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Biomedical subjects

D Regoli

Publications and source records attributed to D Regoli.

At least 271 records · Page 15Linked to original sources
PubMed1986

The actions of kinin antagonists on B1 and B2 receptor systems.

The newly discovered bradykinin antagonist [Thi5,8,D-Phe7]Bradykinin, supplied by J.-M. Stewart and three other compounds, [D-Phe7]BK, [Thi5,8,D-Phe7]Bradykinin and [Thi6,9,D-Phe8]Kallidin synthesized in our laboratory, were tested for their ability to antagonize bradykinin in four B2 receptor systems, the guinea-pig ileum, the rabbit jugular vein, the dog carotid artery and the dog urinary bladder as well as against desArg9-bradykinin in the rabbit aorta (a B1 receptor system). [D-Phe7]Bradykinin is a partial agonist, while [Thi5,8,D-Phe7]Bradykinin and [Thi6,9,D-Phe8]Kallidin are pure antagonists, the second one showing little BK-like activity on three of the four preparations. The kallidin analogue is more potent in all preparations than the bradykinin one. The two [Thi5,8,D-Phe7]BK (that supplied by J.-M. Stewart and that prepared in our laboratory) show very similar affinities in all preparations. The bradykinin analogue as well as the kallidin one are also active against desArg9-bradykinin in the rabbit aorta, at concentrations similar to those active on B2 receptor systems. The kinin antagonists are however specific for the kinins, since they do not interfere with the myotropic effects of angiotensin or substance P (SP) in the various preparations.

Animals↗
PubMed1986

Kinins, receptors, antagonists.

Kinins are potent myotropic agents acting on a variety of smooth muscle preparations: isolated arteries, veins, intestines, tracheae, urinary bladders, uteri, etc. In these tissues, kinins activate at least two different receptor types, B1 and B2. B1 and B2 receptors for kinins have been identified by measuring the order of potency of agonists and the affinities of specific and competitive antagonists. Results of pharmacological studies have been confirmed by several investigators using binding assays with labelled bradykinin (BK) or desArg9BK. Antagonists for kinins active on B1 and B2 receptors have been identified. Anti-B1 antagonists are specific, competitive and fairly potent: anti-B2 antagonists have been identified among compounds primarily developed as anti-tachykinins: these compounds are non-specific, non-competitive and rather weak. They however may provide interesting new pharmacological tools, active against both kinins and tachykinins, two groups of endogenous peptides involved in the inflammatory process. The type (direct, indirect) and the site (endothelial cell, smooth muscle fiber, autonomic nerve endings) of action of kinins in isolated vessels have been investigated. The results of various studies indicate that kinins do not act on the sympathetic nerve terminals of isolated organs in contrast with other peptides. Kinins do not promote the release of histamine or of 5-hydroxy-tryptamine from isolated arteries and veins. Kinins are equally active in the presence and absence of indomethacin (an inhibitor of cyclooxygenase) or of BW 755C (an inhibitor of lipoxygenase) in some organs, while the actions of kinins on other organs are reduced to a variable extent by these inhibitors. In general, B1 receptor systems do not depend on the activation of arachidonic acid, while B2 receptor systems do: activation of the arachidonic acid cascade may be a feature of B2 receptors. Stimulant effects of kinins on arterial or venous vessels are independent on the endothelium, while the relaxant effect on the dog carotid artery occurs only in vessels with intact endothelium. The mechanism of action of kinins and tachykinins appears to be different from that of acetylcholine, since the peptides effects are not influenced by BW 755C and ETYA, two inhibitors of lipooxygenase that reduce significantly the effect of acetylcholine.

Animals↗
PubMed1986

Histamine release and local responses of rat and human skin to substance P and other mammalian tachykinins.

