In order to elucidate the role of protein tyrosine phosphorylation involved in various intracellu... more In order to elucidate the role of protein tyrosine phosphorylation involved in various intracellular signaling pathways, peptides containing O-phosphotyrosine have been developed. However, in order to improve the stability of the phosphorylated amino acid, we have designed some years ago a hydrolytically stable analogue, the 4-(phosphonomethyl)phenylalanine (Pmp). Introduced in peptide sequences, this residue, which is resistant to phosphatase action, was shown also able to inhibit substrate recognition by protein targets. With the aim to design peptidomimetics endowed with improved affinity and selectivity, we report in this study the synthesis of five new sterically hindered amino acids derived from Pmp. These modifications include α-methyl, β-methyl, β,β-dimethyl substitutions, α,β-cyclization of Pmp and methyl substitution on the phosphomomethyl group of Pmp.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Derivatives of amino acids bearing various zinc-coordinating moieties (SH, COOH, CONHOH, and PO3H... more Derivatives of amino acids bearing various zinc-coordinating moieties (SH, COOH, CONHOH, and PO3H2) were synthesized and tested for their ability to inhibit aminopeptidase N (APN). Among them, beta-amino thiols were found to be the most efficient with IC50's in the 11-50 nM range. These results suggest that the S1 subsite of APN is a deep but not very large hydrophobic pocket, optimally fitting side chains of moderate bulk endowed with some degree of freedom. The iv administration of the inhibitors, alone, did not induce antinociceptive responses on the hot plate test in mice. However, in presence of 10 mg/kg acetorphan, a prodrug of the neutral endopeptidase inhibitor thiorphan, these compounds gave a large increase in the jump latency time with ED50's of 2 and 2.4 mg/kg for the disulfides of methioninethiol H2NCH(CH2CH2SCH3)CH2S]2 and S-oxomethioninethiol [H2NCH(CH2CH2S(O)CH3)CH2S]2, respectively. These results show that the disulfide forms of beta-amino thiols are efficient prodrugs of aminopeptidase N inhibitors capable of crossing the blood-brain barrier.
Nitrous oxide (N(2)O), a pharmacological active gas and an antagonist of N-methyl-D-aspartic acid... more Nitrous oxide (N(2)O), a pharmacological active gas and an antagonist of N-methyl-D-aspartic acid receptors, has been reported to be effective in the treatment of alcohol and tobacco withdrawal syndrome. However, the neurobiological bases of N(2)O effects are unknown. The aim of the present studies was to examine the effect of N(2)O on acquisition and expression of morphine- (10 mg/kg; s.c.) and cocaine- (20 mg/kg; i.p.) induced conditioned place preference (CPP) in mice. Unbiased place conditioning method was used. Mice were exposed to N(2)O during the conditioning phase (acquisition of CPP) or during postconditioning phase (expression of CPP). The same protocol was used to evaluate the impact of N(2)O on locomotor activity, two-trial recognition task (memory), spontaneous alternation, sucrose consumption (anhedonic state), forced swim (depressive state) and elevated O-maze tests (anxiety state). In all these tests, mice were treated with morphine (10 mg/kg, s.c.) the first day, th...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
Stimulation of the brain CCK2 receptor by the C-terminal octapeptide CCK8 of cholecystokinin (CCK... more Stimulation of the brain CCK2 receptor by the C-terminal octapeptide CCK8 of cholecystokinin (CCK) negatively modulates opioid responses. This suggests the existence of physiologically relevant interactions between endogenous CCK and opioid peptides, opening new perspectives particularly in the treatment of pain or drug addiction. CCK2 receptor-deficient mice were used to analyze the incidence of this gene invalidation on opioid system. Compared with wild-type mice, mutants exhibited the following: (1) a hypersensitivity to the locomotor activity induced by inhibitors of enkephalin catabolism or by morphine; (2) a spontaneous hyperalgesia to thermal nociceptive stimulus, which was reversed by previous administration of the NMDA antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], and a large reduction in analgesic effects of endogenous or exogenous opioids; and (3) a more severe withdrawal syndrome after chronic morphine treatment. As expec...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
The endogenous opioid system is often assumed to play a role in vulnerability to drug abuse. Howe... more The endogenous opioid system is often assumed to play a role in vulnerability to drug abuse. However, controversial results have been reported regarding the levels of enkephalins or preproenkephalin in neurons of rodent brains after opiate administration. The present study was performed to determine the extracellular levels of enkephalins and its physiological antagonist cholecystokinin (CCK), using in vivo microdialysis in freely moving rats after morphine-induced physical dependence or positive place conditioning. A large increase (340%) of Met-enkephalin was observed in the periaqueductal gray matter, a structure involved in morphine withdrawal syndrome, in morphine-dependent rats. No change in CCK immunoreactivity occurred in these conditions. Moreover, using the conditioning place preference paradigm, we observed for the first time opposite changes of enkephalin outflow in the nucleus accumbens (NAc). Thus, an increase in enkephalin levels was observed in rats placed in the dru...
