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Biomedical subjects

P Bousquet

Publications and source records attributed to P Bousquet.

At least 19 recordsLinked to original sources
PubMed2001

Synthesis and biological evaluation of pyrrolinic isosteres of rilmenidine. Discovery of cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine (LNP 509), an I1 imidazoline receptor selective ligand with hypotensive activity.

To find new compounds selective for purported I1 imidazoline receptors (I1Rs) over I2 imidazoline binding sites (I2BS) and alpha2-adrenoceptors (alpha2ARs), a series of pyrrolinic isosteres of rilmenidine has been prepared and their biological activity at I1Rs, I2BS, and alpha2ARs evaluated. This isosteric replacement provided us with compounds which still bound to I1Rs but not to I2BS nor to alpha2ARs. A limited structure-affinity relationship was generated around the heterocyclic moiety of these ligands. One compound in this series, LNP 509 (1e) [cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine], had no detectable affinity at alpha2ARs yet was capable of lowering blood pressure after central administration. These pyrrolinic analogues constitute a new chemical class of imidazoline related compounds with high selectivity for the I1Rs. They could be used as new tools in the study of I1Rs and in the conception of new centrally acting hypotensive drugs.

Adrenal Medulla↗
PubMed2001

Respective contributions of alpha-adrenergic and non-adrenergic mechanisms in the hypotensive effect of imidazoline-like drugs.

The hypotensive effect of imidazoline-like drugs, such as clonidine, was first attributed to the exclusive stimulation of central alpha2-adrenoceptors (alpha2ARs). However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. This work aims (i) to check whether imidazoline-like drugs with no alpha2-adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an alpha2ARs agonist alpha-methylnoradrenaline (alpha-MNA). We selected S23515 and S23757, two imidazoline-like drugs with negligible affinities and activities at alpha2ARs but with high affinities for non-adrenergic imidazoline binding sites (IBS). S23515 decreased BP dose-dependently (-27+/-5% maximal effect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 microg kg(-1) i.c.) was prevented by S23757 (1 mg kg(-1) i.c.) and efaroxan (10 microg kg(-1) i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive effect of alpha-MNA (3 and 30 microg kg(-1) i.c.). Moreover, the alpha2ARs antagonist rauwolscine (3 microg kg(-1) i.c.) did not prevent the effect of S23515. Finally, whilst 3 microg kg(-1) of S23515 or 0.5 microg kg(-1) of alpha-MNA had weak hypotensive effects, the sequential i.c. administration of these two drugs induced a marked hypotension (-23+/-2%). These results indicate that an imidazoline-like drug with no alpha2-adrenergic properties lowers BP and interacts synergistically with an alpha(ARs agonist.

Animals↗
PubMed2001

Nitric oxide and central antihypertensive drugs: one more difference between catecholamines and imidazolines.

NO is known to be involved in the peripheral and central regulation of the cardiovascular function. It plays a neuromodulatory role via a direct action on presynaptic nerve terminals, stimulating the release of gamma-aminobutyric acid, glutamate, and norepinephrine. Our aim was to study the possible role of NO in the cardiovascular effects of the central antihypertensive drugs clonidine, rilmenidine, and alpha-methyl-norepinephrine (alpha-MNA). Sites and mechanisms of the hypotensive action of these drugs were different; clonidine and rilmenidine acted on imidazoline receptors in the nucleus reticularis lateralis, whereas alpha-MNA acted upon alpha(2)-adrenoceptors in the nucleus tractus solitarius. The influence of N:(G)-nitro-L-arginine, an NO synthase inhibitor, on the central hypotensive effects of these drugs was investigated in pentobarbital-anesthetized rabbits. The intracisternal (IC) administration of alpha-MNA (30 microg/kg) induced hypotension (79+/-2 versus 103+/-4 mm Hg) and bradycardia (222+/-8 versus 278+/-4 bpm) (P:<0.05) (n=5). Clonidine (0.07 microg/kg IC) also induced hypotension (69+/-5 versus 99+/-4 mm Hg) and bradycardia (266+/-7 versus 306+/-10 bpm) (P:<0.05) (n=5). In addition to clonidine, rilmenidine (1 microg/kg IC) induced hypotension (64+/-4 versus 97+/-4 mm Hg) and bradycardia (264+/-11 versus 310+/-4 bpm) (P:<0.05) (n=5). Pretreatment with N:(G)-nitro-L-arginine (900 microg/kg IC) completely prevented the hypotensive effect of alpha-MNA but influenced the cardiovascular effects of neither clonidine nor rilmenidine. These results confirm that imidazoline drugs, such as clonidine, rilmenidine, and the catecholamine alpha(2)-adrenoceptor agonist alpha-MNA, have distinct mechanisms of action.

