Hubert DABIRÉ - Academia.edu (original) (raw)
Papers by Hubert DABIRÉ
PubMed, Nov 1, 1988
In normotensive anaesthetized rats, 8-OH-DPAT, RU 24969 and 5-MeODMT, three 5-HT1-like receptor a... more In normotensive anaesthetized rats, 8-OH-DPAT, RU 24969 and 5-MeODMT, three 5-HT1-like receptor agonists, decreased blood pressure and heart rate. The decrease in blood pressure was suppressed by pithing or pretreatment with hexamethonium. Bilateral section of the vagus nerves, pretreatment with a beta-adrenoceptor blocking agent or with atropine, combination of bivagotomy plus beta-adrenoceptor blockade strongly reduced the bradycardia. These results are compatible with a centrally-mediated decrease in sympathetic tone and increase in vagal tone, as the cause of the hypotension and bradycardia induced by these 5-HT1-like receptor agonists in normotensive anaesthetized rats.
PubMed, 1990
Serotonin (5-HT) induced a transient decrease followed by an increase and then a longer-lasting d... more Serotonin (5-HT) induced a transient decrease followed by an increase and then a longer-lasting decrease in blood pressure. The initial decrease in blood pressure results from a reduction in cardiac output as a result of the profound bradycardia. The secondary increase in blood pressure is caused by an increase in both cardiac output and total peripheral resistance. The final decrease in blood pressure is ascribed to a reduction in total peripheral resistance. The effects of 5-HT on regional haemodynamics are known to vary according to the vascular bed and even in the same vascular bed. Accordingly, 5-HT induced either vasoconstriction or vasodilatation. Vasoconstriction occurred in most cases in large arteries and is due to stimulation of 5-HT2 receptors. However, 5-HT1-like receptors are probably also implicated. 5-HT-induced vasodilatation is attributed to stimulation of 5-HT1-like receptors. However, limited evidence suggests also an implication of 5-HT3 and even 5-HT2 receptors in the dilator effects of 5-HT. 5-HT1A receptor agonists decreased blood pressure by a reduction in total peripheral resistance. This vasodilatation seems to be widespread. Other 5-HT1-like receptor agonists have differential effects according to the animal species used.
PubMed, Apr 1, 1986
The pharmacological properties of idazoxan, 2-[2-(1,4-benzodioxanyl)]-2-imidazoline, were first d... more The pharmacological properties of idazoxan, 2-[2-(1,4-benzodioxanyl)]-2-imidazoline, were first described four years ago; since then, this compound has been revealed to be one of the most selective alpha 2-adrenoceptor blocking agent presently available. At peripheral sites, idazoxan antagonized the effects of alpha 2 agonists such as azepexole, B-HT 920, M 7, UK 14,304, alpha-methylnoradrenaline, clonidine but was ineffective against alpha 1 agonists such as cirazoline and phenylephrine. At presynaptic sites idazoxan increased the tachycardia due to the stimulation of the cardioaccelerator nerve of the dog and antagonized the inhibitory effects of alpha 2 agonists in dogs and rats. As compared to the classical alpha 2-adrenoceptor blocking agents, idazoxan was more selective and as potent as yohimbine, rauwolscine, RS 21361, Wy 26703. At central sites, idazoxan has been found to antagonize the sympathoinhibitory effects of alpha 2 agonists. Therefore, idazoxan is a potent and probably the most selective alpha 2-adrenoceptor blocking agent presently available and is now frequently used for the investigation of peripheral and central alpha 2-adrenoceptors.
PubMed, Nov 1, 1991
Both intravenous and central administration of ketanserin, a 5-HT2 receptor antagonist, decrease ... more Both intravenous and central administration of ketanserin, a 5-HT2 receptor antagonist, decrease blood pressure and sympathetic nerve activity, suggesting a central origin of its effects. However, ketanserin also possesses alpha 1-adrenoceptor blocking properties. Selective 5-HT2 receptor antagonists devoid of alpha 1-adrenoceptor blocking properties, e.g. LY 53857 and cinanserin, fail to reduce blood pressure and sympathetic nerve activity. In addition, 5-HT2 receptor agonists increase blood pressure and sympathetic nerve discharge. Therefore, it seems improbable that blockade of central 5-HT2 receptors alone could lead to a reduction in blood pressure. In contrast, the selective 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan decrease blood pressure and heart rate by a centrally-mediated decrease in sympathetic tone and an increase in vagal tone. The sympatho-inhibitory effects of 5-HT1A receptor agonists result from the stimulation of postsynaptic 5-HT1A receptors within the ventrolateral pressor area. These results suggest that selective 5-HT1A receptor agonists acting in the central nervous system could be developed for the treatment of hypertension. Indeed, drugs such as flesinoxan and urapidil are effective in this setting.