The human immunodeficiency virus type 1 (HIV-1) genome encodes a highly conserved 16 kDa regulato... more The human immunodeficiency virus type 1 (HIV-1) genome encodes a highly conserved 16 kDa regulatory gene product, Vpr (viral protein of regulation, 96 amino acid residues), which is incorporated into virions, in quantities equivalent to those of the viral Gag proteins. In the infected cells, Vpr is believed to function in the early phase of HIV-1 replication, including nuclear migration of preintegration complex, transcription of the provirus genome and viral multiplication by blocking cells in the G2 phase. Vpr has a critical role in long-term AIDS disease by inducing infection in nondividing cells such as monocytes and macrophages. Mutations have suggested that the N-terminal domain of Vpr encompassing the first 40 residues could be required for nuclear localization, packaging into virions and binding of transcription factor (TFIIB, Sp1), viral proteins (p6) and cellular proteins (RIP1, UNG, karyopherins). To gain insight into the structure-function relationship of Vpr, (1-51)Vpr ...
The effects of two selective CCK(B) agonists, BC 264 and BC 197, on memory processes were investi... more The effects of two selective CCK(B) agonists, BC 264 and BC 197, on memory processes were investigated in rats using a recently developed two-trial recognition memory task. Control animals showed recognition memory after a 2 but not a 6 h time interval between the two trials, thus allowing a memory impairing (2 h) or improving (6 h) effect of pharmacological treatments to be measured. Drugs were injected i.p. before the second trial (retrieval phase). This experimental procedure was first studied with scopolamine and DL-amphetamine, for which a significant deficit after a 2 h interval or improvement after a 6 h interval of performance was observed, respectively. The CCK(B) agonist, BC 264, was ineffective after a 2 h time interval, whereas the dose of 0.3 microg/kg significantly enhanced performance after a 6 h inter-trial interval. In contrast, BC 197 (30 microg/kg) produced a significant disruption of performance after a 2 h inter-trial interval but was without effect after a 6 h ...
Aminopeptidase A is a membrane-bound zinc metalloprotease which cleaves angiotensin II into angio... more Aminopeptidase A is a membrane-bound zinc metalloprotease which cleaves angiotensin II into angiotensin III. Using a new specific aminopeptidase A inhibitor, EC33, we evaluated its enzymatic activity in several microdissected brain nuclei involved in the control of cardiovascular functions and in the pituitary. We compared this distribution with that of the angiotensin I-converting enzyme which converts angiotensin I to angiotensin II. Aminopeptidase A activity was heterogenously distributed with a 150-fold difference between the lowest and the highest levels. The pituitary and the circumventricular organs were the richest source of enzyme, followed by the median eminence, the arcuate nucleus, the area postrema, the choroid plexus and the supraotic and paraventricular nuclei. We did not find any close parallel between aminopeptidase A and angiotensin I-converting enzyme distributions. We examined both enzymatic activities in brain nuclei of spontaneously hypertensive rats. Aminopept...
International journal of peptide and protein research, 1987
The preferential conformations of the delta selective opioid peptides DPLPE (Tyr-c[D X Pen-Gly-Ph... more The preferential conformations of the delta selective opioid peptides DPLPE (Tyr-c[D X Pen-Gly-Phe-Pen]) and DTLET (Tyr-D X Thr-Gly-Phe-Leu-Thr) were studied by 400 MHz 1H n.m.r. spectroscopy in DMSO-d6 solution. In neutral conditions, the weak NH temperature coefficients of the C-terminal residue (Pen5 or Thr6), associated with interproton NH-NH and alpha-NH NOE's (ROESY experiments), indicated large analogies between the backbone folding tendency of both the linear and cyclic peptides. Various gamma and/or beta turns may account for these experimental data. A similar orientation of the N-terminal tyrosine related to the folded backbones is observed for the two agonists, with a probable gamma turn around the amino acid in position 2. Finally, a short distance, about 10 A, between Tyr and Phe side chains and identical structural roles for threonyl and penicillamino residues are proposed for both peptides. These results suggest the occurrence of similar conformers in solution for...
