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Biomedical subjects

D Regoli

Publications and source records attributed to D Regoli.

At least 217 records · Page 12Linked 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↗
PubMed1990

Bradykinin stimulates the production of cyclic GMP via activation of B2 kinin receptors in cultured porcine aortic endothelial cells.

The production of endothelium-derived relaxing factor(s) in response to kinins was investigated in cultured porcine aortic endothelial cells. The production was estimated by the measurement of the accumulation of cyclic GMP, a response which can be attributed to activation of the soluble guanylate cyclase of the endothelial cells by endothelium-derived relaxing factor(s). Bradykinin increased markedly the levels of cyclic GMP in endothelial cells without affecting those of cyclic AMP. The bradykinin-stimulated production of cyclic GMP was transient and concentration-dependent. Kallidin (an agonist at B2-kinin receptors) but not des-Arg9 bradykinin and des-Arg10 kallidin (agonists at B1 kinin receptors) also increased, in a concentration-dependent manner, the content of cyclic GMP. The B2 kinin receptor antagonist, D-Arg0 [Hyp3, D-Phe7]bradykinin but not the B1 kinin receptor antagonists Leu8-des-Arg9 bradykinin and Leu9-des-Arg10 kallidin inhibited the production of cyclic GMP upon stimulation of the endothelial cells with either bradykinin or kallidin. Both the basal and kinin (bradykinin and kallidin)-stimulated productions of cyclic GMP were reduced by hemoglobin and potentiated by superoxide dismutase. Methylene blue also reduced kinin-stimulated production of cyclic GMP. These findings suggest that cultured porcine aortic endothelial cells possess B2 kinin receptors which are associated with the production and/or release of endothelium-derived relaxing factor(s). The endothelium-derived relaxing factor(s) produced in turn enhances the activity of soluble guanylate cyclase and induces the accumulation of cyclic GMP.

Animals↗
PubMed1989

Role of the N-terminal arginine in the histamine-releasing activity of substance P, bradykinin and related peptides.

A series of substance P (SP)- and bradykinin (BK)-related peptides have been compared for their histamine-releasing activities on rat peritoneal mast cells. Some of these peptides only differed in the N-acetylation of the N-terminal arginine residue or by the removal of charged residue at the N-terminal. The aim was to examine the role of the N-terminal positive charges in the histamine-releasing activity of compounds that are selective for the SP receptor (named NK-1) or for the B2 type bradykinin receptor. Only compounds with positive charges at the N-terminal caused non-cytotoxic histamine release from rat mast cells. It is suggested that SP- and BK-related peptides caused histamine release by a mechanism which appeared to be non-specific and not related to the activation of mast cell NK-1 or B2 receptors, respectively. Our results show that NK-1 agonists or B2 antagonists devoid of histamine-releasing activity, which could be of potential use in the clinic, can be obtained by removing the positively charged N-terminal aminoacids or by N-acetylation of the N-terminal arginine.

Animals↗
PubMed1989

Effect of thiorphan on response of the guinea-pig gallbladder to tachykinins.

Tachykinins produced a concentration-related contraction of the isolated guinea-pig gallbladder, with a rank order of potency neurokinin A (NKA) greater than Arg-neurokinin B = neurokinin B (NKB) greater than substance P (SP). Only the effect of SP was potentiated by thiorphan (0.1-10 microM). A significant enhancement of the response to SP was also produced by captopril (1 microM). [Nle10]NKA-(4-10) and [beta-Ala8]NKA-(4-10), selective NK-2 receptor agonists, were active, whereas [Pro9]SP sulfone (selective NK-1 agonist) was almost ineffective. [MePhe7]NKB (selective NK-3 agonist) had some activity but only at high concentrations. Septide was almost ineffective and DiMeC7 had an action comparable to that of [MePhe7]NKB. None of the effects induced by these synthetic tachykinin analogs were significantly potentiated by thiorphan. Capsaicin (10 microM) produced a contraction which was unaffected by thiorphan. Both capsaicin and NKA-induced contractions were antagonized by Spantide at concentrations (5-10 microM) which had no effect against the atropine-sensitive contractions produced by electrical field stimulation. Capsaicin (1 microM) produced a consistent release of SP-like immunoreactivity (SP-LI) and a second application of the drug had no further effect, indicating complete desensitization. SP-LI release by capsaicin was almost doubled in the presence of thiorphan. These findings indicate that NK-2 and possibly some NK-3 receptors mediate the contractile response of the guinea-pig gallbladder to tachykinins. Both exogenous and endogenous (released by capsaicin) SP were degraded to a significant extent in this organ via a thiorphan-sensitive mechanism, the identity of which remains to be established.