Springer eBooks, 1990
Injections of 8-OH-DPAT (0.1-6 micrograms/kg) into the vertebral artery or into the cisterna magn... more Injections of 8-OH-DPAT (0.1-6 micrograms/kg) into the vertebral artery or into the cisterna magna (5 micrograms/kg) produced a dose-dependent decrease in blood pressure, heart rate and renal sympathetic nerve activity in intact anaesthetized dogs and baroreceptor-denervated dogs. 8-OH-DPAT reduced the renal sympathetic nerve activity without changing the blood pressure or heart rate in catecholamine-depleted animals. Methiothepin (0.2 mg/kg) injected into the vertebral artery reduced the blood pressure without changing the heart rate or renal sympathetic nerve activity in baroreceptor-denervated dogs. The pressor response to i.v. phenylephrine was largely attenuated. Subsequent administration of 8-OH-DPAT (3 micrograms/kg) into the vertebral artery failed to alter the sympathetic discharge. Methiothepin (0.2 mg/kg) injected into the vertebral artery reversed the sympatho-inhibitory effect of 8-OH-DPAT (3 micrograms/kg) injected by the same route without changing the blood pressure. (+/-)Pindolol (0.2 mg/kg) injected into the vertebral artery of baroreceptor-denervated dogs reduced the blood pressure and heart rate without changing renal sympathetic activity. Subsequent administration of 8-OH-DPAT (3 micrograms/kg) failed to alter the sympathetic discharge. Bilateral microinjection of 8-OH-DPAT (1 microgram) into the nucleus tractus solitarii or into the medullary raphe nuclei failed to alter the blood pressure, heart rate or renal sympathetic activity. In contrast, bilateral microinjections of 8-OH-DPAT into the ventrolateral pressor area (VLPA) (0.2 microgram) produced a marked decrease in blood pressure, heart rate and renal sympathetic nerve activity. These effects were prevented or reversed by microinjections of methiothepin (10 micrograms) at the same sites. These results indicate that the central sympatho-inhibitory effects of 8-OH-DPAT were due to the stimulation of 5-HT1A receptors located in the ventrolateral pressor area. 5-HT autoreceptors did not seem to be involved.
PubMed, Aug 1, 1993
The systemic and regional haemodynamic effects of DOI were investigated in the anaesthetized rat.... more The systemic and regional haemodynamic effects of DOI were investigated in the anaesthetized rat. DOI (1-300 micrograms/kg i.v.) increased mean arterial pressure (MAP), total peripheral resistance (TPR) and all regional vascular resistances studied (hindquarters, mesenteric and renal). DOI was more effective on renal vascular bed. Cardiac output (CO) and heart rate (HR) did not change. The effects of DOI were antagonized by LY 53857 (10 micrograms/kg i.v.) and spiperone (10 or 100 micrograms/kg i.v.), selective 5-HT2 receptor antagonists. Intracerebroventricular administration of DOI (100 micrograms/kg) increased MAP, TPR, regional vascular resistances and did not change HR and CO. Pretreatment with xylamidine (10 micrograms/kg i.v.), a selective peripheral 5-HT2 receptor antagonist, blocked i.v. and i.c.v. effects of DOI. These results suggest that: 1) the increase in MAP induced by the stimulation of 5-HT2 receptors is due to an increase in TPR. All regional vascular resistances participate in the increase of TPR. 2) Peripheral and central 5-HT2 receptors seem to be implicated in the control of regional vascular resistances.
Fundamental & Clinical Pharmacology, Aug 1, 1992
Summary— A pharmacological analysis of the effects of 5‐HT on heart rate has been performed in th... more Summary— A pharmacological analysis of the effects of 5‐HT on heart rate has been performed in the pithed rat. 5‐HT induced a dose‐dependent increase in heart rate whereas 5‐HT, receptor agonists — 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), 5‐methoxy‐N,N‐dimethyl‐tryptamine (5‐MeODMT), 5‐methoxy 3‐(1,2,3,6‐tetrahydro‐4‐piridinyl) 1H indole (RU 24969) and 1‐(m‐trifluoromethylphenyl)‐piperazine (TFMPP) — failed to increase heart rate. The increase in heart rate induced by the selective 5‐HT2 receptor agonist 1‐(2,5‐dimethoxy‐4‐iodo‐phenyl)‐2‐aminopropane (DOI) was not significant. The dose‐response curve to 5‐HT for its tachycardic effects was shifted two‐fold to the right by ketanserin and LY 53857 and nine‐fold to the right by methiothepin. The effects of high doses of 5‐HT (higher than 100 μg/kg iv) were antagonized by methiothepin, (‐)propranolol, 2‐{2‐[4(O‐methoxyphenyl)‐piperazine‐1‐yl]‐ethyl}4,4‐dimethyl‐1,3 (2H‐4H) isoquinoline‐dione (AR‐C 239) and by pretreatment with reserpine. The 5‐HT1 receptor antagonists, pindolol and spiroxatrine, the 5‐HT3 receptor antagonist MDL 72222 and the α2‐adrenoceptor blocking agent idazoxan failed to antagonize the tachycardia induced by 5‐HT. It is concluded that in the pithed rat, the tachycardia induced by 5‐HT remained unexplained (implication of 5‐HT2 receptors probably different from the classical vascular 5‐HT2 receptor, or implication of 5‐HT1C receptors?). Moreover, at high doses (higher than 100 μ/kg iv), 5‐HT may increase heart rate by releasing catecholamines.