The 31st IEEE International Conference on Plasma Science, 2004. ICOPS 2004. IEEE Conference Record - Abstracts., 2004
Summary form only given. Sphinx is the new name of the facility developed for soft X-ray producti... more Summary form only given. Sphinx is the new name of the facility developed for soft X-ray production at Centre d'Etudes de Gramat (CEG), France. This facility is based on the ECF2 generator which was designed as a 1-3 MJ, 1 μs rise time, 5-10 MA current driver. In this paper, we present a detailed view of the technology used for
The endogenous peptides enkephalins and cholecystokinin appear to play an opposite role in the co... more The endogenous peptides enkephalins and cholecystokinin appear to play an opposite role in the control of pain. In this work, the effect of the selective CCKB receptor antagonist PD-134,308 on antinociceptive effects induced by morphine or by a complete inhibitor of enkephalin-metabolizing enzymes, RB 101, was studied using the formalin test. In mice, s.c. injection of formalin into the dorsal
The most simple and efficient method to study the physiological role of enkephalins is to increas... more The most simple and efficient method to study the physiological role of enkephalins is to increase the lifetime of these endogenous opioid peptides by inhibiting their inactivating enzymes. Enkephalins are degraded by the concomitant action of two metallopeptidases: neutral endopeptidase (NEP, EC3.4.21.11) and aminopeptidase N (APN, EC3.4.11.2), both enzymes releasing inactive metabolites. Potent dual inhibitors have been developed, such as RB101. However, NEP and APN have a broad specificity and can cleave various peptides in vitro. Therefore, it was essential to investigate the specific involvement of enkephalins in the various pharmacological responses induced by dual inhibitors. We compared the pharmacological responses induced by RB101 in wild-type and preproenkephalin-deficient mice (Penk1-/-) using several behavioural assays. In all the tests used (hot plate test, force swim test, castor-oil-induced diarrhoea), RB101 induced strong effects in wild-type animals, whereas slight effects were observed in Penk1-/- animals. These residual effects are blocked by pre-administration of the opioid antagonist naloxone, supporting the involvement of the opioid receptors in the responses observed. The pharmacological effects induced by dual inhibitors acting on both NEP and APN are mainly due to the protection of the endogenous enkephalins at supraspinal and peripheral levels. It could be speculated that the residual effects observed in Penk1-/- mice after RB101 administration could be due to the direct action of other opioid peptides or through an indirect effect involving the protection of other peptide substrates of NEP or APN, as substance P or angiotensin.
Neutral endopeptidase inhibitors (NEPI) potentiate the hypotensive effect of converting enzyme in... more Neutral endopeptidase inhibitors (NEPI) potentiate the hypotensive effect of converting enzyme inhibitors (CEI) in conscious spontaneously hypertensive rats (SHR) but the mechanism of this potentiation remains unknown. The present study assesses the hemodynamic effects of a CEI (enalaprilat 1 mg/kg; n = 9), a NEPI (retrothiorphan 25 mg/kg + 25 mg/kg/h; n = 9) and the combination (CEI+NEPI; n = 9) versus a control group (n = 9) in anesthetized spontaneously hypertensive rats. CEI alone induced a significant hypotensive effect due to a decrease (-35.1%) in total peripheral resistance (TPR), with no significant increase in cardiac output (CO). NEPI alone had a slight hypotensive effect due to a small decrease in CO. CEI+NEPI decreased the mean arterial pressure to the same extent (-26.7%) as the CEI-induced hypotensive effect, decreased TPR (-44.4%) and induced an increase in CO (+38.2%) with an increase in heart rate. In summary, NEPI combined with CEI induces large decreases in blood pressure and in TPR which do not significantly differ from the CEI-induced effects. It also induces increases in heart rate and in cardiac output in anesthetized SHR.
... 23,24'45 Conformationally constrained thiol 36 G. Waksman, R. Bouboutou, J. ... more ... 23,24'45 Conformationally constrained thiol 36 G. Waksman, R. Bouboutou, J. Devin, S. Bourgoin, F. Cesselin, M. Hamon, MC Fournid-Zaluski, and BP Roques, Eur. J. Pharmacol. ... Ul, 956 (1994). 90 F. Hernando, JA Fuentes, BP Roques, and M. Ruiz-Gayo, Eur. J. Pharmacol. ...
