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N Rouissi

Publications and source records attributed to N Rouissi.

33 records · Page 2Linked to original sources
PubMed1991

DuP 753 is a specific antagonist for the angiotensin receptor.

2-n-Butyl-4-chloro-5-hydroxy-methyl-1-[(2'-(1H)-tetrazol-5-yl)biph enyl-4- yl)methyl]imidazol potassium salt (DuP 753) is a nonpeptide angiotensin II receptor antagonist that inhibits the contractile effects of angiotensin II competitively and shows pA2 values of 8.27 on the rabbit aorta and jugular vein, 8.66 on the rat portal vein and stomach, 8.19 on the rat urinary bladder, and 8.36 on human colon, ileum, and urinary bladder. This agent (more than 10(-5) M) exhibits no agonistic activity and does not affect the contractile effects of norepinephrine, acetylcholine, bradykinin, desArg9-bradykinin, substance P, neurokinin A, neurokinin B, or bombesin in the various tissues. The present results demonstrate that DuP 753 is a potent nonpeptide antagonist with high affinity, specificity, and selectivity for the angiotensin receptor.

Adrenergic alpha-Antagonists↗
PubMed1990

Antagonists for the neurokinin NK-3 receptor evaluated in selective receptor systems.

Four isolated vessels that are monoreceptor systems for neurokinins, the dog carotid artery and rabbit jugular vein (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3), were used to compare the activities of selective neurokinin agonists and evaluate the affinities of new NK-3 antagonists. Chemical modifications in the partial sequences NKA (4-10) and NKB (4-10), particularly the replacement of Val7 with an aromatic residue (Tyr, MePhe or Trp) and the extension of the peptide backbone in position 8, obtained with beta-Ala, led to compounds that maintain weak agonistic activities on the NK-1 and NK-2, and some of them also on NK-3 receptors but exert potent antagonism against NKB on the NK-3 receptor of the rat portal vein. Antagonistic affinity is the highest when Trp is used in position 7 of [beta-Ala8]-NKA (4-10) and MePhe in position 7 of [beta-Ala8]-NKB (4-10). Antagonism is selective for NKB or [MePhe7]-NKB, and appears to be specific, since the most active compound [Trp7, beta-Ala8]-NKA (4-10) is inactive against bradykinin on the rabbit jugular vein (B2 receptor), against SP on the rabbit jugular vein (NK-1 receptor), against desArg9-bradykinin on the rabbit aorta (B1 receptor), and against angiotensin II and histamine (AT and H receptors, respectively) in the rabbit aorta. The new NK-3 receptor antagonists described in the present study provide useful tools for neurokinin receptor characterization and for determining the roles of neurokinins in physiopathology.

Animals↗
PubMed1990

The rabbit jugular vein is a contractile NK-1 receptor system.

Rabbit isolated jugular veins respond to substance P and related neurokinins with concentration-dependent contractions which appears to be due to the activation of a single neurokinin receptor of the NK-1 type. This is demonstrated by the order of potency of neurokinins and some of their fragments as well as by the strong activity of NK-1-selective agonists and the weakness of NK-2- and NK-3-selective agonists. The present results indicate that the rabbit jugular vein provides a sensitive, specific and selective NK-1 preparation which responds directly to neurokinins with contractions and therefore can be useful for characterization of NK-1 agonists and antagonists.

Angiotensin II↗
PubMed1990

Receptors for neurokinins in human bronchus and urinary bladder are of the NK-2 type.

Human tissues such as the isolated bronchus and urinary bladder respond to neurokinins with concentration-dependent contractions, which appear to be due to the activation of receptors. We characterized these receptors in the present study using agonists (the naturally occurring neurokinins and some selective agonists) as well as newly identified antagonists. The order of potency of the agonists in the two preparations was as follows: neurokinin A (NKA) greater than substance P (SP) greater than neurokinin B (NKB) (bronchus) and NKA greater than NKB greater than SP (bladder), which suggests the presence of NK-2 receptors. This was confirmed by data obtained with two antagonists, one of which was shown to be competitive and selective for NK-2 type receptors. It thus appears that receptors of the NK-2 type are present in humans along the tracheo-bronchial tree and in the urinary system.

Bronchi↗
PubMed1990

[Leu9 psi(CH2NH)Leu10]-neurokinin A (4-10) (MDL 28,564) distinguishes tissue tachykinin peptide NK2 receptors.