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↗
PubMed1989

Capillary permeability induced by intravenous neurokinins. Receptor characterization and mechanism of action.

The effects on plasma extravasation of three increasing doses from 6.5 pmol to 650 nmol/kg of substance P (SP), SP fragments, neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were assessed in three cutaneous tissues (skin of hind paws, dorsal skin and ears) by intravenous (i.v.) administration in the pentobarbitone anaesthetized rat. Dose-dependent increases in plasma extravasation were observed with the following rank orders of potency (SP greater than NKA greater than NKB) for neurokinins and (SP greater than [p-Glu6]SP(6-11) greater than SP(4-11) greater than [p-Glu5]SP(5-11) greater than SP(7-11] for C-terminal SP fragments. The metabolically stable SP analogue [p-Glu5, MePhe8, Sar9]SP(5-11) was slightly more potent than [p-Glu5]SP(5-11). The N-terminal fragments SP(1-4), SP(1-7) and SP(1-9) were inactive up to 650 nmol/kg. The NK-1 receptor selective agonists [Sar9, Met(O2)11]SP and [beta-Ala4, Sar9, Met (O2)11]SP(4-11) were more potent than the NK-2 [( Nle10]NKA(4-10] and NK-3 [( MePhe7]NKB and [beta-Asp4, MePhe7]NKB(4-10] receptor selective agonists. Plasma extravasation induced by SP (6.5 nmol/kg) was unchanged in the presence of atropine, methysergide, diphenhydramine or during the i.v. and intra-arterial (i.a.) infusion of D-Arg0[Hyp3.D-Phe7]BK, an antagonist of bradykinin. Plasma extravasation induced by SP and [Sar9, Met(O2)11]SP was significantly reduced by indomethacin while that induced by NKA, NKB, [beta-Ala4, Sar9, Met(O2)11]SP(4-11), SP(4-11) and [p-Glu6]SP(6-11) was unaffected by the cyclooxygenase inhibitor. Compound 48/80 (0.75 mg/kg), histamine (10 mg/kg) and 5-HT (10 mg/kg) caused an increase in plasma extravasation, only the effect of compound 48/80 was abolished by indomethacin. Pretreatment with compound 48/80 prevented its own action on plasma extravasation and significantly reduced that induced by 6.5 nmol/kg of SP. These results rule out the involvement of acetylcholine (muscarinic receptors), 5-HT (5-HT1 and 5-HT2 receptors), histamine (H1 receptors) and kinins (B2 receptors) in the response to SP and indicate that the two positively charged amino acids (Arg, Lys) at the N-terminal end of the SP molecule are essential to trigger the release of prostaglandins from mast cells. This mechanism is responsible for the indirect effect of SP and related peptides on capillary permeability and does not appear to be mediated by a selective SP receptor. In addition, neurokinins may increase capillary permeability by direct activation of a NK-1 receptor type on the vascular endothelium.

Animals↗
PubMed1989

Characterization of the peripheral action of neurokinins and neurokinin receptor selective agonists on the rat cardiovascular system.