In order to elucidate the role of protein tyrosine phosphorylation involved in various intracellu... more In order to elucidate the role of protein tyrosine phosphorylation involved in various intracellular signaling pathways, peptides containing O-phosphotyrosine have been developed. However, in order to improve the stability of the phosphorylated amino acid, we have designed some years ago a hydrolytically stable analogue, the 4-(phosphonomethyl)phenylalanine (Pmp). Introduced in peptide sequences, this residue, which is resistant to phosphatase action, was shown also able to inhibit substrate recognition by protein targets. With the aim to design peptidomimetics endowed with improved affinity and selectivity, we report in this study the synthesis of five new sterically hindered amino acids derived from Pmp. These modifications include α-methyl, β-methyl, β,β-dimethyl substitutions, α,β-cyclization of Pmp and methyl substitution on the phosphomomethyl group of Pmp.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Derivatives of amino acids bearing various zinc-coordinating moieties (SH, COOH, CONHOH, and PO3H... more Derivatives of amino acids bearing various zinc-coordinating moieties (SH, COOH, CONHOH, and PO3H2) were synthesized and tested for their ability to inhibit aminopeptidase N (APN). Among them, beta-amino thiols were found to be the most efficient with IC50's in the 11-50 nM range. These results suggest that the S1 subsite of APN is a deep but not very large hydrophobic pocket, optimally fitting side chains of moderate bulk endowed with some degree of freedom. The iv administration of the inhibitors, alone, did not induce antinociceptive responses on the hot plate test in mice. However, in presence of 10 mg/kg acetorphan, a prodrug of the neutral endopeptidase inhibitor thiorphan, these compounds gave a large increase in the jump latency time with ED50's of 2 and 2.4 mg/kg for the disulfides of methioninethiol H2NCH(CH2CH2SCH3)CH2S]2 and S-oxomethioninethiol [H2NCH(CH2CH2S(O)CH3)CH2S]2, respectively. These results show that the disulfide forms of beta-amino thiols are efficient prodrugs of aminopeptidase N inhibitors capable of crossing the blood-brain barrier.
Nitrous oxide (N(2)O), a pharmacological active gas and an antagonist of N-methyl-D-aspartic acid... more Nitrous oxide (N(2)O), a pharmacological active gas and an antagonist of N-methyl-D-aspartic acid receptors, has been reported to be effective in the treatment of alcohol and tobacco withdrawal syndrome. However, the neurobiological bases of N(2)O effects are unknown. The aim of the present studies was to examine the effect of N(2)O on acquisition and expression of morphine- (10 mg/kg; s.c.) and cocaine- (20 mg/kg; i.p.) induced conditioned place preference (CPP) in mice. Unbiased place conditioning method was used. Mice were exposed to N(2)O during the conditioning phase (acquisition of CPP) or during postconditioning phase (expression of CPP). The same protocol was used to evaluate the impact of N(2)O on locomotor activity, two-trial recognition task (memory), spontaneous alternation, sucrose consumption (anhedonic state), forced swim (depressive state) and elevated O-maze tests (anxiety state). In all these tests, mice were treated with morphine (10 mg/kg, s.c.) the first day, th...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
Stimulation of the brain CCK2 receptor by the C-terminal octapeptide CCK8 of cholecystokinin (CCK... more Stimulation of the brain CCK2 receptor by the C-terminal octapeptide CCK8 of cholecystokinin (CCK) negatively modulates opioid responses. This suggests the existence of physiologically relevant interactions between endogenous CCK and opioid peptides, opening new perspectives particularly in the treatment of pain or drug addiction. CCK2 receptor-deficient mice were used to analyze the incidence of this gene invalidation on opioid system. Compared with wild-type mice, mutants exhibited the following: (1) a hypersensitivity to the locomotor activity induced by inhibitors of enkephalin catabolism or by morphine; (2) a spontaneous hyperalgesia to thermal nociceptive stimulus, which was reversed by previous administration of the NMDA antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], and a large reduction in analgesic effects of endogenous or exogenous opioids; and (3) a more severe withdrawal syndrome after chronic morphine treatment. As expec...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
The endogenous opioid system is often assumed to play a role in vulnerability to drug abuse. Howe... more The endogenous opioid system is often assumed to play a role in vulnerability to drug abuse. However, controversial results have been reported regarding the levels of enkephalins or preproenkephalin in neurons of rodent brains after opiate administration. The present study was performed to determine the extracellular levels of enkephalins and its physiological antagonist cholecystokinin (CCK), using in vivo microdialysis in freely moving rats after morphine-induced physical dependence or positive place conditioning. A large increase (340%) of Met-enkephalin was observed in the periaqueductal gray matter, a structure involved in morphine withdrawal syndrome, in morphine-dependent rats. No change in CCK immunoreactivity occurred in these conditions. Moreover, using the conditioning place preference paradigm, we observed for the first time opposite changes of enkephalin outflow in the nucleus accumbens (NAc). Thus, an increase in enkephalin levels was observed in rats placed in the dru...