Animals↗
PubMed2001

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.

Administration, Oral↗
PubMed2000

Regional changes in carbon dioxide fluxes of land and oceans since 1980.

We have applied an inverse model to 20 years of atmospheric carbon dioxide measurements to infer yearly changes in the regional carbon balance of oceans and continents. The model indicates that global terrestrial carbon fluxes were approximately twice as variable as ocean fluxes between 1980 and 1998. Tropical land ecosystems contributed most of the interannual changes in Earth's carbon balance over the 1980s, whereas northern mid- and high-latitude land ecosystems dominated from 1990 to 1995. Strongly enhanced uptake of carbon was found over North America during the 1992-1993 period compared to 1989-1990.

Journal Article↗
PubMed2000

Imidazoline receptors: a challenge.

The hypotensive effect of imidazoline-like drugs (IMs) directly injected into the rostroventrolateral part of the brainstem (NRL/RVLM) was shown to involve non-adrenergic imidazoline specific receptors (IRs). Some IMs caused hypotension when injected there, irrespective of their affinity and selectivity for any alpha-adrenoceptor subtype. Compounds, such as LNP 509, S 23515, S 23757 or benazoline with very high selectivities for IRs over alpha 2-adrenoceptors (A2Rs), became available recently. Some of these compounds (LNP 509, S 23515) caused hypotension when injected alone into the NRL/RVLM region. Nevertheless, high selectivity for IRs will not predict by its own the capability of IMs to elicit hypotension as some of these substances behaved as antagonists towards the hypotensive effects of the latter. As far as hybrid drugs, i.e., with mixed binding profiles (I1/alpha 2), were concerned, a significant correlation has been reported between their central hypotensive effect and their affinity for IRs. Imidazoline antagonists, such as idazoxan, were repeatedly shown to competitively prevent and reverse the centrally induced hypotensive effect of IMs. The sole stimulation of A2Rs within the NRL/RVLM region was not sufficient to decrease blood pressure as much as IMs did, as shown by the lack of significant blood pressure lowering effect of alpha-methylnoradrenaline (alpha-MNA). No correlation was observed between affinity of IMs for A2Rs and their central hypotensive effects. It is also noticeable that yohimbine, an A2Rs antagonist, was repeatedly shown to abolish the hypotensive effect of hybrids but usually in a non-competitive manner. Mutation of A2Rs was shown to prevent the hypotensive effects of centrally acting drugs. It is concluded that (i) drugs highly selective for I1Rs over A2Rs can reduce blood pressure by their own; (ii) the central hypotensive effect of IMs needs implication of IRs and appears to be facilitated by additional activation of A2Rs; and (iii) this effect requires intact A2Rs along the sympathetic pathways.

Animals↗
PubMed2000

Identification and characterization of I1 imidazoline receptors: their role in blood pressure regulation.

It has been shown that only imidazolines and related compounds cause a fall in blood pressure when administered at the site of the hypotensive action of clonidine; no phenylethylamine compounds were capable of producing such an effect at this site. Extensive biochemical and pharmacologic studies have confirmed the involvement of imidazoline receptors in the regulation of vasomotor tone and in the mechanism of action of some centrally acting antihypertensive drugs. Imidazoline-specific binding sites (IBS) did not bind catecholamines. Functional studies using selective antagonists have confirmed that the hypotensive effects of clonidine-like drugs are mediated by imidazoline-specific receptors, whereas their sedative action clearly involves alpha2-adrenergic receptors located in the locus coeruleus. Compared with clonidine, second-generation centrally acting antihypertensive drugs such as rilmenidine have been shown to be more selective for imidazoline receptors than for alpha2-adrenergic receptors. This selectivity may explain the reduced incidence of side effects of these drugs at hypotensive doses. Very recently, new imidazoline-like compounds have been synthesized that are highly selective for both subtypes of IBS (I1 and I2). Some of these compounds lowered blood pressure when injected centrally in animals, indicating that an action on imidazoline I1 receptors alone is sufficient to lower blood pressure. With the help of such selective tools, we have also shown that imidazoline receptors and alpha2-adrenoceptors might cooperate to control vasomotor tone, and might jointly be involved in the hypotensive action of centrally acting hybrid drugs (ie, drugs that bind to both types of receptor).

Animals↗
PubMed2000

Imidazoline receptors in cardiovascular and metabolic diseases.