Substance P and two recently identified neurokinins, substance K and neuromedin K as well as the nonmammalian tachykinin kassinin were compared for histamine-releasing abilities from rat mast cells, plasma extravasation effects on rat skin, and wheal and flare responses on human skin. Among the four tachykinins, a significantly dose-dependent histamine release from rat mast cells and a flare response in human skin was observed only with substance P, indicating the possible implication of histamine in this response. On the other hand, the four peptides were similarly active on the wheal response (plasma extravasation produced by increased permeability of capillaries and venules) in human skin and on the plasma extravasation in the rat skin, suggesting a dissociation of effects and possibly of receptors.

Animals↗
PubMed1986

Tachykinins: effects on motility and metabolism of rat polymorphonuclear leucocytes.

Chemotactic and chemoluminescent activities of substance P, substance K, kassinin and the substance P fragments SP 4-11, SP 7-11, SP 1-4 have been investigated in order to identify the minimum active molecular structure responsible for rat polymorphonuclear activation. Substance P, SP 4-11 and SP 7-11 stimulated directed locomotion (chemotaxis) and were found to be active also in the chemoluminescence assay while SP 1-4 had no effect. Moreover, all peptides, except substance K and SP 1-4, inhibited the chemotactic response of polymorphonuclears to the peptide formyl-methionyl-leucyl-phenylalanine and, to a minor extent, also to leukotriene B4. A maximum of activity was observed with the C-terminal sequence SP 4-11. Substance K was found to be inactive. Kassinin exhibited a weak chemotactic effect and exerted a slight inhibition of attracting activity of peptide-formyl-methionyl-leucyl-phenylalanine. Considering that substance P and related peptides are active only at very high concentrations, it cannot be affirmed that these agents activate specific receptors. If receptors are involved, they would be of the SP-P type, since substance K is inactive.

Animals↗
PubMed1986

Activation of micturition reflex by substance P and substance K: indirect evidence for the existence of multiple tachykinin receptors in the rat urinary bladder.

The ability of substance P (SP) and substance K (SK) to activate motility of the rat urinary bladder "in vivo" and "in vitro" have been compared. In urethane-anesthetized rats topical application of tachykinins on the serosal surface of the bladder elicited a series of neurogenic rhythmic contractions (micturition reflex). SK is about 13.5 times more potent than SP. The extent of the effects of both SP and SK depends on the bladder initial volume. SP and SK are equally effective in: contracting the tetrodotoxin-pretreated rat bladder in vivo; contracting the isolated rat bladder in vitro; enhancing the contractions induced by field stimulation; and delaying relaxation of bladder muscle in response to stretch. These findings suggest the existence of two different sites (receptors) for tachykinins in the rat bladder whose activation is responsible for initiation of the micturition reflex and direct smooth muscle contraction, respectively. The higher potency of SK, as compared to SP, in activating the micturition reflex suggests the involvement of a receptor of the SP-E type, possibly located on the afferent nerve endings, in the mediation of this type of response. The other receptor, located on the smooth muscle cell (and possibly on the efferent nerve endings) appears to be of the SP-P type, as it is equally sensitive to the two tachykinins.

Administration, Topical↗
PubMed1985

Tachykinin receptors in smooth muscles: a study with agonists (substance P, neurokinin A) and antagonists.