The effects on mean arterial pressure (MAP) and heart rate (HR) of increasing doses (0.65-65 nmol/kg) of substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were measured after intravenous (i.v.) injection in urethane anaesthetized rats. Neurokinins (NKs) elicited a vasodepressor effect with the following rank order of potency: SP (100%) greater than NKB (17.5%) greater than NKA (10%). The two undecapeptide NK-1 selective agonists, [Pro9, Met(O2)11]SP (787%) and [Sar9, Met(O2)11]SP (697%), evoked a significantly (P less than 0.05) greater vasodepressor response than SP, while the potency of the octapeptide NK-1 selective agonist [beta-Ala4, Sar9, Met(O2)11]SP (4-11) (316%) was not significantly different from SP. Conversely, the NK-2 selective agonist NKA (4-10) (less than 2%) caused only a small effect. The vasodepressor effect elicited by [MePhe7]NKB (112%) and [beta-Asp4, MePhe7]NKB (4-10) (92%), two NK-3 selective agonists, were not significantly different from that of SP. Senktide (1,095%) is the most potent NK-3 agonist, and is significantly (P less than 0.01) more potent than SP. No cross-desensitization, of the vasodepressor response, was observed between NK-1 and NK-3 selective agonists. I.V. injection of 32.5 nmol/kg of NKA, NKA (4-10) and [beta-Ala4, Sar9, Met(O2)11]SP (4-11) raised HR, while NKB and the NK-3 selective agonists produced a rapid and marked bradycardia. SP and the two undecapeptide, NK-1 selective agonists, produced an initial increase in HR and a latent long-lasting bradycardia. The bradycardia elicited by [Sar9, Met(O2)11]SP (32.5 nmol/kg) was blocked by methylatropine, hexamethonium, indomethacin and by treatment with capsaicin or compound 48/80. Although the bradycardia elicited by [beta-Asp4, MePhe7]NKB (4-10) (32.5 nmol/kg) was also blocked by hexamethonium, methylatropine, and by bilateral vagotomy, it remained unaffected after indomethacin, or in rats pretreated with either capsaicin or compound 48/80. The drop in MAP produced by the NK-1 and NK-3 agonists were reduced by hexamethonium, methylatropine and bilateral vagotomy (NK-3 agonist), but remained unaffected by indomethacin, capsaicin, and compound 48/80. The tachycardia to NKA (4-10) (65 nmol/kg) was blocked entirely by sotalol or metoprolol and potentiated by hexamethonium. Guanethidine and bilateral adrenalectomy (48 h) failed to affect the tachycardia induced by the agonist, whereas the combination of both treatments abolished the response. Rats sympathectomized with 6-hydroxydopamine (48 h) reduced the increase in HR to NKA (4-10) only at 1 min post-administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Potent angiotensin II antagonists with non-beta-branched amino acids in position 5.

Amino acids with lipophilic side chains that contain more than one functional group on the beta-carbon, i.e. a beta-branched hydrocarbon moiety, are required in position 5 of angiotensin II (AII) analogue with potent agonist activity. This requirement for agonist activity does not follow for AII analogues with potent antagonist activity. Straight-chain amino acids may be substituted into position 5 of [Sar1,X5,Ile8]AII with retention or enhancement of antagonist activity, e.g. (X5,pA2 rabbit aorta) Phe, 9.15; Tyr, 9.6; His, 9.0; Glu,9.0; Nle, 8.85, compared to Ile, 9.1. beta-Branched side chains can still enhance the antagonist activities of [Sar1,X5,Ile8]AII analogues, e.g. X5 = (beta Me)Phe, pA2 = 9.3. An X-ray crystal structure of the Boc-(beta Me)Phe DCHA salt, prepared for the synthesis of [Sar1,-(beta Me)Phe5, Ile8]AII, revealed an S,S configuration of alpha- and beta-carbon atoms. Contrary to previous literature reports, chemical nonequivalence of the deta-protons of Pro was observed in the 1H NMR spectra of [Sar1,X5,Ile8]AII analogues bearing both beta-branched X5 side chains (X5 = Ile) and non-beta-branched X5 side chains (X5 = Ala, His).

Angiotensin II↗
PubMed1989

The role of position 4 in angiotensin II antagonism: a structure-activity study.

A number of [Sar1,(pX)Phe4]-ANG II and [Sar1,(pX)Phe4,Ile8]-ANG II analogues were prepared. A good correlation between pX structure in [Sar1,(pX)Phe4]-ANG II and antagonist activity could not be found. However, the data suggest a general trend: Position 4 para substituents that are hydrophilic and capable of donating a hydrogen atom in a hydrogen bond promote agonist activity, while para substituents that are hydrophobic and incapable of donating a hydrogen atom promote antagonist activity. These properties were found to be optimal in the p-chloro substituent. The resulting analogue [Sar1,(pCl)Phe4]-ANG II is a potent ANG II antagonist in vivo. The pX substituents that promote antagonist activity in the [Sar1,(pX)Phe4]-ANG II series were unfavorable in [Sar1,(pX)Phe4,Ile8]-ANG II analogues. ANG II analogues that are antagonists by virtue of an alteration in position 8 require a position 4 agonist side chain. Concurrent modifications of positions 4 and 8 do not give rise to potent antagonists with reduced partial agonist activity.

