to research for new therapeutic options for COVID-19. Nevertheless, continuity of care for patients suffering from other diseases represents a crucial challenge, and clinical research is no exception in this respect. This study aims to assess the impact of the strict Covid-19 lockdown on non-Covid-19 clinical research in the French University Hospital of Strasbourg. MATERIALS AND METHODS: Clinical research activity (non-Covid-19) from the point of view of pharmacy department was estimated and compared to the pre-lockdown period. The impact of lockdown was assessed through five indicators: site initiation visits, the initiation of experimental therapies in non-Covid-19 patients, the delivery of non-Covid-19 investigational medical products, the number of drug shipments to patients' homes, and the number of monitoring or closure visits. RESULTS: During the study period, the number of site initiation visits decreased by 90%, total inclusions by 72%, and delivery of investigational medical products by 30%. During the lockdown period, 15 treatments were sent to patients' homes. Monitoring activity decreased by 98%. CONCLUSIONS: Although the COVID-19 outbreak has created an incredible momentum in the field of clinical research, research not focused on SaRS-CoV-2 has suffered greatly from this situation. The impact on patients is difficult to estimate but should be further investigated.

I(1) imidazoline receptors involved in cardiovascular regulation: where are we and where are we going?

Clonidine-like drugs (hybrid drugs) reduce blood pressure by acting centrally at both alpha(2)-adrenergic receptors (alpha(2)AR) and I(1) receptors (I(1)R). Some attempts at cloning I(1)R have failed, probably because of the lack of selectivity of the ligands. Recently, compounds acting exclusively at I(1)R were synthesized: LNP 911, LNP509, and S23515. For example, LNP911 has a K(d) value of 1.7 nmol/L at I(1)R. LNP509 and S23515 reduce blood pressure when injected centrally in anesthetized animals, whereas S23757 behaves as an antagonist of hypotensive imidazolines. LNP509 reduces blood pressure even in genetically engineered mice lacking functional alpha(2)AR. An exclusive action at central I(1)R is therefore sufficient to modify blood pressure. With the help of drugs selective for I(1)R and alpha-methylnoradrenaline, selective for alpha(2)AR, we showed that imidazoline and alpha(2)-adrenergic mechanisms interact synergistically in controlling the blood pressure. Such a synergism may explain the very powerful hypotensive effects of hybrid drugs. The new ligands selective for I(1)R will be very helpful to investigate the molecular features and the signaling system of I(1)R.

Effects of centrally-acting glutamatergic modulators on cardiovascular responses to stress in humans.

Sympathetic overactivity is a common feature of certain cardiovascular diseases. An acute activation of the sympathetic nervous system can provoke angina pectoris attacks through the increase of myocardial oxygen demand, frequently associated to coronary arterial constriction. It can also promote cardiac arrhythmias leading, in some cases, to cardiac sudden death. The aim of the present study was to evaluate the cardiovascular effects of a single oral dose of baclofen or ifenprodil (two drugs modulating central glutamatergic relays) at rest and during three laboratory stressors (a cold pressor test, a mental arithmetic stress test and an exercise test on a cycloergometer), in human healthy volunteers. Ifenprodil increased resting heart rate and did not reduce the cardiovascular response to any test. In contrast, baclofen reduced the tachycardic response to mental stress test and so limited the increase of myocardial oxygen demand during the test. Nevertheless, this drug was not able to affect the cardiovascular response to exercise. Finally, we have shown in this study that baclofen exhibits a profile of a central sympathomodulator without cardiodepression. Its activity towards mental stress induced cardiovascular responses leads us to proposing this compound for testing after a chronic treatment, in patients with silent myocardial ischemia and mental stress test induced ischemia.

Ablation of serotonin 5-HT(2B) receptors in mice leads to abnormal cardiac structure and function.

