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Biomedical subjects

N E Rhaleb

Publications and source records attributed to N E Rhaleb.

52 records · Page 3Linked to original sources
PubMed1990

Vasoactive peptides and their receptors.

Peptides act as vasoconstrictors (for instance angiotensins, vasopressin) or vasodilators (the kinins, the neurokinins), both through direct activation of specific receptors in the vascular smooth muscles or indirectly through the release of other endogenous inhibitors of the vascular tone. Kinins and neurokinins as well as their multiple receptors have been analyzed in the present study to assess the possible contributions of peptides to vasodilatation. Kinin receptors, B1 and B2, have been characterized, using new selective agonists and antagonists. B1 and B2 receptors appear to present in endothelium (B2) and in smooth muscles (B2, B1) of a variety of isolated vessels of the dog and the rabbit, where they subserve both stimulatory and inhibitory effects. Vasodilator inhibitory mechanisms depend on the release of the endothelium-relaxing factor and/or of prostanoids from the endothelium or the smooth muscles, especially in the dog renal vessels, where both B1 and B2 receptors appear to be involved in causing vasodilatation. B2 receptors have also been shown to activate cardiovascular reflexes through a direct action on sensory fibers or on reflexogenic areas of the epicardium. Three types of receptors for neurokinins, namely NK-1, NK-2 and NK-3, have been identified by the use of naturally occurring peptides and of some analogues that act as selective agonists of a single receptor type. NK-1 receptors (particularly sensitive to substance P) have been shown to be present in endothelia where they promote the release of the endothelium relaxing factor, while NK-2 receptors (sensitive to neurokinin A) are found in the pulmonary artery of the rabbit and act directly to contract the smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Kinin receptor subtypes.

Bradykinin, kallidin, and some of their metabolites exert potent biological effects in a variety of organs and tissues. These effects are mediated by specific receptors, of two different types B1 and B2, according to the classification proposed in 1980 by Regoli and Barabé. This classification has recently been challenged by several authors on the basis of data obtained with a variety of synthetic analogs (both agonists and antagonists) of bradykinin and kallidin. B2-receptor subtypes and even a new receptor type, B3 have been considered. Other workers have shown that some of the kinins' biological effects, such as the activation of prostaglandins or histamine release, may occur through nonreceptor mechanisms. Recently, a variety of new kinin-related peptides have been prepared and tested. In particular, new selective agonists for both B1 and B2 receptors have been identified and used for receptor characterization, particularly in complex biological systems. Antagonists are critically reviewed, because several of them are in effect partial agonists. Pure antagonists have been obtained and used for receptor characterization in various organs. Activation of receptors and nonreceptor mechanisms by kinins bring about direct effects on smooth muscles and other cells and indirect effects mediated by endothelium-derived relaxing factor, or by prostacyclin, prostaglandins, leukotrienes, histamine, etc. Interaction of kinins with their receptors activates second messengers that may be different from one cell to another (in the same tissue) and that are activated either by kinins or by other endogenous mediators released by kinins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗
PubMed1988

Bradykinin antagonism: differentiation between peptide antagonists and antiinflammatory agents.

Three non-steroidal antiinflammatory agents were tested for their ability to antagonize bradykinin in the rabbit jugular vein, the dog carotid artery and the guinea pig trachea. The new agents were compared with indomethacin, as well as with [Thi5,8,D-Phe7] bradykinin and [Thi6,9,D-Phe8] kallidin, two B2 receptor antagonists. The antiinflammatory agents did not alter the effects of bradykinin in the two isolated vessels while they completely blocked (like indomethacin) the relaxation induced by bradykinin in guinea pig tracheae contracted with histamine or neurokinin A. The two bradykinin antagonists significantly reduced the contractions of the rabbit jugular vein and the relaxation of the dog carotid artery (with endothelium) in response to bradykinin: these antagonists were however inactive against bradykinin in the guinea pig trachea. The data now reported suggest that B2 receptors are involved in the opposite (stimulant or inhibitor) effects of the kinins in the two isolated vessels while the relaxation of the guinea pig trachea is a prostaglandin-dependent phenomenon which does not involve the activation of B1 or B2 receptors.

Animals↗
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↗
PubMed1987

Receptors for substance P and neurokinins. Correlation between binding and biological activities.

The biological activities of neurokinin-related peptides were compared with their binding affinities measured in various laboratories. A positive significant correlation was demonstrated between the relaxation of the dog carotid artery and the binding of Bolton-Hunter [125I]substance P to rat brain synaptosomes, the contractions of the rat duodenum and the rabbit pulmonary artery and the binding of Bolton-Hunter [125I]neurokinin A to duodenum smooth muscle plasma membranes, and the contraction of the rat portal vein and the binding of [125I]Bolton-Hunter NH-senktide to rat cerebral cortex membranes.

Animals↗
PubMed1987

Specific agonists for neurokinin B receptors.