The human immunodeficiency virus type 1 (HIV-1) genome encodes a highly conserved 16 kDa regulato... more The human immunodeficiency virus type 1 (HIV-1) genome encodes a highly conserved 16 kDa regulatory gene product, Vpr (viral protein of regulation, 96 amino acid residues), which is incorporated into virions, in quantities equivalent to those of the viral Gag proteins. In the infected cells, Vpr is believed to function in the early phase of HIV-1 replication, including nuclear migration of preintegration complex, transcription of the provirus genome and viral multiplication by blocking cells in the G2 phase. Vpr has a critical role in long-term AIDS disease by inducing infection in nondividing cells such as monocytes and macrophages. Mutations have suggested that the N-terminal domain of Vpr encompassing the first 40 residues could be required for nuclear localization, packaging into virions and binding of transcription factor (TFIIB, Sp1), viral proteins (p6) and cellular proteins (RIP1, UNG, karyopherins). To gain insight into the structure-function relationship of Vpr, (1-51)Vpr ...
The effects of two selective CCK(B) agonists, BC 264 and BC 197, on memory processes were investi... more The effects of two selective CCK(B) agonists, BC 264 and BC 197, on memory processes were investigated in rats using a recently developed two-trial recognition memory task. Control animals showed recognition memory after a 2 but not a 6 h time interval between the two trials, thus allowing a memory impairing (2 h) or improving (6 h) effect of pharmacological treatments to be measured. Drugs were injected i.p. before the second trial (retrieval phase). This experimental procedure was first studied with scopolamine and DL-amphetamine, for which a significant deficit after a 2 h interval or improvement after a 6 h interval of performance was observed, respectively. The CCK(B) agonist, BC 264, was ineffective after a 2 h time interval, whereas the dose of 0.3 microg/kg significantly enhanced performance after a 6 h inter-trial interval. In contrast, BC 197 (30 microg/kg) produced a significant disruption of performance after a 2 h inter-trial interval but was without effect after a 6 h ...
Aminopeptidase A is a membrane-bound zinc metalloprotease which cleaves angiotensin II into angio... more Aminopeptidase A is a membrane-bound zinc metalloprotease which cleaves angiotensin II into angiotensin III. Using a new specific aminopeptidase A inhibitor, EC33, we evaluated its enzymatic activity in several microdissected brain nuclei involved in the control of cardiovascular functions and in the pituitary. We compared this distribution with that of the angiotensin I-converting enzyme which converts angiotensin I to angiotensin II. Aminopeptidase A activity was heterogenously distributed with a 150-fold difference between the lowest and the highest levels. The pituitary and the circumventricular organs were the richest source of enzyme, followed by the median eminence, the arcuate nucleus, the area postrema, the choroid plexus and the supraotic and paraventricular nuclei. We did not find any close parallel between aminopeptidase A and angiotensin I-converting enzyme distributions. We examined both enzymatic activities in brain nuclei of spontaneously hypertensive rats. Aminopept...
International journal of peptide and protein research, 1987
The preferential conformations of the delta selective opioid peptides DPLPE (Tyr-c[D X Pen-Gly-Ph... more The preferential conformations of the delta selective opioid peptides DPLPE (Tyr-c[D X Pen-Gly-Phe-Pen]) and DTLET (Tyr-D X Thr-Gly-Phe-Leu-Thr) were studied by 400 MHz 1H n.m.r. spectroscopy in DMSO-d6 solution. In neutral conditions, the weak NH temperature coefficients of the C-terminal residue (Pen5 or Thr6), associated with interproton NH-NH and alpha-NH NOE's (ROESY experiments), indicated large analogies between the backbone folding tendency of both the linear and cyclic peptides. Various gamma and/or beta turns may account for these experimental data. A similar orientation of the N-terminal tyrosine related to the folded backbones is observed for the two agonists, with a probable gamma turn around the amino acid in position 2. Finally, a short distance, about 10 A, between Tyr and Phe side chains and identical structural roles for threonyl and penicillamino residues are proposed for both peptides. These results suggest the occurrence of similar conformers in solution for...