The neurokinin A analogue, MDL 28,564 (Asp-Ser-Phe-Val-Gly-Leu-CH2NH-Leu-NH2), inhibited 125I-NKA binding to hamster urinary bladder NK2 receptors with a KI of 130 nM. For rat submaxillary gland NK1 receptors and cerebral cortical NK3 receptors, the KI's for MDL 28,564 were greater than 250 microM and greater than 500 microM, respectively. MDL 28,564 did not relax dog carotid artery (NK1 tissue) or contract rat portal vein (NK3 tissue). In guinea-pig trachea tissues, MDL 28,564 stimulated phosphatidylinositol turnover and induced contraction with maximum effects similar to those of neurokinin A. In hamster urinary bladder tissue, MDL 28,564 stimulated phosphatidylinositol turnover with maximum effect only 10% of that of neurokinin A, did not produce sustained contraction itself and antagonized NKA-induced contraction. MDL 28,564 also produced full contraction in rabbit pulmonary artery (NK2 tissue) but was inactive in rat vas deferens (NK2 tissue). These data with MDL 28,564 are consistent with the NK2 receptors in guinea-pig trachea and rabbit pulmonary artery being different from those in hamster urinary bladder and rat vas deferens.

Amino Acid Sequence↗
PubMed1990

Structure-activity studies on bradykinin and related peptides: agonists.

1. Bradykinin, kallidin, T-kinin, [Hyp3]-bradykinin and several analogues were prepared by solid-phase synthesis and purified by high performance liquid chromatography. 2. The various peptides were tested for their abilities to relax the dog carotid and renal arteries, or to contract the rabbit jugular vein and aorta, in order to measure their activities on BK2 (the first three preparations) or BK1 (the rabbit aorta) receptors. The dog renal artery without endothelium was also used as a BK1 receptor system. 3. T-kinin was found to be less active than bradykinin, while the replacement of Pro3 with Hyp favoured BK2 receptor occupation. [Hyp3,Tyr(Me)8]-BK was found to be a selective BK2 receptor agonist. 4. Amidation or methylation of the C-terminal carboxyl decreased activity, while extension of the N-terminal with Sar or D-Arg increased affinity and selectivity for BK1 (Sar) and affinity for BK2 (D-Arg) receptors. Acetylation of N-terminal amide brought affinity down to 10% or less. 5. Replacement of the peptide bonds Phe8-Arg9 to protect from kininase I and II, decreased affinities slightly, but was incompatible with additional changes at the N-terminal or in the peptide bond Gly4-Phe5. 6. Substitution of C-terminal Phe in desArg9-BK (the BK1 receptor stimulant) with D-Phe increased potency and selectivity for BK1 receptors while protecting from carboxypeptidases. Sar[D-Phe8]desArg9-BK was found to be a potent and selective BK1 receptor agonist.

Animals↗
PubMed1990

Inhibitors of peptidases: how they influence the biological activities of substance P, neurokinins, kinins and angiotensins in isolated vessels.

Myotropic effects of various peptides were measured in three isolated vessels, the dog carotid artery, the rabbit pulmonary artery and the rat portal vein in the absence and in presence of several peptidase inhibitors, in order to evaluate the interference by metabolism with the peptides' biological activities. After adequate controls, captopril (4.6 x 10(-6) mol/l), thiorphan (1.0 x 10(-6) mol/l), phosphoramidon (4.6 x 10(-6) mol/l), chymostatin (1 mg/l), bestatin (8.1 x 10(-6) mol/l) or bacitracin (1.4 x 10(-5) mol/l) were left in contact with the tissues for 20-40 min to inhibit tissue peptidases before measuring again the biological effects of the various peptides. In some experiments, mergetpa (5.4 x 10(-6) mol/l) was used. All peptidase inhibitors were inactive on their own and only captopril potentiated the effects of substance P, neurokinins, bradykinin and inhibited angiotensin I in two preparations, the dog carotid artery, the rat portal vein, and, excluding bradykinin, also in the rabbit pulmonary artery. Captopril and thiorphan significantly potentiated the maximal response of the rat portal vein to substance P and mergetpa inhibited completely the effect of bradykinin on the rabbit pulmonary artery. The present findings suggest that the most active proteolytic enzyme interfering with the biological effects of vasoactive peptides on three isolated vessels is the angiotensin-converting enzyme (kininase II).

Angiotensin II↗
PubMed1990

Inhibitors of peptidases: how they influence the biological activities of substance P, neurokinins, bradykinin and angiotensin in guinea pig, hamster and rat urinary bladders.