The site of the hypotensive action of imidazoline compounds, such as clonidine, was first identified within the rostroventrolateral part of the brainstem. Afterwards, it was shown that imidazolines reduced blood pressure when applied in this area, whereas no catecholamine was capable of such an effect. These data led us to suggest the existence of receptors specific for imidazolines different from the alpha-adrenergic receptors. Soon after, the existence of imidazoline binding sites (IBS) was reported in the brain and in a variety of peripheral tissues including pancreatic gland and kidney. As expected, these specific binding sites do not bind the catecholamines. The IBS are classified in two groups: the I1 type, sensitive to clonidine and idazoxan; and the I2 type, sensitive to idazoxan and largely insensitive to clonidine. Imidazoline receptors were shown to be involved in several physiological regulations and pathological processes such as hypertension, diabetes mellitus and some mood disorders. Evidence for their implication in the nervous regulation of blood pressure and in the insulin secretion control will be presented. The hypotensive effects of clonidine-like drugs involve imidazoline receptors (I1Rs), while their most frequent side-effects only involve alpha2-adrenergic receptors. A new class of centrally acting antihypertensive drugs selective for I1Rs is now available. At hypotensive doses, these drugs are devoid of significant side effects. It was shown that the good acceptability of these drugs is likely due to their selectivity for I1Rs.

Animals↗
PubMed2000

Coupling of I(1) imidazoline receptors to the cAMP pathway: studies with a highly selective ligand, benazoline.

Clonidine and benazoline are two structurally related imidazolines. Whereas clonidine binds both to alpha(2)-adrenoceptors (alpha(2)R) and to I(1) imidazoline receptors (I(1)R), benazoline showed a high selectivity for imidazoline receptors. Although the alpha(2)R are negatively coupled to adenylate cyclase, no effect on cAMP level by activation of I(1)R has been reported so far. We therefore aimed to compare the effects of clonidine and benazoline on forskolin-stimulated cAMP levels in cell lines expressing either I(1)R only (PC12 cells), alpha(2)R only (HT29 cells), or I(1)R and alpha(2)R together (NG10815 cells). Clonidine proved able to decrease the forskolin-stimulated cAMP level in the cells expressing alpha(2)R and this effect could be blocked by rauwolscine. In contrast, in cells lacking these adrenoceptors, clonidine had no effect. On the other hand, benazoline and other I(1) receptor-selective imidazolines decreased forskolin-stimulated cAMP level in the cells expressing I(1)R, in a rauwolscine- and pertussis toxin-insensitive manner. These effects were antagonized by clonidine. According to these results, we demonstrated that 1) alpha(2)R and I(1)R are definitely different entities because they are expressed independently in different cell lines; 2) alpha(2)R and I(1)R are both implicated in the cAMP pathway in cells (one is sensitive to pertussis toxin and the other is not); and 3) I(1)R might be coupled to more then one transduction pathway. These new data will be essential to further understand the physiological implications of the I(1)R and the functional interactions between I(1) receptors and alpha(2)-adrenoceptors.

Adenylate Cyclase Toxin↗
PubMed1999

Identification of human I1 receptors and their relationship to alpha 2-adrenoceptors.

I1 imidazoline receptors (I1R) were defined as receptors insensitive to catecholamines and highly sensitive to [3H]clonidine and analogs. By contrast, the I2R subtype is more sensitive to [3H]idazoxan. [3H]clonidine and [3H]idazoxan imidazoline specific binding sites (IBS) have been detected in crude human membranes. Pharmacologic characterization by binding assays clearly differentiates IBS from alpha 2-adrenoceptors, whereas differences between [3H]clonidine and [3H]idazoxan IBS are less clear in crude preparations. In fact, only moderate affinity for [3H]clonidine was detectable in such preparations. However, purification procedures allowed detection of high affinity [3H]clonidine IBS in the human brain, corresponding to the I1R. Difficulties in the characterization of the I1R in crude membranes are due to multiple factors including heterogeneity of IBS, their low Bmax value, the existence of allosteric modulation, and possibly the presence of natural binding inhibitors. Immunologic studies with specific anti-idiotypic antibodies revealed a 43-kD protein as the best candidate for I1R as binding activity coincides with immunodetection. No cross-reaction was found with anti-monoamine oxidase (MAO) A/B antibodies and the 43-kD protein, ruling out the possibility of this protein being an MAO-associated I2R. Neither anti-alpha 2A- nor anti-alpha 2B-specific antibodies were able to immunodetect the 43-kD protein in crude membrane preparations or in purified fractions. These results and further biochemical characterization (pHi, N-glycosylation) of the 43-kD protein definitely assessed that human brain I1R and alpha 2-adrenoceptors clearly differ physically. However, coexpression of I1R and alpha 2-adrenoceptors in synaptic plasma membranes of the bovine brainstem reinforce the possibility of a functional relationship between the two types of receptor.

Animals↗