BACKGROUND: Identification of factors regulating myocardial structure and function is important to understand the pathogenesis of heart disease. Because little is known about the molecular mechanism of cardiac functions triggered by serotonin, the link between downstream signaling circuitry of its receptors and the heart physiology is of widespread interest. None of the serotonin receptor (5-HT(1A), 5-HT(1B), or 5-HT(2C)) disruptions in mice have resulted in cardiovascular defects. In this study, we examined 5-HT(2B) receptor-mutant mice to assess the putative role of serotonin in heart structure and function. METHODS AND RESULTS: We have generated G(q)-coupled 5-HT(2B) receptor-null mice by homologous recombination. Surviving 5-HT(2B) receptor-mutant mice exhibit cardiomyopathy with a loss of ventricular mass due to a reduction in number and size of cardiomyocytes. This phenotype is intrinsic to cardiac myocytes. 5-HT(2B) receptor-mutant ventricles exhibit dilation and abnormal organization of contractile elements, including Z-stripe enlargement and N-cadherin downregulation. Echocardiography and ECG both confirm the presence of left ventricular dilatation and decreased systolic function in the adult 5-HT(2B) receptor-mutant mice. CONCLUSIONS: Mutation of 5-HT(2B) receptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated disks. 5-HT(2B) receptor is required for cytoskeleton assembly to membrane structures by its regulation of N-cadherin expression. These results constitute, for the first time, strong genetic evidence that serotonin, via the 5-HT(2B) receptor, regulates cardiac structure and function.

Does it make sense to develop new centrally acting cardiovascular drugs?

1. The autonomic nervous system plays a pivotal role in modulating all the components of the cardiovascular regulation. Therefore, one can assume that drugs targeting this system may be useful in the management of several cardiovascular diseases. 2. Drugs acting on central nervous system centres seem to be modulators rather than blockers; as such, they are expected to preserve the contraregulatory processes and to generate only a few side effects. 3. Because the sympathetic nervous system is largely involved in the regulation of vasomotor tone, centrally acting antihypertensive drugs were developed first. 4. Recently, new leader compounds selective for non- adrenergic imidazoline recepetors have been synthetized. Although such drugs have no capacity to activate alpha2-adrenoceptors, they have been proven to be hypotensive. These drugs are expected to be even better tolerated than the currently available centrally active drugs. They may also have additional beneficial effects. 5. Here, the experimental evidence suggesting that such drugs may be useful in the management of some cardiac arrhythmias and/or left ventricular dysfunction will be reviewed.

Cardiovascular effects of chronic ifenprodil in a model of central sympathetic stimulation.

In the present study we investigated the effects of a long-term treatment (14 days) with ifenprodil on the excitatory haemodynamic responses induced by central pharmacological stimulation in anaesthetised rabbits. The intracerebroventricular injection of L-glutamate (3 mg/kg) induced important rises in dP/dtmax (32.9%), mean arterial pressure (42.6%) and in the myocardial oxygen consumption index: the triple product (84.2%). Ifenprodil (1.5, 3 and 6 mg/kg/day, i.p.) reduced the increases in myocardial oxygen demand induced by intracerebral L-glutamate in a dose-related manner. Interestingly, ifenprodil also reduced in a dose-dependent manner the maximum values of the oxygen demand indices reached during the central nervous system stimulation. These results indicate that the long-term treatment with ifenprodil can reduce the myocardial oxygen consumption induced by central nervous system stimulation without significant depression of the resting cardiac function. This favourable effect of ifenprodil is in fact a consequence of the association of mild inhibitory effects on the three parameters taken into account in the triple product index of myocardial oxygen consumption.

Effects of ifenprodil and baclofen on exercise-induced increase of myocardial oxygen demand in normotensive rats.

Central glutamatergic relays are known to be present in the central sympathetic pathways. Ifenprodil (an N-methyl-D-aspartate antagonist) and baclofen (a gamma-aminobutyric acid(B) agonist) are both modulators of these synapses; we previously reported their ability to reduce the cardiovascular responses induced by a central hypothalamic stimulation in rabbits. In this work, we investigated the actions of chronic treatments with these two drugs on the increase of myocardial oxygen demand induced by exercise in normotensive rats. Moreover, their effects on the baroreceptor heart rate reflex were observed. Male normotensive WKY rats were treated with placebo (two groups), baclofen, or ifenprodil for 14 days. They were then submitted to a progressively increased exercise test on a treadmill. In another three groups of animals, the same treatment was applied but, at the end, a baroreflex study was performed by the injection of phenylephrine (vagal component of the reflex) and of sodium nitroprusside (sympathetic component). Ifenprodil and baclofen reduced by nearly 50% the level of the increase of the rate x pressure product during exercise as compared with control rats. This effect appeared to be mainly due to a reduction of the hypertensive response. In the same conditions, neither baclofen nor ifenprodil significantly altered the baroreceptor heart rate reflex. The fact that these two drugs are capable of reducing the myocardial oxygen demand encourages us to test them in a model of myocardial ischemia associated with sympathetic hyperactivity.

