Biomedical subjects

S Dion

Publications and source records attributed to S Dion.

At least 19 recordsLinked to original sources

PubMed2001

Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis.

Proinflammatory cytokines, pathological iron deposition, and oxidative stress have been implicated in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). HO-1 mRNA levels and mitochondrial uptake of [(55)Fe]Cl(3)-derived iron were measured in rat astroglial cultures exposed to interleukin-1beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha) alone or in combination with the heme oxygenase-1 (HO-1) inhibitors, tin mesoporphyrin (SnMP) or dexamthasone (DEX), or interferon beta1b (INF-beta). HO-1 expression in astrocytes was evaluated by immunohistochemical staining of spinal cord tissue derived from MS and control subjects. IL-1beta or TNF-alpha promoted sequestration of non-transferrin-derived (55)Fe by astroglial mitochondria. HO-1 inhibitors, mitochondrial permeability transition pore (MTP) blockers and antioxidants significantly attenuated cytokine-related mitochondrial iron sequestration in these cells. IFN-beta decreased HO-1 expression and mitochondrial iron sequestration in IL-1beta- and TNF-alpha-challenged astroglia. The percentage of astrocytes coexpressing HO-1 in affected spinal cord from MS patients (57.3% +/- 12.8%) was significantly greater (p < 0.05) than in normal spinal cord derived from controls subjects (15.4% +/- 8.4%). HO-1 is over-expressed in MS spinal cord astroglia and may promote mitochondrial iron deposition in MS plaques. In MS, IFN-beta may attenuate glial HO-1 gene induction and aberrant mitochondrial iron deposition accruing from exposure to proinflammatory cytokines.

Animals↗

PubMed1998

Bladder distension and activation of the efferent function of sensory fibres: similarities with the effect of capsaicin.

1. The effects of the tachykinin NK2 receptor antagonist MEN 11420 (100 nmol kg(-1), i.v.) and isoprenaline (400 nmol kg(-1), i.v.) were compared in a model of distension-induced bladder activity in isovolumetric conditions. MEN 11420 induced a relaxation of the basal tone of the urinary bladder that was dependent on the volume of the viscus: the effect was absent at low volumes (0.2 and 0.5 ml) and it was maximal at high volumes of distension (1 and 2 ml), approaching about 60% of the isoprenaline-induced relaxation. The relaxant effect of isoprenaline was always evident at all volumes of distension. 2. Tetrodotoxin (1-100 microM, intravesically applied) abolished distension-evoked micturition contractions, but did not prevent the relaxant effect of MEN 11420- or isoprenaline on the bladder tone. 3. The cyclo-oxygenase inhibitor S-ketoprofen (0.5 micromol kg(-1), i.v.) produced a marked decrease of the bladder tone and a concomitant reduction of bladder motility at 1 ml volume of distension. At 2 ml of distension, S-ketoprofen still decreased the minimal pressure but had no significant effect on other parameters of vesical motility. In S-ketoprofen-pretreated rats, the relaxant effect of MEN 11420 was significant at 2 but not at 1 ml of distension, and that of isoprenaline was reduced by 50% at both 1 and 2 ml. 4. Ruthenium red (10 micromol kg(-1), i.v.) had no effect at a low volume of distension (0.2 ml) or at highest volume (2 ml) but decreased the basal tone and the frequency of bladder contractions at 1 ml of distension. In ruthenium red-pretreated rats, MEN 11420 failed to decrease bladder tone at 1 ml, whereas at 2 ml the effect of MEN 11420 was not different from that observed in controls (43 vs 60% of isoprenaline-induced relaxation, respectively). 5. At both 1 and 2 ml of distension, capsaicin pretreatment (164 micromol kg(-1), s.c. 5 days before) reduced the frequency of micturition contractions but had no effect on the bladder tone. Capsaicin pretreatment prevented the relaxant effect of MEN 11420 on the bladder tone both at 1 and at 2 ml of distension. 6. It is concluded that the release of tachykinins from capsaicin-sensitive afferent nerves induced by bladder distension is resistant to tetrodotoxin and to prostaglandin synthesis inhibition. Tachykinins modulate the vesical tone by acting through NK2 receptors.

Adrenergic beta-Agonists↗

PubMed1998

Hyperreflexia of the urinary bladder: possible role of the efferent function of the capsaicin sensitive primary afferents.