European Journal of Pharmacology, Jun 1, 1999
The contribution of tyrosine kinase activity to vasoreactivity in normotensive Wistar–Kyoto (WKY)... more The contribution of tyrosine kinase activity to vasoreactivity in normotensive Wistar–Kyoto (WKY) and spontaneously hypertensive (SHR) rats was investigated on isolated aortic preparations by the use of two tyrosine kinase inhibitors: methyl-2,5-dihydroxycinnamate (30 μM) and genistein (30 μM). The pretreatment of endothelium denuded aorta with methyl-2,5-dihydroxycinnamate reduced the sensitivity of the rings to noradrenaline to a larger extent in SHR
Fundamental & Clinical Pharmacology, Dec 1, 1997
Journal of Hypertension, Jun 1, 2011
treatment with valsartan is able to reduce the SBP in the same extent as a continuous one. Nevert... more treatment with valsartan is able to reduce the SBP in the same extent as a continuous one. Nevertheless, the increased arterial stiffness and cardiac hypertrophy observed in DT rats compared with CT rats indicate that despite the same decrease of SBP, an intermittent treatment with valsartan may not achieve the full cardiovascular benefits observed with a continuous treatment. Our results suggest that this experimental model is useful to investigate the impact of chronical increased amplitude of variations in SBP on target organ damage. These results that mimics partial adherence to therapy may have important clinical implications in hypertensive patients.
PubMed, Aug 1, 2001
Several studies have well demonstrated that obesity is associated with changes in cardiovascular ... more Several studies have well demonstrated that obesity is associated with changes in cardiovascular vagosympathetic activity. The aim of the present work was to evaluate this activity in normotensive and in mildly hypertensive obese patients, and to correlate this activity with clinical and biological indexes of insulin resistance. Heart rate (HR) and systolic blood pressure (sBP) were examined by spectral analysis in 70 normotensive obese patients (group 1), 32 mildly hypertensive obese patients (group 2), and 21 controls. The high frequency peak of HR variations at a controlled breathing rate (vagal activity) was significantly reduced in both groups (p < 0.001). The mid frequency peak of sBP in the standing position (sympathetic activity) was similar in both groups and in the control group. In groups 1 and 2, the high frequency peak correlated negatively with age (p = 0.005 and 0.034 respectively). In group 1, the mid frequency peak correlated positively with fat mass, fasting plasma insulin and triglyceride levels, and insulin resistance index (p < or = 0.03). In group 2, the mid frequency peak correlated positively with fasting insulin and insulin resistance index (p = 0.006 and 0.007 respectively). This study shows that, in obese patients: 1. cardiac vagal activity is reduced in normotensive and mildly hypertensive subjects; 2. vascular sympathetic activity is unchanged in means but may be increased as a consequence of adiposity, hyperinsulinemia and insulin resistance, and this increase is likely to be involved in the increase of blood pressure.
American Journal of Physiology-Heart and Circulatory Physiology, 1998
The aim of the present work was to obtain insights into the pathophysiology of cardiovascular dec... more The aim of the present work was to obtain insights into the pathophysiology of cardiovascular deconditioning (CVD) induced by tail suspension (TS) in the rat: during TS, when central venous pressure (CVP) has been normalized (E. Martel, P. Champéroux, P. Lacolley, S. Richard, M. Safar, and J. L. Cuche. J. Appl. Physiol. 80: 1390–1396, 1996), and during simulated orthostatism (SO), when transient episodes of hypotension and bradycardia are disclosed, bradycardia with SO represents a response that seems peculiar to the rat compared with humans. According to basic physiology, a reduced activity of the sympathetic system induced by increased CVP was suspected but was not supported by data obtained through spectral analysis of blood pressure (BP) and heart rate (HR) variability or measurements of plasma catecholamine concentration during TS. Nonetheless, indirect evidence was obtained. During SO, plasma catecholamine concentration was lower in TS rats than in controls, suggesting a reduc...
Journal de pharmacologie
1. 170 150 (imidazolinyl-2)-2-benzodioxane 1-4), as does piperoxan, competitively antagonizes the... more 1. 170 150 (imidazolinyl-2)-2-benzodioxane 1-4), as does piperoxan, competitively antagonizes the hypertension induced by clonidine in the pithed rat. Piperoxan appears slightly less potent than 170 150 in this preparation as shown by the comparison of the apparent pA10 values: 5.3 for piperoxan versus 5.4 for 170 150. 2. The two drugs antagonize the reduction of the electrically-induced tachycardia produced by clonidine. 170 150 appears to be 3-fold more potent than piperoxan in this preparation. 3. These results are compatible with a blockade of alpha 2-pre and postsynaptic adrenoceptors of the rat by piperoxan and 170 150 appears to be 3-fold more potent than piperoxan in this preparation. 3. These results are compatible with a blockade of alpha 2-pre and postsynaptic adrenoceptors of the rat by piperoxan and 170 150 and they are in agreement with our previous results which indicate that compound 170 150 shows a preferential affinity for alpha 2-adrenoceptors.
Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie, 1984
The effects of the stereoisomers of two alpha adrenoceptor antagonists [S 10089 (Imidazolinyl-2)-... more The effects of the stereoisomers of two alpha adrenoceptor antagonists [S 10089 (Imidazolinyl-2)-2 benzocyclobutane and S 9871 (Imidazolinyl-2)-2 dihydro 2,3 benzofuran] were studied in pithed Rats. Vasoconstriction elicited via stimulation of alpha 1 adrenoceptors by cirazoline was antagonized, stimulation of alpha 2 adrenoceptors by azepexole was also antagonized by all these derivatives except (-) S 9871 which was ineffective on the pressor response of azepexole.
Archives internationales de pharmacodynamie et de thérapie, 1984
In the present investigation, the alpha-adrenoceptor blocking effect of (imidazolinyl-2)-2-dihydr... more In the present investigation, the alpha-adrenoceptor blocking effect of (imidazolinyl-2)-2-dihydro 2,3 benzofurane or S 9871 and its stereoisomers was studied. In the pithed rat (+/-) and (+) S 9871 competitively antagonized the pressor effects of azepexole and clonidine more effectively than those of cirazoline and phenylephrine. (-) S 9871 only blocked the pressor response of the alpha 1-agonists used: phenylephrine and cirazoline. (+/-) and (+) S 9871 antagonized the inhibitory effects of clonidine on the increase in heart rate produced by stimulation of the sympathetic efferent fibres of the thoracic spinal cord. (-) S 9871 was twenty times less potent on the decrease in heart rate induced by clonidine. On the vas deferens of the rat, (+/-) and (+) S 9871 appeared to be more potent than (-) S 9871 in antagonizing the inhibitory effects of clonidine on the twitch response produced by electrical stimulation. Therefore, (+/-) and (+) S 9871 appear to be more preferential for alpha ...
Journal de pharmacologie
In anaesthetized dog, the adrenaline induced hypertension is reversed by both alpha 1- and alpha ... more In anaesthetized dog, the adrenaline induced hypertension is reversed by both alpha 1- and alpha 2-adrenoceptor blocking agents such as AR-C 239 and yohimbine. After alpha 1 or alpha 2 and beta-blockade, adrenaline induced again an increase in blood pressure. This hypertensive effect was suppressed by an alpha 2-adrenoceptor blocking agent when an alpha 1-adrenoceptor blocking was responsible for the reversal of adrenaline-induced hypertension, and conversely. After beta-blockade, both alpha 1- and alpha 2-adrenoceptor blockade is necessary for suppressing any tensional effect of adrenaline. On the other hand, alpha 1- and alpha 2-adrenoceptor blockade are both required to prevent beta-blockade from restoring adrenaline hypertensive effect. Similar effects were observed wih noradrenaline. In fact, only a significant decrease of the noradrenaline-induced hypertension was observed after each alpha-blocker. Both alpha 1- and alpha 2-adrenoceptor blocking agent also significantly inhibi...
Archives internationales de pharmacodynamie et de thérapie, 1981
While the specificities of alpha 1-adrenoceptor blocking agents are considered as satisfactory, t... more While the specificities of alpha 1-adrenoceptor blocking agents are considered as satisfactory, those of alpha 2-adrenoceptor blocking agents are only weak. Therefore, a more selective alpha 2-adrenoceptor blocking agent is needed. In anaesthetized dogs and rats, (imidazolinyl-2)-2-benzodioxane 1-4 (170 150), a benzodioxane derivative, antagonized the pressor effects induced by adrenaline, noradrenaline and phenylephrine, but did not modify the effects of acetylcholine, histamine and isoprenaline. Therefore, its selectivity is satisfactory. In the anaesthetized dog, 170 150 (0.1 mg.kg-1) increased the tachycardia induced by electrical stimulation of the cardiac sympathetic nerve and antagonized the inhibitory effects of clonidine. In addition, 170 150 blocked and reversed some centrally mediated effects of clonidine such as the fall in blood pressure, bradycardia and reduction of splanchnic discharges in the dog, and the loss of the righting reflex induced by clonidine in the chicke...
Archives des maladies du coeur et des vaisseaux, 1990
In anaesthetized dogs, intravenous administration of 8-OH-DPAT (1-300 micrograms/kg i.v.) induced... more In anaesthetized dogs, intravenous administration of 8-OH-DPAT (1-300 micrograms/kg i.v.) induced dose-dependent decrease in blood pressure (BP) and total peripheral resistance (TPR). Heart rate (HR) and cardiac output (CO) changed little. 5-Carboxamidotryptamine (5-CT) (0.3-3 micrograms/kg i.v.) dose-dependently decreased BP and TPR but increased HR, CO, myocardial contractility and pulmonary arterial pressure (PAP). 5-MeODMT and RU 24969 decreased BP only after the highest dose used (300 micrograms/kg i.v. and 1 mg/kg i.v. respectively) but significantly increased PAP at all doses used. These results indicated that in dogs as in other animal species, 8-OH-DPAT decreases BP by systemic vasodilatation without a reflex activation of the myocardium. This lack of a reflex tachycardia suggests a centrally-mediated effects of 8-OH-DPAT. In contrast to 8-OH-DPAT, the vasodilatation induced by 5-CT triggers a reflex tachycardia. The increase in PAP induced by 5-MeODMT, RU 24969 and--to a l...