Does a second generation of centrally acting antihypertensive drugs really exist?

The site of the hypotensive action of imidazoline compounds, such as clonidine, was first identified within the rostroventrolateral part of the brainstem: the nucleus reticularis lateralis. After that, it was shown that imidazolines and related substances reduced blood pressure when applied in this area whereas catecholamines were not capable of producing such an effect. These data led us to suggest the existence of receptors specific for imidazoline-like compounds different from the alpha2-adrenoceptors. Soon after, the existence of imidazoline binding sites was reported in the brain and in a variety of peripheral tissues including the human kidney. As expected, these specific binding sites do not bind the catecholamines. The imidazoline binding sites are already subclassified in two groups: the I1-subtype sensitive to clonidine and idazoxan, and the I2-subtype, sensitive to idazoxan and nearly insensitive to clonidine. Functional studies confirmed that the hypotensive effects of clonidine-like drugs involved imidazoline receptors while their most frequent side effects only involved alpha2-adrenoceptors. However, recent functional evidence suggests that a cross talk between imidazoline receptors and alpha2-adrenoceptors is necessary to trigger a hypotensive effect within the ventral brainstem. Rilmenidine and Moxonidine are the leader compounds of a new class of antihypertensive drugs selective for imidazoline receptors. At hypotensive doses, these drugs are devoid of significant sedative effect. Rilmenidine evoked hypotension when injected within the nucleus reticularis lateralis region; it competed for [3H]-clonidine bound to specific imidazoline binding sites in human medullary membrane preparations but proved more selective for cerebral imidazoline receptors than clonidine. It is suggested that this selectivity might explain the low incidence of their side effects. Additional potentially beneficial actions on cardiac arrhythmias or congestive heart failure enlarge the therapeutic interest of imidazoline-related drugs. Recent binding and functional data throw a new light on the optimal pharmacological profile of this second generation of centrally acting antihypertensive drugs.

Autonomic nervous system as a target for cardiovascular drugs.

1. Drugs acting within the autonomic nervous system (ANS) are of particular interest when autonomic abnormalities are implicated in the development and maintenance of various cardiovascular pathologies. For example, it has been documented that in the early stages of hypertensive disease (i.e. hyperkinetic borderline hypertension) a sympathetic hyperactivity associated with a decreased parasympathetic activity results in increased cardiac output and heart rate. 2. Several classes of drugs acting within the central, as well as the peripheral ANS, are very efficient in treating hypertensive disease. One of these classes of drugs, the second generation of centrally acting drugs, has proved beneficial in this respect because, in addition to their therapeutic efficacy, these drugs are well tolerated. 3. The central nervous system may also be the target for drugs with the potential to treat other cardiovascular diseases. Some recent experimental and clinical data supporting such new perspectives concerning idiopathic dysrhythmias, angina pectoris and congestive heart failure will be summarized.

Inhibition of centrally induced ventricular arrhythmias by rilmenidine and idazoxan in rabbits.

In a model of ventricular arrhythmias of central origin, we investigated the effects of rilmenidine, an oxazoline with antihypertensive properties, and idazoxan, an imidazoline that is an antagonist of the hypotensive effects of rilmenidine. Bicuculline, a GABAA receptor antagonist, was administered intracisternally (i.c.) to produce arrhythmias in pentobarbitone anaesthetised rabbits; 10 micrograms/kg bicuculline i.c. induced polymorphic ventricular ectopic beats and ventricular tachycardia while blood pressure increased by about 50-60% and sinusal heart rate decreased by about 20%. Rilmenidine, either administered intravenously (0.01, 0.1, 1 mg/kg i.v.) or i.c. (3, 10, 30 micrograms/kg) dose-dependently prevented the occurrence of bicuculline-induced arrhythmias while, because of a lower base-line, the blood pressure values reached were less as compared to controls. Idazoxan administered i.v. (3, 10 mg/kg) had a similar action. Idazoxan i.c. (15 micrograms/kg) had no significant antiarrhythmic effect but antagonized in part the haemodynamic and antiarrhythmic effects of rilmenidine (1 mg/kg i.v.; 30 micrograms/kg i.c.). It is suggested that the antiarrhythmic effects observed with rilmenidine are mainly mediated by blunting the bicuculline-induced increase in the sympathetic nervous output to the heart and the vascular beds. These effects of rilmenidine are likely to originate both from the central and peripheral nervous system. The antiarrhythmic effects of idazoxan i.v. might be related to a blocking action on alpha 2-adrenoceptors at the level of the coronary arteries and other vascular beds.