Four preparations, sensitive to tachykinins, the guinea-pig urinary bladder, the rat duodenum, the hamster and dog urinary bladders have been investigated and compared with four other preparations described before: the guinea-pig ileum and trachea, the dog carotid artery and the rabbit mesenteric vein. On the basis of the order of potency of agonists, evaluated with substance P, physalaemin, eledoisin, kassinin and neurokinin A, the preparations can be separated into three groups, the guinea-pig urinary bladder and the dog carotid artery, in which substance P is the most potent and neurokinin A the weakest tachykinin, the rabbit mesenteric vein, the guinea-pig trachea and the rat duodenum, in which the opposite order is observed and the hamster and dog urinary bladders, in which kassinin is the most potent agonist. The guinea-pig ileum shows similar sensitivity to the five tachykinins. C-terminal partial sequences appear to be weaker than SP-(1-11) in three of the four new preparations, SP-(6-11) being first in the rat duodenum and slightly weaker than SP-(1-11) in the hamster and dog urinary bladders. Studies performed with antagonists or inhibitors of endogenous agents suggest that substance P and neurokinin A act directly on specific receptors. The effects of the two peptides are reduced by antagonists analogues of the sequence SP-(4-11). One of the antagonists, [D-Pro4,Lys6,D-Trp7,9,10, Phe11]SP-(4-11) has been shown to be competitive against substance P and neurokinin A in the guinea-pig ileum, the guinea-pig urinary bladder and the rat duodenum. This compound, shows definitely higher activity against neurokinin A and kassinin, compared to substance P in various preparations. [D-Tyr4,D-Trp7,9,Nle11]SP-(4-11) is the most potent tachykinin antagonist in the hamster and dog urinary bladders. In these preparations, the antagonists act also against substance P, but with lower affinity. These findings with antagonists support the indication, emerged from the order of potency of agonists, that tachykinins may act on two and possibly three different receptor types.

Animals↗
PubMed1985

Peptides and histamine release from rat peritoneal mast cells.

Various vasoactive peptides were compared for their histamine releasing effects on rat mast cells. Neurotensin, substance P (SP), and kallidin were the most active natural peptides, followed by bradykinin; neurokinin A and B, bombesin, angiotensin and tuftsin were practically inactive. Several kinins and tachykinin-related peptides were tested in an attempt to characterize the receptors mediating histamine liberation. The order of potency of the kinins was the following: kallidin greater than [Tyr(Me)8]bradykinin = bradykinin greater than [desArg10]kallidin greater than desArg9-bradykinin, the same as that found in smooth muscle possessing receptors of the B2 type. Tachykinin-related peptides were potent stimulants and followed the order: [D-Tryp7,9,10]SP-(1-11) greater than [D-Pro2,D-Tryp7,9,10]SP-(1-11) greater than SP-(1-11) greater than SP-(1-9) greater than [D-Pro4,D-Tryp7,9,Leu11]SP-(4-11) greater than SP-(1-7) greater than SP-(4-11) greater than neurokinin A = neurokinin B, indicating that: (a) undecapeptide antagonists of SP behave as superagonists; (b) both N- and C-terminal portions of SP-(1-11) are essential for activity; and (c) receptors for the tachykinins mediating histamine release appear to be of the SP-P type.

Animals↗
PubMed1985

Tachykinin antagonists: substitutions in positions 5 and 6 with amino acids from the primary sequence of substance P homologues.

A series of tachykinin antagonists has been synthetized by substituting the amino acids of eight naturally occurring tachykinins into the general antagonist [pro4, trp7,9, Phe 11]tachykinin-(4-11). Five decapeptide antagonists were also synthetized. These antagonists were tested on four smooth muscle preparations, the rabbit mesenteric vein, the guinea-pig ileum, the guinea-pig trachea and the rat urinary bladder. On all tissues, except the rat urinary bladder, antagonists that had amino acids other than Gln5 Gln6 found in the substance P molecule were inactive as antagonists, and some had marked intrinsic activity on the guinea-pig ileum and the guinea-pig trachea. The inhibitory activity of these antagonists on the rat urinary bladder, however, was quite marked. The activities of these antagonists on the rat urinary bladder can be summarized as follows: (a) In general decapeptide antagonists were of low affinity. (b) Octapeptide antagonists showed variable affinities against the various tachykinins and some were selective. The only two antagonists which were fairly active against all tachykinins were [pro4, trp7,9, Phe11]SP-(4-11) and [pro4, trp7,9, Phe11] UPE-(4-11). (c) Physalaemin was frequently antagonized in a non-surmountable manner. (d) Eledoisin and kassinin were each inhibited by only one antagonist, and the antagonist was different for each tachykinin. Some tachykinin receptors on smooth muscle have a binding site which is highly selective for Gln5 Gln6, especially if the affinity of antagonists is considered. Another tissue, the rat urinary bladder, does not exhibit this selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1985

Effects of peptides and non-peptides on isolated arterial smooth muscles: role of endothelium.