PubMed, Nov 1, 1988
In normotensive anaesthetized rats, 8-OH-DPAT, RU 24969 and 5-MeODMT, three 5-HT1-like receptor a... more In normotensive anaesthetized rats, 8-OH-DPAT, RU 24969 and 5-MeODMT, three 5-HT1-like receptor agonists, decreased blood pressure and heart rate. The decrease in blood pressure was suppressed by pithing or pretreatment with hexamethonium. Bilateral section of the vagus nerves, pretreatment with a beta-adrenoceptor blocking agent or with atropine, combination of bivagotomy plus beta-adrenoceptor blockade strongly reduced the bradycardia. These results are compatible with a centrally-mediated decrease in sympathetic tone and increase in vagal tone, as the cause of the hypotension and bradycardia induced by these 5-HT1-like receptor agonists in normotensive anaesthetized rats.
PubMed, 1990
Serotonin (5-HT) induced a transient decrease followed by an increase and then a longer-lasting d... more Serotonin (5-HT) induced a transient decrease followed by an increase and then a longer-lasting decrease in blood pressure. The initial decrease in blood pressure results from a reduction in cardiac output as a result of the profound bradycardia. The secondary increase in blood pressure is caused by an increase in both cardiac output and total peripheral resistance. The final decrease in blood pressure is ascribed to a reduction in total peripheral resistance. The effects of 5-HT on regional haemodynamics are known to vary according to the vascular bed and even in the same vascular bed. Accordingly, 5-HT induced either vasoconstriction or vasodilatation. Vasoconstriction occurred in most cases in large arteries and is due to stimulation of 5-HT2 receptors. However, 5-HT1-like receptors are probably also implicated. 5-HT-induced vasodilatation is attributed to stimulation of 5-HT1-like receptors. However, limited evidence suggests also an implication of 5-HT3 and even 5-HT2 receptors in the dilator effects of 5-HT. 5-HT1A receptor agonists decreased blood pressure by a reduction in total peripheral resistance. This vasodilatation seems to be widespread. Other 5-HT1-like receptor agonists have differential effects according to the animal species used.
PubMed, Apr 1, 1986
The pharmacological properties of idazoxan, 2-[2-(1,4-benzodioxanyl)]-2-imidazoline, were first d... more The pharmacological properties of idazoxan, 2-[2-(1,4-benzodioxanyl)]-2-imidazoline, were first described four years ago; since then, this compound has been revealed to be one of the most selective alpha 2-adrenoceptor blocking agent presently available. At peripheral sites, idazoxan antagonized the effects of alpha 2 agonists such as azepexole, B-HT 920, M 7, UK 14,304, alpha-methylnoradrenaline, clonidine but was ineffective against alpha 1 agonists such as cirazoline and phenylephrine. At presynaptic sites idazoxan increased the tachycardia due to the stimulation of the cardioaccelerator nerve of the dog and antagonized the inhibitory effects of alpha 2 agonists in dogs and rats. As compared to the classical alpha 2-adrenoceptor blocking agents, idazoxan was more selective and as potent as yohimbine, rauwolscine, RS 21361, Wy 26703. At central sites, idazoxan has been found to antagonize the sympathoinhibitory effects of alpha 2 agonists. Therefore, idazoxan is a potent and probably the most selective alpha 2-adrenoceptor blocking agent presently available and is now frequently used for the investigation of peripheral and central alpha 2-adrenoceptors.
PubMed, Nov 1, 1991
Both intravenous and central administration of ketanserin, a 5-HT2 receptor antagonist, decrease ... more Both intravenous and central administration of ketanserin, a 5-HT2 receptor antagonist, decrease blood pressure and sympathetic nerve activity, suggesting a central origin of its effects. However, ketanserin also possesses alpha 1-adrenoceptor blocking properties. Selective 5-HT2 receptor antagonists devoid of alpha 1-adrenoceptor blocking properties, e.g. LY 53857 and cinanserin, fail to reduce blood pressure and sympathetic nerve activity. In addition, 5-HT2 receptor agonists increase blood pressure and sympathetic nerve discharge. Therefore, it seems improbable that blockade of central 5-HT2 receptors alone could lead to a reduction in blood pressure. In contrast, the selective 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan decrease blood pressure and heart rate by a centrally-mediated decrease in sympathetic tone and an increase in vagal tone. The sympatho-inhibitory effects of 5-HT1A receptor agonists result from the stimulation of postsynaptic 5-HT1A receptors within the ventrolateral pressor area. These results suggest that selective 5-HT1A receptor agonists acting in the central nervous system could be developed for the treatment of hypertension. Indeed, drugs such as flesinoxan and urapidil are effective in this setting.