MK-801 and memantine inhibit a centrally induced increase in myocardial oxygen demand in rabbits.

Electrical stimulation of the paraventricular nucleus of the hypothalamus in the anaesthetized rabbit induces an increase in indexes of myocardial oxygen demand. This increase in myocardial oxygen demand is due to the activation of sympathetic pathways which include glutamatergic relays. In this model, systemic injection of dizolcipine (MK-801) and memantine inhibited these responses. Because these drugs have only one pharmacological property in common i.e. blockade of the NMDA receptor channel complex, these results fit with our previous results concerning the possible involvement of NMDA receptors in the central control of sympathetic activation. Memantine appears to be an interesting prototype for centrally acting cardioprotective drugs devoid of serious side effects.

Comparative effects of idazoxan, prazosin, and yohimbine on coronary ligation-induced arrhythmias in spontaneously hypertensive rats.

We investigated whether certain drugs with alpha-adrenergic antagonist activity display anti-arrhythmic effects in hypertensive animals subjected to acute coronary artery ligation. The left anterior descending coronary artery (LAD) was ligated in open-chest pentobarbital-anesthetized spontaneously hypertensive rats (SHR); arrhythmias were subsequently recorded for 30 min. Drugs were administered intravenously, (i.v.) 5 min before ligation. The effects of yohimbine and idazoxan were compared with those of prazosin. Prazosin (100 mu g/kg) increased the occurrence of ventricular tachycardia (VT). In contrast, yohimbine 1.6 mg/kg decreased both the occurrence and the duration of VT and the occurrence and the duration of ventricular fibrillation, (VF). The results obtained with idazoxan 1 mg/kg were similar to those with yohimbine. The ECG alterations induced by coronary artery ligation in rats treated with yohimbine and idazoxan were more pronounced than in controls and in rats treated with prazosin, suggesting that the antiarrhythmic effects observed were not mediated by antiischemic activity. The protective effects against ligation-induced arrhythmias were preceded by a hypotensive effect and a decrease in the rate-pressure product in yohimbine-treated but not in idazoxan-treated animals. In rats treated with prazosin, more arrhythmic events were observed, although hemodynamics were similar to those in rats treated with yohimbine. Our results suggest that the yohimbine-induced antiarrhythmic action is not due to an alteration of conduction or repolarization rates. In this model, yohimbine and idazoxan appear to protect against ligation-induced arrhythmias. These data suggest that drugs with alpha-adrenergic properties might influence the nervous drive to the heart in SHR with cardiac ischemia. However, further investigations are needed to ascertain whether the alpha-adrenoceptor blockade participates in this effect.

GABAergic and glutaminergic modulation of centrally evoked arrhythmias in rats.

A standard electrical stimulus applied to the posterior hypothalamus evoked cardiac arrhythmogenic responses in the spontaneously hypertensive rat. Isolated premature ventricular beats or doublets and nonsustained ventricular tachycardic salvos were observed. This effect was associated with a large rise in blood pressure (79 +/- 3 mm Hg). The same stimulus in normotensive Wistar-Kyoto rats produced no significant cardiac arrhythmias, and the rise in blood pressure was smaller (36 +/- 2 mm Hg). We investigated the influence of baclofen, a GABAB receptor agonist, and two N-methyl-D-aspartate receptor antagonists on the arrhythmogenic response to hypothalamic stimulation. Intravenous baclofen (3 mg/kg) had no effect in the normotensive Wistar-Kyoto rats, but in the spontaneously hypertensive rats it enhanced the adjusted mean value of the number of extrasystoles from 0.5 +/- 0.5 to 18 +/- 1 (P < .001). This value was also increased (from 3 +/- 1 to 17 +/- 1, P < .001) by an intracisternal injection of baclofen (1 micrograms/kg). This facilitatory effect of baclofen was prevented by treatment with atenolol (0.5 mg/kg). Two glutamate receptor antagonists, ketamine (7.5 mg/kg IV) and kynurenic acid (200 micrograms/kg intracerebroventricularly), prevented both the arrhythmogenic response to the hypothalamic stimulation and its facilitation by baclofen. The study confirms that hypothalamic stimulation facilitates the development of arrhythmias through a sympathetic drive and that these arrhythmias are easier to induce in spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. Both the central GABAergic and the glutamatergic systems are implicated in the development of these ventricular arrhythmias, since baclofen could disinhibit the glutamatergic central pathway. These results could account for the ability of the spontaneously hypertensive rats to develop ventricular arrhythmias of central origin.