Peptides and non-peptides acting as vasoconstrictors or vasodilators have been tested in dog isolated carotid arteries with and without endothelium and in the presence and absence of a variety of antagonists and inhibitors of endogenous substances. It has been found that substance P and several other tachykinins, bradykinin, neurotensin, bombesin and acetylcholine relax the isolated artery only when the endothelium is present, while VIP, isopropylnoradrenaline, adenosine, histamine, prostaglandins E1 and E2, glucagon and insulin relax and angiotensin, vasopressin, oxytocin, 5-HT and noradrenaline contract the isolated vessel, no matter whether the endothelium is present or not. Peptide and non-peptide antagonists have been used with success to show that vasoconstrictors and vasodilators act on specific receptors, since their effects are reduced in the presence of antagonists, specific for one or another of the various agents. Inhibitors of the arachidonic acid cascade only reduce the effect of acetylcholine, suggesting that at least two different mechanisms are involved in the endothelium-mediated relaxation of arterial smooth muscles to peptide and non-peptide agents. The results summarised in this paper suggest that the site of action of several vasodilators is the endothelium, while other vasodilators and all the vasoconstrictors influence the arterial vessels tone presumably by acting on the smooth muscle cells.

Animals↗
PubMed1985

Anti-substance P anti-idiotypic antibodies. Characterization and biological activities.

Antibodies to substance P (SP) produced in rabbits have been characterized for their specificity toward SP and some 30 SP-related peptides. For each compound, we observed a close correlation between capacity of binding to anti-SP antibodies and biological activity, namely their spasmogenic effect on guinea pig ileum in vitro and their hypotensive effect in the rat in vivo, indicating that the combining sites of anti-SP and SP receptor(s) are structurally very similar. Further immunization of five rabbits with anti-SP immunoglobulins elicited in two allotype-matched animals the production of anti-SP anti-idiotypic antibodies. These latter antibodies were found to strongly inhibit the spasmogenic action of SP on the guinea pig ileum. In contrast, they specifically enhanced, like SP, phospholipid turnover in rat parotid gland cells, a physiological function mediated through an activation of SP receptors. Immunocytochemical studies actually revealed the presence of specific membranous binding sites for anti-idiotypic antibodies on the parotid gland-dissociated cells. The anti-idiotypic antibodies described here, which thus behave either as agonists or antagonists for SP depending on the biological test, might be used as original and powerful tools not only in studies of the receptor stereospecificity but also in attempts to purify the membranous SP receptors.

Animals↗
PubMed1985

Comparison of the effects of substance P and substance K on blood pressure, salivation and urinary bladder motility in urethane-anaesthetized rats.

The effects of substance P and substance K on blood pressure, salivation and urinary bladder motility were investigated in urethane-anaesthetized rats. On intravenous administration, both peptides produced dose-related reductions in blood pressure, substance P being 25-30 times more potent than substance K. Substance P induced a dose-dependent increase of salivation, while substance K was half as active and induced only 40% of the maximum effect of substance P. The two tachykinins induced contractions of the urinary bladder, substance K being about twice as effective as substance P. Substance K was more effective than substance P in activating micturition. These findings provide further evidence that multiple receptor types are involved in mediating the effects of tachykinins in peripheral organs.

Anesthesia↗
PubMed1985

Activities and antagonism of bombesin on urinary smooth muscles.