Angiotensin II↗
PubMed1989

Effects of tachykinins and selective tachykinin receptor agonists on vascular permeability in the rat lower urinary tract: evidence for the involvement of NK-1 receptors.

1. Intravenous administration of three mammalian tachykinins (substance P, neurokinin A and neurokinin B) and three non-mammalian tachykinins (physalaemin, eledoisin and kassinin) induced dose-dependent increases in vascular permeability, as measured by Evans blue leakage technique, in various segments of the lower urinary tract (bladder dome and neck, proximal urethra, ureters) in urethane-anaesthetized rats. 2. Plasma extravasation induced by substance P (3.71 nmol kg-1 i.v.) was unaffected by pretreatment with antihistaminic drugs or methysergide. 3. A comparison of the relative potencies of various tachykinins did not allow characterization of a distinct type of receptor involved in the increase in vascular permeability. 4. The effects of tachykinin-related peptides which are selective agonists at the NK-1 (substance P-methylester, [Pro9]-SP-sulphone), NK-2 receptor [( Nle10]-NKA(4-10] or NK-3 receptor [( MePhe7]-NKB(4-10) and Senktide) indicated that NK-1 agonists are effective in the whole lower urinary tract, while NK-2 or NK-3 agonists are inactive or weakly active. 5. [beta-Ala4, Sar9]-SP(4-11)-sulphone, a selective NK-1 receptor agonist devoid of histamine-releasing properties, was highly potent and effective in producing plasma extravasation in the rat lower urinary tract. 6. These findings indicate that NK-1 receptors mediate the effect of intravenous tachykinins on vascular permeability in the rat lower urinary tract, through a histamine-independent mechanism.

Animals↗
PubMed1989

Classification of tachykinin receptors in muscularis mucosae of opossum oesophagus.

1. Muscularis mucosae of the distal oesophagus of the opossum contracts in response to substance P and to a variety of tachykinins. To delineate the nature of the receptors present in this tissue, we evaluated contractile responses to substance P, neurokinin A, neurokinin B, eledoisin and analogues believed to be highly selective for NK-1, NK-2 and NK-3 receptors. In addition, the effects of prolonged exposure to each of these agents (10(-6) M or 10(-5) M) on contractile responses to substance P and to itself were evaluated. Similarly effects of prolonged exposure to the various tachykinins and their analogues on the field-stimulated responses of this muscle were studied. 2. All naturally occurring tachykinins were full agonists and differed in potency (comparing ED50 values) by less than ten fold. In nearly all cases there was cross tachyphylaxis between substance P and the other tachykinins and each reduced tonic responses to field stimulation, a response previously shown to be mediated by a substance P like agent. Eledoisin failed to cause tachyphylaxis under the conditions of these experiments. 3. When highly selective tachykinin analogues were used, only that believed to activate NK-1 receptors was a full agonist. [beta-Ala4,Sar9,MetO2(11)]SP(4-11) was also only slightly less potent than substance P. In contrast, an agonist selective for NK-2 (NK-A) receptors, [Nle10]NKA(4-10), and one selective for NK-3 (NK-B) receptors, [beta-Asp4, MePhe7]NKB(4-10) were unable to produce a response equal to 50% of the maximum even at 10(-5) M. However, all three selective tachykinin analogues reduced responses to substance P but not to carbachol. They usually reduced both phasic and tonic responses to field stimulation. 4. We conclude, based on this and earlier study, that the tachykinin receptors of opossum oesophagus muscularis mucosae recognize all naturally occurring tachykinins but may represent only NK-1 receptors. The ability of analogues selective for other types of tachykinin receptors to reduce responses to substance P raises the possibility that their selectivity depends in part on diminished efficacy rather than totally on diminished affinity at some classes of receptor.

Animals↗
PubMed1989

Prostacyclin release induced by neurokinins in cultured human endothelial cells.