A series of analogues of the partial sequence NKB-(4-10) (H-Asp-Phe-Phe-Val-Gly-Leu-Met.NH2) was prepared in an attempt to identify selective agonists for the neurokinin B receptor type. The compounds were tested in the dog carotid artery, the rabbit pulmonary artery and the rat portal vein to evaluate their affinity for the receptors of substance P, neurokinin A and neurokinin B respectively. It has been shown that the replacement of Val7 with MePhe increased significantly the affinity of NKB-(4-10) for the neurokinin B receptor and confered marked selectivity. [MePhe7]NKB-(4-10) was practically inactive as stimulant of the receptor for NKA and was a weak agonist on the receptor for SP. Such significant changes in the pharmacological spectrum of [MePhe7]NKB-(4-10) cannot be attributed to protection from metabolism and appear to be due to changes in the peptide conformation.

Animals↗
PubMed1987

The rat isolated portal vein: a preparation sensitive to neurokinins, particularly neurokinin B.

The rat isolated portal vein is a pharmacological preparation more sensitive to neurokinin B than to any other neurokinin or tachykinin. The preparation is more sensitive to C-terminal partial sequences of substance P (SP) particularly SP-(6-11) than to the whole undecapeptide. The order of potency of neurokinins is as follows: neurokinin B greater than neurokinin A greater than substance P. The preparation shows high sensitivity also to kassinin and eledoisin. Comparative tests performed with strips of the rat portal vein suspended in a microbath under continuous perfusion (system 1) or in ordinary baths for isolated smooth muscles (system 2) have given similar results and have shown that the myotropic effect of neurokinin B is not modified by a variety of antagonists of endogenous agents as well as by inhibitors of the arachidonic acid cascade. The present results suggest that neurokinin B contracts the rat portal vein by activating specific receptors, presumably located on the smooth muscle membrane, different from those of biologically active amines and peptides which are active stimulants of the vein. Neurokinin B is ten times more active than neurokinin A and at least 100 times more than substance P. Such an order of potency of agonists suggests the existence of a new neurokinin receptor type, particularly sensitive to neurokinin B.

Animals↗
PubMed1987

Selective agonists for substance P and neurokinin receptors.

A series of neurokinin analogues and fragments have been prepared in an attempt to identify selective agonists for NK-P, NK-A and NK-B receptors. The compounds have been tested on the dog carotid artery (NK-P receptor system), the rabbit pulmonary artery (NK-A) and the rat portal vein (NK-B). C-terminal substituted analogues of the three neurokinins have provided indication that NK-P receptor selectivity is improved by the oxidation of methionine to Met(O2), while selectivity for NK-A is favoured by replacing Met with NIe. Selectivity for NK-P receptors is further improved by the replacement of Gly9 with Sar. Selectivity and affinity for NK-B receptors is markedly increased when Val7 is replaced with MePhe in both the fragment NKB (4-10) and NKB. The results of the present study indicate that a) [Sar9,Met(O2)11]SP is a potent and selective agonist for the NK-P receptors of the dog carotid artery; b) [MePhe7]NKB is a very potent and selective stimulant of receptors for neurokinin B and c) [Nle10]NKA (4-10) is a promising compound, showing some selectivity for NK-A receptor; further modifications are however needed to improve its affinity.

Animals↗
PubMed1986

Conversion of kinins and their antagonists into B1 receptor activators and blockers in isolated vessels.

A carboxypeptidase inhibitor (DL-2-mercaptomethyl-3-guanidoethylthiopropranoic acid) (mergetpa) was used to block the conversion of kinins and B2 receptor antagonists into metabolites devoid of the C-terminal Arg. Experiments were carried out on rabbit isolated aortae (a B1 receptor system) or rabbit jugular veins and dog carotid arteries (two B2 receptor systems). The contractile effect of bradykinin in the rabbit aorta was significantly reduced by mergetpa while that of desArg9-BK was not modified. pA2 values of B2 receptor antagonists, [Thi5,8,D-Phe7]bradykinin and [Thi6,9,D-Phe8]kallidin were markedly reduced by mergetpa. The apparent affinity (pA2) of a B1 receptor antagonist, [Leu9]desArg10-kallidin was not affected. Carboxypeptidases inhibition did not modify the activities of bradykinin or the affinities of B2 receptor antagonists in the rabbit jugular vein and the dog carotid artery. An inhibitor of kininase II (D-3-mercapto-2-methylpropranoyl-L-proline (S,S] (captopril) reduced the contractile effects of angiotensin I in the three preparations and potentiated the stimulatory or inhibitory effects of bradykinin: captopril did not have effect on the affinities of B2 receptor antagonists and did not modify the effects of angiotensin II. Comparative experiments performed in tissues with or without endothelium gave the same results with both mergetpa and captopril. The present findings suggest that bradykinin and B2 receptor antagonists are converted by carboxypeptidases into biologically active B1 receptor agonist or antagonists. This is the reason why B2 receptor antagonists are not selective.

3-Mercaptopropionic Acid↗
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↗