Evidence for a spinal origin of the effect of baclofen on the myocardial oxygen demand indexes.

In a previous study in anaesthetized rabbits we observed that electrical stimulation of the hypothalamic paraventricular nucleus (PVN) elicited substantial rises in the maximum rate of change of left ventricular pressure (dP/dtmax) and in myocardial oxygen demand indexes (rate-pressure product and triple product), similar to the changes observed during stress or physical effort. Baclofen, a selective GABA(B) receptor agonist, injected intravenously prevented these responses. In the present study, we show that low doses of baclofen (0.1, 0.3 and 1 microgram/kg), injected intrathecally (i.t.) at the T9 level, reduced the myocardial oxygen demand during PVN stimulation. After 0.3 microgram/kg baclofen i.t., the peak value of the triple product during stimulation was 140 +/- 20 compared with 193 +/- 20 before treatment. An i.t. injection (500 micrograms/kg), of saclofen a selective GABA(B) receptor antagonist, did not modify the resting haemodynamics significantly but attenuated the inhibitory effects of baclofen (3 mg/kg i.v.). These results suggest that the main site of the effects of baclofen is located within the spinal cord and that GABA(B) receptors probably mediate these effects by modulating the central control of cardiac function. In conclusion, baclofen might be a useful tool to prevent the centrally evoked increases of myocardial oxygen demand.

Inhibition of the centrally induced increases in myocardial oxygen demand in rabbits by chronic treatment with baclofen, a selective GABAB agonist.

1. A previous study from our group demonstrated that neurones of the paraventricular nucleus of the hypothalamus (PVN) are selectively involved in the central control of the cardiac function. Moreover, in that study, it was shown that baclofen, a selective GABAB receptor agonist, is capable of modulating the increases in myocardial contractility and oxygen demand evoked by electrical or pharmacological stimulation of the PVN. Nevertheless, the acute administration of this compound was frequently accompanied by a cardiodepressant effect. 2. In the present study, the effects of a long term treatment (14 days) with baclofen (3 or 10 mg kg-1, i.p.) have been examined on the excitatory haemodynamic responses evoked by central pharmacological stimulation in anaesthetized rabbits. 3. The i.c.v. injection of L-glutamate (3 mg kg-1) induced marked increases in dP/dtmax (32%), mean arterial pressure (39%) and on two indices of myocardial oxygen consumption: the rate-pressure product (34%) and the triple product (78%). 4. Baclofen blunted the positive inotropic response and the increases in myocardial oxygen consumption induced by L-glutamate in a dose-related manner. The higher dose of baclofen (10 mg kg-1, i.p.), reduced by more than 50% these excitatory effects of L-glutamate without eliciting any significant negative effect on basal haemodynamics. The same doses of baclofen were not able to blunt the hypertensive response induced by central stimulation. 5. These results confirm and extend our previous findings suggesting that it is possible to discriminate the central control of vasomotor tone from that of cardiac function and also that baclofen can modulate the latter. It is concluded that when given chronically, baclofen modulates the increases in myocardial oxygen demand induced by activation of the central nervous system in doses which do not depress the resting cardiac function.

Prevention by NMDA receptor antagonists of the centrally-evoked increases of cardiac inotropic responses in rabbits.