Springer eBooks, 1990
Injections of 8-OH-DPAT (0.1-6 micrograms/kg) into the vertebral artery or into the cisterna magn... more Injections of 8-OH-DPAT (0.1-6 micrograms/kg) into the vertebral artery or into the cisterna magna (5 micrograms/kg) produced a dose-dependent decrease in blood pressure, heart rate and renal sympathetic nerve activity in intact anaesthetized dogs and baroreceptor-denervated dogs. 8-OH-DPAT reduced the renal sympathetic nerve activity without changing the blood pressure or heart rate in catecholamine-depleted animals. Methiothepin (0.2 mg/kg) injected into the vertebral artery reduced the blood pressure without changing the heart rate or renal sympathetic nerve activity in baroreceptor-denervated dogs. The pressor response to i.v. phenylephrine was largely attenuated. Subsequent administration of 8-OH-DPAT (3 micrograms/kg) into the vertebral artery failed to alter the sympathetic discharge. Methiothepin (0.2 mg/kg) injected into the vertebral artery reversed the sympatho-inhibitory effect of 8-OH-DPAT (3 micrograms/kg) injected by the same route without changing the blood pressure. (+/-)Pindolol (0.2 mg/kg) injected into the vertebral artery of baroreceptor-denervated dogs reduced the blood pressure and heart rate without changing renal sympathetic activity. Subsequent administration of 8-OH-DPAT (3 micrograms/kg) failed to alter the sympathetic discharge. Bilateral microinjection of 8-OH-DPAT (1 microgram) into the nucleus tractus solitarii or into the medullary raphe nuclei failed to alter the blood pressure, heart rate or renal sympathetic activity. In contrast, bilateral microinjections of 8-OH-DPAT into the ventrolateral pressor area (VLPA) (0.2 microgram) produced a marked decrease in blood pressure, heart rate and renal sympathetic nerve activity. These effects were prevented or reversed by microinjections of methiothepin (10 micrograms) at the same sites. These results indicate that the central sympatho-inhibitory effects of 8-OH-DPAT were due to the stimulation of 5-HT1A receptors located in the ventrolateral pressor area. 5-HT autoreceptors did not seem to be involved.
PubMed, Aug 1, 1993
The systemic and regional haemodynamic effects of DOI were investigated in the anaesthetized rat.... more The systemic and regional haemodynamic effects of DOI were investigated in the anaesthetized rat. DOI (1-300 micrograms/kg i.v.) increased mean arterial pressure (MAP), total peripheral resistance (TPR) and all regional vascular resistances studied (hindquarters, mesenteric and renal). DOI was more effective on renal vascular bed. Cardiac output (CO) and heart rate (HR) did not change. The effects of DOI were antagonized by LY 53857 (10 micrograms/kg i.v.) and spiperone (10 or 100 micrograms/kg i.v.), selective 5-HT2 receptor antagonists. Intracerebroventricular administration of DOI (100 micrograms/kg) increased MAP, TPR, regional vascular resistances and did not change HR and CO. Pretreatment with xylamidine (10 micrograms/kg i.v.), a selective peripheral 5-HT2 receptor antagonist, blocked i.v. and i.c.v. effects of DOI. These results suggest that: 1) the increase in MAP induced by the stimulation of 5-HT2 receptors is due to an increase in TPR. All regional vascular resistances participate in the increase of TPR. 2) Peripheral and central 5-HT2 receptors seem to be implicated in the control of regional vascular resistances.
Fundamental & Clinical Pharmacology, Aug 1, 1992
Summary— A pharmacological analysis of the effects of 5‐HT on heart rate has been performed in th... more Summary— A pharmacological analysis of the effects of 5‐HT on heart rate has been performed in the pithed rat. 5‐HT induced a dose‐dependent increase in heart rate whereas 5‐HT, receptor agonists — 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), 5‐methoxy‐N,N‐dimethyl‐tryptamine (5‐MeODMT), 5‐methoxy 3‐(1,2,3,6‐tetrahydro‐4‐piridinyl) 1H indole (RU 24969) and 1‐(m‐trifluoromethylphenyl)‐piperazine (TFMPP) — failed to increase heart rate. The increase in heart rate induced by the selective 5‐HT2 receptor agonist 1‐(2,5‐dimethoxy‐4‐iodo‐phenyl)‐2‐aminopropane (DOI) was not significant. The dose‐response curve to 5‐HT for its tachycardic effects was shifted two‐fold to the right by ketanserin and LY 53857 and nine‐fold to the right by methiothepin. The effects of high doses of 5‐HT (higher than 100 μg/kg iv) were antagonized by methiothepin, (‐)propranolol, 2‐{2‐[4(O‐methoxyphenyl)‐piperazine‐1‐yl]‐ethyl}4,4‐dimethyl‐1,3 (2H‐4H) isoquinoline‐dione (AR‐C 239) and by pretreatment with reserpine. The 5‐HT1 receptor antagonists, pindolol and spiroxatrine, the 5‐HT3 receptor antagonist MDL 72222 and the α2‐adrenoceptor blocking agent idazoxan failed to antagonize the tachycardia induced by 5‐HT. It is concluded that in the pithed rat, the tachycardia induced by 5‐HT remained unexplained (implication of 5‐HT2 receptors probably different from the classical vascular 5‐HT2 receptor, or implication of 5‐HT1C receptors?). Moreover, at high doses (higher than 100 μ/kg iv), 5‐HT may increase heart rate by releasing catecholamines.