Substance P (SP), bombesin (BB) and bradykinin (BK) induce dose-dependent contractions of the rat and guinea-pig urinary bladders (RUB, GPUB). The three peptides differ in their affinities and intrinsic activities, BB being the most active both in terms of affinity (pD2 8.33 in the RUB and 8.83 in the GPUB), SP (8.03 and 7.53), BK (7.20 and 7.35), and of intrinsic activity. The myotropic effects of BB and SP are not modified by antagonists of neurotransmitters and autacoids that occur in peripheral organs, but that of BK is reduced in the presence of both the cyclooxygenase and lipoxygenase inhibitors. Undeca- and octapeptide antagonist analogues of SP and SP-(4-11) show similar pA2 values against BB and SP and are inactive against BK: the compound [D-Pro4, Lys6, D-Trp7,9,10, Phe11] SP-(4-11) is however more active (pA2 6.36 in the RUB and 6.18 in the GPUB) against BB than against SP (pA2 5.33 and 5.65 respectively), while it is inactive against BK. These results confirm data from the literature as to the ability of some tachykinin-antagonists to act against BB and shows chemical modifications that can improve the antagonist potency selectively against BB.

Animals↗
PubMed1985

Characterization of spinal actions of four substance P analogues.

Four substance P (SP) analogues were tested on reaction time (RT) in the tail flick test and on the decrease in RT produced by the SP homologue physalaemin. The four analogues were [D-Trp7,9,10]SP, denoted A, [D-Pro4,D-Trp7,9,Nle11]SP-(4-11), denoted B, [D-Pro2,D-Trp7,9,10]SP, denoted C and [D-Pro4,D-Trp7,9,10,Phe11]SP-(4-11), denoted D. Physalaemin alone (1.89 nmol) reduced RT. The analogue A, at 3.25 nmol, blocked the effects of physalaemin without altering basal RT. The analogues B and D, which block the action of physalaemin in peripheral tissues, had neither agonistic nor antagonistic effects in doses up to 6.5 nmol. The replacement of L-Pro2 by D-Pro2 in the analogue A yielded the analogue C, which had no antagonistic activity. All analogues produced a flaccid paralysis of the hindlimbs and the tail; this effect was inconsistent, though, occurring only in some rats, and appearing in some cases after the first administration of the analogue yet in other cases only after a subsequent administration. Because B and D are inactive in the spinal cord, our results suggest that physalaemin activates receptors in the spinal cord different from those it activates in peripheral tissues. Furthermore, because all four analogues produced a flaccid paralysis none is suitable for use as an SP antagonist in vivo in the CNS.

Animals↗
PubMed1985

Substance P antagonists showing some selectivity for different receptor types.

Five antagonists have been used against substance P (SP) and neurokinin A (NA) in isolated smooth muscle preparations containing either SP-P (the guinea pig ileum (G.P.I.), the dog carotid artery (D.C.A.) or SP-E receptors (the rat duodenum (R.D.), the dog (D.U.B.) and hamster urinary bladders (H.U.B.]. [D-Pro4,D-Trp7,9,10, Phe11]SP-(4-11) was found to be selective for SP-P receptors, since it showed high affinity both against SP and NA, on the G.P.I. and D.C.A., while it was found to be inactive on some SP-E receptor systems (D.U.B., H.U.B.) and very weak in others (R.D.). Two octapeptide antagonists, modified in position 6, [D-Pro4,Ala6,D-Trp7,9,10,Phe11]SP-(4-11) and [D-Pro4,Lys6,D-Trp7,9,10,Phe11]SP-(4-11) showed some selectivity for SP-E receptors since they acted as full agonists on one SP-P preparation (the D.C.A.) and the first compound contracted also the G.P.I. In addition to being pure antagonists on the D.U.B., H.U.B. and on the R.D., the two octapeptides showed a higher potency against the SP-E stimulant NA, compared to SP, in the R.D. Two undecapeptide antagonists were active against SP and NA on both SP-P and SP-E receptor preparations and therefore were less discriminative than the octapeptides. They were however more active against NA on the R.D., similar to the octapeptides modified in position 6. It is concluded that: (a) both agonists and antagonists appear to be useful for the characterization of tachykinins receptors; (b) either the whole N-terminal portion of SP or a shorter sequence, modified in position 6, increase the antagonist affinity against NA in the SP-E receptor system of the rat duodenum.

Angiotensin II↗
PubMed1985

Bradykinin levels in inflammatory exudates.