Neurokinins, bradykinin and angiotensins were tested in isolated urinary bladder of the guinea pig, the hamster and the rat, in the absence and in presence of a variety of peptidase inhibitors in order to establish if peptide degradation interferes with the bladder contractions elicited by the three types of peptides. Indeed, the effects of neurokinins, bradykinin and angiotensin I in the guinea pig bladder were significantly enhanced by captopril (4.6 x 10(-6) mol/l), chymostatin (1 mg/l), phosphoramidon (4.6 x 10(-6) mol/l) and thiorphan (1.0 x 10(-6) mol/l), while only captopril was found to potentiate the effects of the same peptides in the rat bladder. The four peptidase inhibitors, as well as bacitracin were found to modify the responses of the hamster urinary bladder to one or another or to all three groups of peptides and to DiMeC7. The present results suggest that the urinary bladders of various species have different types of active proteolytic enzymes: only the angiotensin-converting enzyme appears to be present in the rat bladder, while the same enzyme and possibly two additional endopeptidases interfere with the myotropic effects of neurokinins, kinins and angiotensins in the guinea pig and the hamster bladder.

Angiotensin II↗
PubMed1990

Structure-activity study of neurokinins: antagonists for the neurokinin-2 receptor.

A series of 21 peptides were synthesized and tested in a variety of isolated organs in order to determine their potential as neurokinin-2 (NK-2) antagonists. The peptides have been tested in the three monoreceptor systems, the dog carotid artery (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3) as well as on other preparations containing NK-2 receptors, such as the rat vas deferens, the hamster urinary bladder, the guinea-pig trachea and the human urinary bladder. Some of the compounds have also been tested on the human isolated bronchus. Three compounds, of which two are linear peptides, Ac.Leu-Asp-Gln-Trp-Phe-Gly.NH2, Thr-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg.NH2 and a cyclic one, cyclo[Gln-Trp-Phe-Gly-Leu-Met] have been shown to reduce or eliminate the effects of neurokinin A (NKA) in practically all the preparations containing NK-2 receptors. The first compound was found to be selective for the NK-2 receptor and showed only agonistic or no activity on the other receptor systems, while the second compound showed some antagonistic effects not only on the NK-2 but also on the other systems. The cyclic compound was found to be fairly selective for the NK-2 receptor. The first compound (Ac.Leu-Asp-Gln-Trp-Phe-Gly.NH2) was characterized with respect to its specificity for neurokinins (NK): it was found to be inactive on receptors for acetylcholine, noradrenaline, angiotensin and des Arg9-bradykinin in the rabbit pulmonary artery. Moreover, the compound exerted a competitive type of antagonism on the rabbit pulmonary artery and on the hamster urinary bladder. Although of moderate affinity, the NK-2 receptor antagonists described in this paper provide important tools for pharmacological studies on NK.

Amino Acid Sequence↗
PubMed1989

Receptors for kinins in isolated arterial vessels of dogs.

A variety of kinin peptides, agonists and antagonists were tested with dog carotid and renal arteries in order to characterize kinin receptor types and functions. The dog carotid artery responds to bradykinin with concentration-dependent relaxation only when the endothelium is intact but des-Arg9-bradykinin is practically inactive. The effect of bradykinin is blocked by B2 receptor antagonists, suggesting that the dog carotid artery has B2 receptors in the endothelium. These receptors mediate relaxation of the arterial smooth muscles by promoting the release of an endothelium-derived relaxing factor whose action is prevented by methylene blue. Kinins relax the dog renal artery with or without endothelium. Methylene blue prevents the effect of bradykinin only, suggesting that B2 receptors, promoting the release of endothelium-derived relaxing factor, are present in the endothelium of the dog renal artery. Moreover, the dog renal artery appears to have both B2 and B1 receptors mediating relaxation of the arterial smooth muscle. The presence of the two receptor types has been demonstrated by means of specific agonists and antagonists. Indomethacin blocks the effects of both bradykinin and des-Arg9-bradykinin on the dog renal artery without endothelium, suggesting that muscular B1 and B2 receptors act by promoting the release of prostaglandins. Captopril, a kininase II inhibitor, potentiates the effect of bradykinin on the dog carotid artery more than on the dog renal artery.

Animals↗
PubMed1989

Selective agonists for receptors of substance P and related neurokinins.