PURPOSE: Capsaicin sensitive primary afferents (CSPA) have been implicated in the pathogenesis of hyperreflexia after spinalization. In this study we investigated the role of the efferent function of these fibers in detrusor hyperreflexia and its effect on detrusor physiology and pharmacology. MATERIALS AND METHODS: Four groups of female Sprague Dawley rats were included in our study. These groups were normal controls, capsaicin treated normal rats, spinalized rats and capsaicin treated spinalized rats. Six weeks following spinalization, animals were subjected to cystometric study, and bladders were obtained for either in vitro detrusor contractility study or substance P (SP), neurokinin A (NKA) and calcitonin gene related peptide (CGRP) quantification by radioimmunoassay. RESULTS: Spinalized animals consistently developed hyperreflexia after spinalization in the form of uninhibited contractions more than 15 cm. water in amplitude. This was accompanied by increased urinary bladder total content of the neuropeptides but without any change in the detrusor contractility or neurokinin receptor pharmacology as shown by responses to KCl, electric field stimulation and neurokinin receptor selective agonists in the in vitro study. In the control group, urinary bladder total content of SP, NKA and CGRP was 0.19+/-0.03, 0.15+/-0.01 and 0.84+/-0.1 pmol/bladder respectively. In contrast, in the spinalized animals, these were 0.44+/-0.07, 0.21+/-0.03 and 2.28+/-0.34 pmol/bladder for the same peptides, respectively. Capsaicin treatment abolished hyperreflexia, which corresponded with the decrease in the neuropeptide content of the urinary bladder. The number and amplitude of the uninhibited contractions decreased dramatically. SP, NKA and CGRP reached 0.06+/-0.01, 0.07+/-0.01 and 0.44+/-0.18 pmol/bladder 2 weeks after capsaicin treatment in spinalized animals. This was associated with the occurrence of detrusor super-sensitivity to both neurokinin receptor selective agonists. CONCLUSION: This study demonstrates the importance of the efferent function of the CSPA in the pathogenesis of hyperreflexia. On the other hand, detrusor changes were shown to be a noncrucial factor in the development of hyperreflexia.

Animals↗

PubMed1991

Characterization of bombesin receptors in peripheral contractile organs.

1 Guinea-pig and rat urinary bladders, rat stomach and the guinea-pig gall bladder, four isolated organs that show high sensitivity to bombesin, were used to characterize bombesin receptors in peripheral organs. 2 The order of potency of agonists was determined with several naturally occurring peptides of the bombesin series, namely bombesin (BBS), litorin (Lit), neuromedin B (NMB), the gastrin-releasing peptide (GRP 18-27), neuromedin C (NMC) and with some bombesin fragments. It was found that bombesin, neuromedin C, litorin and two bombesin fragments, BBS (6-14) and AcBBS (6-14) had similar activities in the four preparations, while neuromedin B and [Phe6]-neuromedin C were more active on the rat urinary bladder than on the other tissues. 3 The order of potency of agonists determined in the rat urinary bladder was as follows: BBS = NMB greater than Lit greater than NMC greater than [Phe6]NMC = GRP and it was found to be different from that observed in the other preparations: BBS greater than GRP = Lit greater than or equal to NMC much greater than NMB greater than [Phe6]NMC, suggesting the existence of two different bombesin receptors, BBS1 and BBS2. 4 This interpretation was convalidated by the finding that bombesin antagonists, namely Ac.GRP(20-26)OCH3 and Ac.GRP(20-26)OC2H5 reduced or blocked the effects of bombesin-related peptides on BBS2 receptor systems while being completely inactive on the rat urinary bladder (BBS1 system).

Animals↗

PubMed1991

Structure-activity studies of bradykinin and related peptides. B2-receptor antagonists.

Thirty-seven compounds were tested as antagonists of kinin B2- and B1-receptors to identify the chemical changes required to obtain antagonism, improve antagonist affinity, and eliminate residual agonistic activities. Apparent affinity of antagonists was evaluated in terms of pA2 on the rabbit jugular vein, the dog carotid and renal arteries, the hamster urinary bladder, the guinea pig ileum, the rat vas deferens, the guinea pig trachea, and the rabbit aorta, using bradykinin and desArg9-bradykinin as B2- and B1-receptor activators. Replacement of Pro7 of bradykinin with D-Phe leads to antagonism; substitution of Pro3 by Hyp and extension of the peptide chain at the N-terminal with a D-Arg residue improves the affinity of antagonists; acetylation of N-terminal amine function reduces residual agonistic activity; these changes, combined with the replacement of Phe8 by Leu as in Ac-D-Arg[Hyp3,D-Phe7,Leu8]-bradykinin, led to potent full B2-receptor antagonists. Affinity of antagonists differs markedly between highly sensitive (rabbit jugular vein, dog carotid and renal artery), moderately sensitive (hamster urinary bladder, guinea pig ileum, and rat vas deferens), and insensitive preparations (the guinea pig trachea) in which antagonists act as potent stimulants. High concentrations of antagonists block bradykinin completely in the rabbit jugular vein but not in the guinea pig ileum, suggesting that kinins stimulate the moderately sensitive tissues by two mechanisms, of which only one is blocked by antagonists. It thus appears that kinins act on various B2-receptor subtypes or by different action mechanisms.