An enzyme immunoassay was used to measure the levels of bradykinin (BK)-like immunoreactivity in inflammatory exudates provoked by calcium pyrophosphate (CaPP) or carrageenin. BK-like immunoreactivity increased from 4 to 18 ng/ml in exudates provoked by CaPP and collected from 30 min to 3 h after induction of pleurisy. BK levels decreased progressively (from 16 to 3 ng/ml) in the samples collected at 4 and 6 h. BK levels did not increase in exudates provoked by carrageenin. Control samples of exudates provoked by CaPP but not treated with peptidase inhibitors [orthophenanthroline (OPH) or a mixture of EDTA-captopril-thioglycolic acid (ECT)] as well as samples containing one or the other peptidase inhibitors dissolved in saline, were also negative. The present results indicate that an increased production of kinins is detectable only in exudates induced by CaPP and not in those provoked by carrageenin. Our data also suggest that the kinins are rapidly metabolized, both in vitro (in the exudate sample) and in vivo (in the rat pleural cavity).

Animals↗
PubMed1985

Conformationally restricted C-terminal peptides of substance P. Synthesis, mass spectral analysis and pharmacological properties.

Four cyclic analogues of the C-terminal hepta- or hexapeptide of substance P were prepared by the solution method. The cyclizations were obtained by substituting with cysteine the residues normally present in positions 5 or 6 or 11 of substance P and by subsequent disulfide bond formation. The final products were identified by ordinary analytical procedures and advanced mass spectroscopy. The biological activities were determined on three bioassays: the guinea pig ileum, the guinea pig trachea and the rabbit mesenteric vein. Results obtained with these assays indicate that all peptides with a disulfide bridgehead in position 11 are inactive and that a cycle between positions 5 and 6 already strongly reduces the biological activity. The acyclic precursors containing thiol protection groups display weak biological activities. These results further underline the importance of the side chain in position 11 of substance P and suggest that optimal biological activities may require a linear peptide sequence.

Animals↗
PubMed1984

[Polypeptides and antagonists].

Polypeptides are endogenous agents, involved in the regulation of many physiologic functions and the pathogenesis of several diseases. Polypeptide antagonists form a group of new chemical entities which may provide valid therapeutic agents. Some polypeptides (angiotensin, kinins) are released through the action of proteolytic enzymes (renin, kallikreins) and act as hormones or autacoids; others (substance P, neurotensin) are synthetized by nervous cells to serve as neurotransmitters or neuromodulators. The main homeostatic role of the renin-angiotensin system is to uphold high systemic arterial blood pressure. Overproduction of renin and insufficient checking of renin secretion are among the most common causes of arterial hypertension. Several forms of arterial hypertension (neurovascular, idiopathic) benefit from a reduction in renin-angiotensin system activity. This is achieved either through decreasing renin secretion, by inhibiting conversion of angiotensin I into angiotensin II, or through blocking the peripheral actions (at the receptor sites) of angiotensin II. Renin secretion is very significantly reduced by beta-blocking agents (propranolol); conversion of angiotensin I into angiotensin II is inhibited by teprotide, captopril and their derivatives; peripheral actions of angiotensin II are blocked by saralasin. Bradykinin and related agents produce vasodilation, increase vascular permeability and stimulate pain fibers. Kinins thus reproduce the cardinal features of inflammation and are held to be mediators of the inflammatory reaction. The substance P neuropeptide is found in the brain and bowel; it may act as a transmitter of the sensation of pain at the spinal cord and central nervous system sites. Among other effects outside of the brain, substance P is a potent vasodilator and inhibits renin secretion. Neurotensin is a neuropeptide which produces hypothermia, muscular relaxation and analgesia. Outside of the brain, this peptide is involved in the regulation of gastric secretion, intestinal motility and insulin and glucagon secretion. The vasoactive intestinal peptide, found in certain cholinergic nerve endings, is a large peptide which inhibits gastric secretion, intestinal motility and vascular tone.

Angiotensin II↗