Neurokinins and their receptors are a complex system consisting of at least three endogenous agents--substance P (SP), neurokinin A (NKA), and neurokinin B (NKB)--and their corresponding receptor types, respectively, NK-1, NK-2, and NK-3. Investigations on receptors have been made using sensitive and fairly selective pharmacological preparations (the dog carotid artery for the NK-1, the rabbit pulmonary artery devoid of endothelium for the NK-2, and the rat portal vein for the NK-3 receptor), and some natural peptides of mammalian and nonmammalian origin. Because of the nonselectivity of the natural peptides, analogues of the neurokinins have been found that act on one receptor only and show therefore high selectivity. The selective agonists [Sar9,Met(O2)11]SP, [Nle10]NKA (4-10), and [MePhe7]-NKB have been used successfully for (a) characterizing the three neurokinin receptors, (b) identifying isolated organs whose responses to neurokinins depend on the activation of a single (monoreceptor systems) or of more than one (multireceptor systems) receptor, and (c) elucidating some of the physiological function of the three receptor types. It is suggested that NK-1 mediate peripheral vasodilatation and exocrine secretions, NK-2 stimulate bronchial muscles and facilitate the release of catecholamines, and NK-3 promote the release of acetylcholine in peripheral organs.

Amino Acid Sequence↗
PubMed1987

Characterization of neurokinin receptors in various isolated organs by the use of selective agonists.

The three mammalian neurokinins, substance P, neurokinin A and neurokinin B, as well as some agonists selective for their respective receptors, NK-P, NK-A and NK-B, were tested in a variety of pharmacological preparations in order to evaluate if the biological responses of the various tissues were mediated by single or multiple receptor types. Previous observations that the dog carotid artery, the rabbit pulmonary artery and the rat portal vein are selective preparations respectively for SP, NKA and NKB were confirmed in the present study by showing that only the respective selective agonists were active on these tissues. Multiple functional sites were demonstrated in intestinal tissues (guinea pig ileum, rat duodenum), which apparently contain the three neurokinin receptors. A large number of NK-P, together with some NK-A receptor sites were found in the guinea pig and rat urinary bladder. Similarly, the guinea pig trachea and the rabbit mesenteric vein contain NK-A and NK-P functional sites. Rat and rabbit vas deferens stimulated electrically respond as typical NK-A preparations, since they are almost insensitive to SP or NKB selective agonists. A mixture of NK-A and NK-B receptor sites has been shown to be present in the hamster urinary bladder: dog and human urinary bladder definitely contain NK-A receptors and the dog bladder also some NK-P functional sites.

Animals↗
PubMedDate not supplied

Structure-activity studies of neurokinin A.

A structure-activity study on neurokinin A and its C-terminal fragment NKA (4-10) has been performed in order to find selective agonists for the NK-2 receptor and identify chemical modifications suitable for protecting the peptides from degradation, while maintaining activity. Five series of compounds have been prepared and tested: 1. the complete series of the L-Ala monosubstituted analogues of NKA; 2. a series of NKA fragments from the C- or N-terminal; 3. the complete series of NKA (4-10) analogues monosubstituted with beta-Ala; 4. a series of NKA (4-10) analogues with monosubstitutions in pos. 4, 8, 10 or multisubstitutions in two or more of the same positions; and 5. a series of 6 NKA (4-10) analogues monosubstituted with 1-amino,1-cyclohexane carboxylic acid residue. It has been found that the most selective agonists for the NK-2 receptor system are [beta Ala8]NKA (4-10) and [Nle10]NKA (4-10). Protection from aminopeptidase may be obtained by acetylation of the N-terminal amide of NKA (4-10), while partial protection from endopeptidases should be expected from the presence of beta-Ala in position 8. Conformational constraints induced with 1,amino,1-cyclohexane carboxylic acid residue gave weakly active compounds. Multiple substitutions reduce rather than potentiating the favorable effects of the corresponding monosubstituted compounds.

Animals↗
PubMedDate not supplied

Neurokinin A. A pharmacological study.

Discovered in 1983, the decapeptide neurokinin A has been shown to occur in several peripheral organs and to exert a variety of biological effects. In this article, we review the most sensitive and selective in vivo and in vitro tests which have been used in various laboratories to evaluate naturally occurring or synthetic neurokinin A. A comparison of the effects of neurokinin A and those of its mammalian homologues, substance P and neurokinin B as well as those of tachykinins and related peptides is presented in the frame of a study directed toward characterization of neurokinin receptors. Indeed, neurokinin A has been shown to be particularly active on a neurokinin receptor subtype, the NK-2. Structure-activity studies performed with neurokinin A and its fragments as well as with several analogues of both the decapeptide and the heptapeptide NKA(4-10) have brought to the identification of the minimum structure required for activation of NK-2 receptors. Selective agonists for this receptor have been identified, in particular [Nle10]-NKA(4-10) and [beta-Ala8]-NKA(4-10).

Animals↗