1. The purpose of this study was to investigate further the role of the excitatory amino acid (EAA) system of neurotransmission, particularly of the NMDA receptor, in the central regulation of cardiac function. 2. Electrical stimulation of the paraventricular nucleus of the hypothalamus (PVN) in pentobarbitone anaesthetized rabbits induced a cardiovascular response mainly characterized by a positive inotropic effect, hypertension and a marked increase in the myocardial oxygen demand index. 3. The intracerebroventricular (i.c.v.) or intravenous (i.v.) injection of different EAA antagonists acting on different sites of the NMDA receptor/channel complex dose-dependently blunted the excitatory cardiovascular effects of PVN stimulation. 4. 5,7 Dichlorokynurenic acid was used as a specific glycine site antagonist and 2-amino-5-phosphonovaleric acid was used to block the agonist recognition site; ketamine was used as a channel blocker site antagonist and ifenprodil as a blocker of the polyamine binding site. 5. 5,7 Dichlorokynurenic acid (125 and 250 micrograms kg-1, i.c.v.) virtually abolished the cardiovascular responses, inducing only haemodynamic depression at the highest dose used. 2-Amino-5-phosphonovaleric acid (0.1 to 1.0 mg kg-1, i.c.v.) elicited a reduction of the peak values observed during PVN stimulation which was accompanied by a decrease of the basal cardiovascular parameters. Ketamine (2.5 and 10 mg kg-1) and ifenprodil (1 mg kg-1), injected intravenously, blocked the haemodynamic response induced by PVN stimulation without marked reduction of the basal haemodynamics. 6. It is concluded that glutamate neurotransmission is not only involved in vasomotor tone control but also in the central control of cardiac function and can therefore modulate the myocardial oxygen demand.

Baclofen prevents the increase of myocardial oxygen demand indexes evoked by the hypothalamic stimulation in rabbits.

The electrical stimulation of the paraventricular nucleus (PVN) of the hypothalamus in anaesthetized rabbits elicited important cardiovascular responses which were mainly characterized by increases in arterial pressure, dP/dtmax, and of the indexes of myocardial oxygen consumption, rate-pressure product (from 34 +/- 2 to 40 +/- 2 mmHg.bpm.10(-3) and triple product (from 102 +/- 12 to 162 +/- 19 mmHg2.s-1.bpm.10(-6). The hemodynamic alterations induced by PVN stimulation were similar to those observed during physical effort and stressful situations. Intracerebroventricular (0.1, 0.3 and 1 microgram.kg-1) or intravenous administration (1, 3 and 10 mg.kg-1) of baclofen, a selective GABAB receptor agonist, induced a dose-related decrease in the peak values of dP/dtmax and of the indexes of myocardial oxygen consumption (rate-pressure and triple products) during the electrical PVN stimulation. After 1 microgram.kg-1 baclofen (i.c.v.), the peak value of the triple product during PVN stimulation was 101 +/- 21 as compared to 149 +/- 15 before treatment. At the 10 mg.kg-1 dose (i.v.), the triple product during stimulation only reached 90 +/- 20 vs. 150 +/- 20 before treatment. These results suggested that a type B GABAergic transmission system is involved in the modulation of central control of the cardiac function. Drugs modulating this system could therefore be designed to blunt the myocardial oxygen demand increases.

Selectivity of rilmenidine for the nucleus reticularis lateralis, a ventrolateral medullary structure containing imidazoline-preferring receptors.

Neuronal metabolic activity was studied by in vivo electrochemistry in two brain areas of the anesthetized rat: the nucleus reticularis lateralis (NRL) region of the ventrolateral medulla oblongata - site of the hypotensive action of clonidine-like imidazolines - and the locus coeruleus (LC), which is involved in the sedative effect of these drugs. Hypotensive doses of i.v. rilmenidine (0.3 and 1.5 mg/kg), which is structurally related to clonidine, induced a dose-related inhibition of the metabolic activity of catecholaminergic neurons in the NRL region whereas higher doses (50-fold) were required to inhibit the activity of the catecholaminergic neurons in the locus coeruleus. On the other hand azepexole, another centrally acting antihypertensive drug that is not structurally related to the imidazolines failed to inhibit the neuronal metabolic activity of the NRL region when administered i.v. in hypotensive doses (1 mg/kg). Taken together, these findings suggest that the central hypotensive action of clonidine-like drugs requires the imidazoline structure or pharmacologically compatible compounds like rilmenidine. Our results also show that rilmenidine is twice as selective as clonidine for the NRL region, which contains imidazoline-preferring receptors, compared with the LC, which contains mainly alpha 2-adrenoceptors. In conclusion, this study provides a functional confirmation of the dissociation between the therapeutic (hypotensive) and untoward (sedative) effects of rilmenidine.