Animals↗

PubMed1990

125I-BH[Sar9, Met(O2)11]-SP, a new selective ligand for the NK-1 receptor in the central nervous system.

The selective agonist [Sar9,Met(O2)11]-SP was radioiodinated with 125I-Bolton Hunter in order to study its binding to rat brain membranes and for further comparison with 125I-BH.SP. Specific binding of 125I-BH[Sar9,Met(O2)11]-SP was temperature-dependent, saturable and reversible. In brain homogenates, 125I-BH[Sar9,Met(O2)11]-SP interacted with a single class of high affinity (kd = 1.0 nM) non-interacting binding sites (Bmax of 15 fmol/mg protein). In the central nervous system, 125I-BH-[Sar9,Met(O2)11]-SP apparently labeled the same number of binding sites as 125I-BH.SP (19 fmol/mg proteins). Competition studies with tachykinins, neurokinins and selective neurokinin agonists indicated that the pharmacological profile of the site labeled by 125I-BH[Sar9,Met(O2)11]-SP is identical with that of NK-1 receptors. In dose-displacement studies made with radiolabeled SP and [Sar9,Met(O2)11)]-SP, an excellent correlation (r = 0.96) was found for the Ki values of the different compounds tested; these findings suggest that both radioligands recognize the same receptor in rat brain. The affinity (Ki) of various neurokinin-related peptides for the brain site were compared with their biological activities on various isolated organs (dog carotid artery, guinea-pig ileum, rat portal vein). NK-1 binding sites characterized in rat brain homogenates appear to be identical with those present on the dog carotid artery, a preparation known to possess exclusively the NK-1 receptor type.

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

New selective bradykinin receptor antagonists and bradykinin B2 receptor characterization.

Substantial progress has been made recently in the field of kinin pharmacology with the identification of sensitive bioassay organs and the discovery of bradykinin B2 receptor antagonists. Data obtained with such compounds in various laboratories support the hypothesis that kinins act on multiple (at least two) receptor types. Domenico Regoli and colleagues review here the basic criteria of receptor characterization as they apply to kinins and present a critical analysis of the bioassay organs and B2 receptor antagonists currently used in kinin pharmacology.

Animals↗

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

Competitive antagonists discriminate between NK2 tachykinin receptor subtypes.

1. We have compared the ability of various tachykinins and selective tachykinin receptor agonists to induce contraction of the endothelium-denuded rabbit pulmonary artery (RPA) and hamster trachea (HT) and have estimated the affinity of some newly developed NK2 selective antagonists in the same tissues. 2. In confirmation of previous findings, experiments with the agonists indicated that NK2 receptors are the main if not the sole mediators of the response to tachykinins in both RPA and HT. No evidence for significant degradation of neurokinin A (NKA) was found in either tissue when experiments were repeated in the presence of a mixture of peptidase inhibitors (thiorphan, captopril and bestatin, 1 microM each). 3. The peptide antagonists tested were: Peptide I = [Tyr5, D-Trp6,8,9, Arg10]-NKA(4-10); Peptide II = [Tyr5, D-Trp6,8,9, Arg10]-NKA(3-10); Peptide III = Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2. The three peptides produced a concentration-dependent rightward shift of the concentration-response curve to NKA in both RPA and HT with no significant depression of the maximal response attainable. The slopes of the Schild plots were not significantly different from unity, indicating a competitive antagonism. Peptides I and II were about 100 times more potent in the RPA than in the HT, while Peptide III was about 100 times more potent in the HT than RPA. 4. The pA2 values obtained in these two tissues with the three antagonists were not significantly different when tested in the absence or presence of peptidase inhibitors, or when a selective NK2 receptor agonist, [beta Ala8]-NKA(4-10) was used instead of NKA. Similar pA2 values were obtained after 15 or 90min of incubation with the antagonists. Peptides I, II and III had no inhibitory effect on contractions produced by noradrenaline in the RPA or by carbachol in the HT. 5. Peptides I, II and III showed weak or no antagonistic activity toward the vasodilatator effect of substance P in the dog carotid artery (NK, receptor-mediated) or toward the contractile effect of neurokinin B in the rat portal vein (NK3 receptor-mediated). 6. These results provide pharmacological evidence for heterogeneity of NK2 receptors in the RPA and HT. The NK2 receptors present in these tissues are not discriminated by natural tachykinins or selective agonists, but are recognized with very different affinity by NK2 receptor antagonists.

Amino Acid Sequence↗

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↗

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↗