European Journal of Pharmacology, Jun 1, 1999
The contribution of tyrosine kinase activity to vasoreactivity in normotensive Wistar–Kyoto (WKY)... more The contribution of tyrosine kinase activity to vasoreactivity in normotensive Wistar–Kyoto (WKY) and spontaneously hypertensive (SHR) rats was investigated on isolated aortic preparations by the use of two tyrosine kinase inhibitors: methyl-2,5-dihydroxycinnamate (30 μM) and genistein (30 μM). The pretreatment of endothelium denuded aorta with methyl-2,5-dihydroxycinnamate reduced the sensitivity of the rings to noradrenaline to a larger extent in SHR
Fundamental & Clinical Pharmacology, Dec 1, 1997
Journal of Hypertension, Jun 1, 2011
treatment with valsartan is able to reduce the SBP in the same extent as a continuous one. Nevert... more treatment with valsartan is able to reduce the SBP in the same extent as a continuous one. Nevertheless, the increased arterial stiffness and cardiac hypertrophy observed in DT rats compared with CT rats indicate that despite the same decrease of SBP, an intermittent treatment with valsartan may not achieve the full cardiovascular benefits observed with a continuous treatment. Our results suggest that this experimental model is useful to investigate the impact of chronical increased amplitude of variations in SBP on target organ damage. These results that mimics partial adherence to therapy may have important clinical implications in hypertensive patients.
PubMed, Aug 1, 2001
Several studies have well demonstrated that obesity is associated with changes in cardiovascular ... more Several studies have well demonstrated that obesity is associated with changes in cardiovascular vagosympathetic activity. The aim of the present work was to evaluate this activity in normotensive and in mildly hypertensive obese patients, and to correlate this activity with clinical and biological indexes of insulin resistance. Heart rate (HR) and systolic blood pressure (sBP) were examined by spectral analysis in 70 normotensive obese patients (group 1), 32 mildly hypertensive obese patients (group 2), and 21 controls. The high frequency peak of HR variations at a controlled breathing rate (vagal activity) was significantly reduced in both groups (p < 0.001). The mid frequency peak of sBP in the standing position (sympathetic activity) was similar in both groups and in the control group. In groups 1 and 2, the high frequency peak correlated negatively with age (p = 0.005 and 0.034 respectively). In group 1, the mid frequency peak correlated positively with fat mass, fasting plasma insulin and triglyceride levels, and insulin resistance index (p < or = 0.03). In group 2, the mid frequency peak correlated positively with fasting insulin and insulin resistance index (p = 0.006 and 0.007 respectively). This study shows that, in obese patients: 1. cardiac vagal activity is reduced in normotensive and mildly hypertensive subjects; 2. vascular sympathetic activity is unchanged in means but may be increased as a consequence of adiposity, hyperinsulinemia and insulin resistance, and this increase is likely to be involved in the increase of blood pressure.
American Journal of Physiology-Heart and Circulatory Physiology, 1998
The aim of the present work was to obtain insights into the pathophysiology of cardiovascular dec... more The aim of the present work was to obtain insights into the pathophysiology of cardiovascular deconditioning (CVD) induced by tail suspension (TS) in the rat: during TS, when central venous pressure (CVP) has been normalized (E. Martel, P. Champéroux, P. Lacolley, S. Richard, M. Safar, and J. L. Cuche. J. Appl. Physiol. 80: 1390–1396, 1996), and during simulated orthostatism (SO), when transient episodes of hypotension and bradycardia are disclosed, bradycardia with SO represents a response that seems peculiar to the rat compared with humans. According to basic physiology, a reduced activity of the sympathetic system induced by increased CVP was suspected but was not supported by data obtained through spectral analysis of blood pressure (BP) and heart rate (HR) variability or measurements of plasma catecholamine concentration during TS. Nonetheless, indirect evidence was obtained. During SO, plasma catecholamine concentration was lower in TS rats than in controls, suggesting a reduc...
Journal de pharmacologie
1. 170 150 (imidazolinyl-2)-2-benzodioxane 1-4), as does piperoxan, competitively antagonizes the... more 1. 170 150 (imidazolinyl-2)-2-benzodioxane 1-4), as does piperoxan, competitively antagonizes the hypertension induced by clonidine in the pithed rat. Piperoxan appears slightly less potent than 170 150 in this preparation as shown by the comparison of the apparent pA10 values: 5.3 for piperoxan versus 5.4 for 170 150. 2. The two drugs antagonize the reduction of the electrically-induced tachycardia produced by clonidine. 170 150 appears to be 3-fold more potent than piperoxan in this preparation. 3. These results are compatible with a blockade of alpha 2-pre and postsynaptic adrenoceptors of the rat by piperoxan and 170 150 appears to be 3-fold more potent than piperoxan in this preparation. 3. These results are compatible with a blockade of alpha 2-pre and postsynaptic adrenoceptors of the rat by piperoxan and 170 150 and they are in agreement with our previous results which indicate that compound 170 150 shows a preferential affinity for alpha 2-adrenoceptors.
Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie, 1984
The effects of the stereoisomers of two alpha adrenoceptor antagonists [S 10089 (Imidazolinyl-2)-... more The effects of the stereoisomers of two alpha adrenoceptor antagonists [S 10089 (Imidazolinyl-2)-2 benzocyclobutane and S 9871 (Imidazolinyl-2)-2 dihydro 2,3 benzofuran] were studied in pithed Rats. Vasoconstriction elicited via stimulation of alpha 1 adrenoceptors by cirazoline was antagonized, stimulation of alpha 2 adrenoceptors by azepexole was also antagonized by all these derivatives except (-) S 9871 which was ineffective on the pressor response of azepexole.
Archives internationales de pharmacodynamie et de thérapie, 1984
In the present investigation, the alpha-adrenoceptor blocking effect of (imidazolinyl-2)-2-dihydr... more In the present investigation, the alpha-adrenoceptor blocking effect of (imidazolinyl-2)-2-dihydro 2,3 benzofurane or S 9871 and its stereoisomers was studied. In the pithed rat (+/-) and (+) S 9871 competitively antagonized the pressor effects of azepexole and clonidine more effectively than those of cirazoline and phenylephrine. (-) S 9871 only blocked the pressor response of the alpha 1-agonists used: phenylephrine and cirazoline. (+/-) and (+) S 9871 antagonized the inhibitory effects of clonidine on the increase in heart rate produced by stimulation of the sympathetic efferent fibres of the thoracic spinal cord. (-) S 9871 was twenty times less potent on the decrease in heart rate induced by clonidine. On the vas deferens of the rat, (+/-) and (+) S 9871 appeared to be more potent than (-) S 9871 in antagonizing the inhibitory effects of clonidine on the twitch response produced by electrical stimulation. Therefore, (+/-) and (+) S 9871 appear to be more preferential for alpha ...
Journal de pharmacologie
In anaesthetized dog, the adrenaline induced hypertension is reversed by both alpha 1- and alpha ... more In anaesthetized dog, the adrenaline induced hypertension is reversed by both alpha 1- and alpha 2-adrenoceptor blocking agents such as AR-C 239 and yohimbine. After alpha 1 or alpha 2 and beta-blockade, adrenaline induced again an increase in blood pressure. This hypertensive effect was suppressed by an alpha 2-adrenoceptor blocking agent when an alpha 1-adrenoceptor blocking was responsible for the reversal of adrenaline-induced hypertension, and conversely. After beta-blockade, both alpha 1- and alpha 2-adrenoceptor blockade is necessary for suppressing any tensional effect of adrenaline. On the other hand, alpha 1- and alpha 2-adrenoceptor blockade are both required to prevent beta-blockade from restoring adrenaline hypertensive effect. Similar effects were observed wih noradrenaline. In fact, only a significant decrease of the noradrenaline-induced hypertension was observed after each alpha-blocker. Both alpha 1- and alpha 2-adrenoceptor blocking agent also significantly inhibi...
Archives internationales de pharmacodynamie et de thérapie, 1981
While the specificities of alpha 1-adrenoceptor blocking agents are considered as satisfactory, t... more While the specificities of alpha 1-adrenoceptor blocking agents are considered as satisfactory, those of alpha 2-adrenoceptor blocking agents are only weak. Therefore, a more selective alpha 2-adrenoceptor blocking agent is needed. In anaesthetized dogs and rats, (imidazolinyl-2)-2-benzodioxane 1-4 (170 150), a benzodioxane derivative, antagonized the pressor effects induced by adrenaline, noradrenaline and phenylephrine, but did not modify the effects of acetylcholine, histamine and isoprenaline. Therefore, its selectivity is satisfactory. In the anaesthetized dog, 170 150 (0.1 mg.kg-1) increased the tachycardia induced by electrical stimulation of the cardiac sympathetic nerve and antagonized the inhibitory effects of clonidine. In addition, 170 150 blocked and reversed some centrally mediated effects of clonidine such as the fall in blood pressure, bradycardia and reduction of splanchnic discharges in the dog, and the loss of the righting reflex induced by clonidine in the chicke...
Archives des maladies du coeur et des vaisseaux, 1990
In anaesthetized dogs, intravenous administration of 8-OH-DPAT (1-300 micrograms/kg i.v.) induced... more In anaesthetized dogs, intravenous administration of 8-OH-DPAT (1-300 micrograms/kg i.v.) induced dose-dependent decrease in blood pressure (BP) and total peripheral resistance (TPR). Heart rate (HR) and cardiac output (CO) changed little. 5-Carboxamidotryptamine (5-CT) (0.3-3 micrograms/kg i.v.) dose-dependently decreased BP and TPR but increased HR, CO, myocardial contractility and pulmonary arterial pressure (PAP). 5-MeODMT and RU 24969 decreased BP only after the highest dose used (300 micrograms/kg i.v. and 1 mg/kg i.v. respectively) but significantly increased PAP at all doses used. These results indicated that in dogs as in other animal species, 8-OH-DPAT decreases BP by systemic vasodilatation without a reflex activation of the myocardium. This lack of a reflex tachycardia suggests a centrally-mediated effects of 8-OH-DPAT. In contrast to 8-OH-DPAT, the vasodilatation induced by 5-CT triggers a reflex tachycardia. The increase in PAP induced by 5-MeODMT, RU 24969 and--to a l...