The 31st IEEE International Conference on Plasma Science, 2004. ICOPS 2004. IEEE Conference Record - Abstracts., 2004
Summary form only given. Sphinx is the new name of the facility developed for soft X-ray producti... more Summary form only given. Sphinx is the new name of the facility developed for soft X-ray production at Centre d'Etudes de Gramat (CEG), France. This facility is based on the ECF2 generator which was designed as a 1-3 MJ, 1 μs rise time, 5-10 MA current driver. In this paper, we present a detailed view of the technology used for
The endogenous peptides enkephalins and cholecystokinin appear to play an opposite role in the co... more The endogenous peptides enkephalins and cholecystokinin appear to play an opposite role in the control of pain. In this work, the effect of the selective CCKB receptor antagonist PD-134,308 on antinociceptive effects induced by morphine or by a complete inhibitor of enkephalin-metabolizing enzymes, RB 101, was studied using the formalin test. In mice, s.c. injection of formalin into the dorsal
The most simple and efficient method to study the physiological role of enkephalins is to increas... more The most simple and efficient method to study the physiological role of enkephalins is to increase the lifetime of these endogenous opioid peptides by inhibiting their inactivating enzymes. Enkephalins are degraded by the concomitant action of two metallopeptidases: neutral endopeptidase (NEP, EC3.4.21.11) and aminopeptidase N (APN, EC3.4.11.2), both enzymes releasing inactive metabolites. Potent dual inhibitors have been developed, such as RB101. However, NEP and APN have a broad specificity and can cleave various peptides in vitro. Therefore, it was essential to investigate the specific involvement of enkephalins in the various pharmacological responses induced by dual inhibitors. We compared the pharmacological responses induced by RB101 in wild-type and preproenkephalin-deficient mice (Penk1-/-) using several behavioural assays. In all the tests used (hot plate test, force swim test, castor-oil-induced diarrhoea), RB101 induced strong effects in wild-type animals, whereas slight effects were observed in Penk1-/- animals. These residual effects are blocked by pre-administration of the opioid antagonist naloxone, supporting the involvement of the opioid receptors in the responses observed. The pharmacological effects induced by dual inhibitors acting on both NEP and APN are mainly due to the protection of the endogenous enkephalins at supraspinal and peripheral levels. It could be speculated that the residual effects observed in Penk1-/- mice after RB101 administration could be due to the direct action of other opioid peptides or through an indirect effect involving the protection of other peptide substrates of NEP or APN, as substance P or angiotensin.
Neutral endopeptidase inhibitors (NEPI) potentiate the hypotensive effect of converting enzyme in... more Neutral endopeptidase inhibitors (NEPI) potentiate the hypotensive effect of converting enzyme inhibitors (CEI) in conscious spontaneously hypertensive rats (SHR) but the mechanism of this potentiation remains unknown. The present study assesses the hemodynamic effects of a CEI (enalaprilat 1 mg/kg; n = 9), a NEPI (retrothiorphan 25 mg/kg + 25 mg/kg/h; n = 9) and the combination (CEI+NEPI; n = 9) versus a control group (n = 9) in anesthetized spontaneously hypertensive rats. CEI alone induced a significant hypotensive effect due to a decrease (-35.1%) in total peripheral resistance (TPR), with no significant increase in cardiac output (CO). NEPI alone had a slight hypotensive effect due to a small decrease in CO. CEI+NEPI decreased the mean arterial pressure to the same extent (-26.7%) as the CEI-induced hypotensive effect, decreased TPR (-44.4%) and induced an increase in CO (+38.2%) with an increase in heart rate. In summary, NEPI combined with CEI induces large decreases in blood pressure and in TPR which do not significantly differ from the CEI-induced effects. It also induces increases in heart rate and in cardiac output in anesthetized SHR.
... 23,24'45 Conformationally constrained thiol 36 G. Waksman, R. Bouboutou, J. ... more ... 23,24'45 Conformationally constrained thiol 36 G. Waksman, R. Bouboutou, J. Devin, S. Bourgoin, F. Cesselin, M. Hamon, MC Fournid-Zaluski, and BP Roques, Eur. J. Pharmacol. ... Ul, 956 (1994). 90 F. Hernando, JA Fuentes, BP Roques, and M. Ruiz-Gayo, Eur. J. Pharmacol. ...
Uploads
Papers by Bernard Roques