The effects of neurokinins (NK) and related peptides on the secretion of 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin, were measured. These peptides enhanced three- to five-fold the basal secretion rate with the following rank order of potency (based on threshold concentrations for a significant output): substance P (SP) greater than or equal to NKA greater than SP 4-11 greater than or equal to [pGlu6]SP 6-11 = SP 7-11.NKB and SP 1-9 were inactive. Ac[Arg6, Sar9, Met(O2)11]SP, a NK1 receptor selective agonist, was more potent than other selective agonists for the NK2 and NK3 receptor subtypes. These results suggest that the NK receptors, which mediate the release of prostacyclin from human endothelial cells, belong to the NK1 subtype.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Receptors for substance P and related neurokinins.

The most widely used smooth muscle preparations for neurokinin bioassays have been critically analyzed in order to determine whether neurokinins act directly or by the intermediary of other natural agents. Indeed, part of the contraction of the GPI in response to neurokinins appears to be mediated by acetylcholine and possibly prostaglandins. Active metabolites of the arachidonic acid cascade also intervene in the response of the HUB. Neurokinins produce relaxation of the DCA by stimulating the release of a vascular smooth muscle relaxing factor from the endothelium. In the other preparations (the RD, the RPA without endothelium and the RPV) neurokinins may act directly on the smooth muscle fibers. Neurokinins produce their biological effects by activating specific receptors. Three different receptor types, one for each mammalian neurokinin, have been identified by using four groups of natural peptide sequences and some selective agonists. The receptor for SP is particularly sensitive to SP and physalaemin and shows higher affinity for the whole natural peptides (SP, NKA) than for their C-terminal fragments. The receptor for neurokinin A is highly sensitive to NKA and eledoisin: it shows high affinity for heptapeptide fragments such as NKA4-10 and SP5-11. The receptor for NKB is sensitive to NKB and kassinin more than to the other natural peptides and their fragments. The natural peptides show however little selectivity. Synthetic analogues active on a single receptor type (selective agonists) have been used to find out whether the responses of the isolated organs are due to the activation of one or more than one receptor. It has been found that the GPI, the RD and the HUB contain all three or at least two receptors, while the DCA has only the NK1, the RPA has only the NK2 and the RPV only the NK3 type. Binding sites specific for each neurokinin have been identified in brain and peripheral organs with accurate biochemical assays, using labeled neurokinins. Competitive displacement assays have been performed with a variety of neurokinin-related peptides, and their Ki have been determined. By plotting Ki values against the ED50, estimated from biological assays, positive significant correlations have been found for the monoreceptor (DCA, RPA, RPV) but not for the multiple receptor systems (GPI, RD, HUB). This suggests that pharmacological receptors may be identical with the recognition sites which bind the labeled neurokinins. The availability of monoreceptor systems and of selective agonists opens the way for the identification of potential antagonists and accurate estimation of their affinities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Characterization of neurokinin effects and receptor selectivity in human isolated bronchi.

Sensitive afferent nerves and the neurokinins they release upon activation are considered to be important in controlling bronchomotor tone. Human isolated bronchi respond to neurokinin A (NKA), substance P (SP), and neurokinin B (NKB) with dose-dependent contractions. The order of potency of the three natural neurokinins is NKA greater than SP greater than NKB, suggesting the presence of NK-2 receptors. To further characterize the neurokinin receptors in human bronchi, we used selective agonists for each receptor type (i.e., NK-1, NK-2, and NK-3). In fact, NK-1 selective compounds, [Pro9]SP(1-11) sulfone and [beta-ala4,Sar9]SP(4-11) sulfone, did not induce significant contractions up to 10(-5) M. Similarly, the selective agonist for the NK-3 receptor, [MePhe7]NKB(4-10), was almost inactive. However, the NK-2 selective fragment [Nle]NKA(4-10) was a potent stimulant. The negative log of the peptide concentration that caused 50% of maximal effect (pD2) was 6.99 for NKA and 6.12 for [Nle10]NKA(4-10). Removal of the epithelium significantly enhanced the contractile responses to the three neurokinins and also to the NK-2 selective agonist. Phosphoramidon, an enkephalinase inhibitor, was more potent than epithelium removal in enhancing the contractile responses to these agonists. However, epithelium removal and phosphoramidon did not increase the weak responses to the NK-1 and NK-3 selective compounds. In the presence of phosphoramidon, removal of the epithelium slightly enhanced the contractile responses to NKA and [Nle]NKA(4-10) but not to SP and NKB.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