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D Regoli

Publications and source records attributed to D Regoli.

At least 289 records · Page 16Linked to original sources
PubMed1984

Undeca- and octa-peptide antagonists for substance P, a study on the guinea pig trachea.

Undeca - and octa-peptide analogues of substance P (SP), acting as antagonists in the guinea pig ileum, have been tested on the guinea pig trachea. The antagonistic properties of several octapeptides, particularly of [pro4, trp7 ,9,10,Phe11]SP-(4-11) have been confirmed, while the undecapeptides have been found to be potent stimulants of the trachea. The contractions of the guinea pig trachea in response several undecapeptides , particularly [pro2, trp7 ,9, Leu11 ]SP, undergo rapid tachyphylaxis, are significantly reduced in the presence of diphenhydramine and are not influenced by octapeptide antagonists of SP. These contractions appear to be due to the activation of tissue sites mediating the release of intramural histamine and different from SP receptors. On repeated applications, the stimulant effects of undecapeptides are eliminated and the compounds can be tested as antagonists. Undecapeptide antagonists have been found to be more potent against eledoisin and kassinin than against SP or physalaemin, while the octapeptides are equally active against the four homologues. Both undeca - and octa-peptides seem however to exert a competitive type of antagonism against all the SP-related peptides tested in the present study. Differences of antagonistic affinities have been interpreted as indicative of the existence of two different receptor types for SP and related peptides in the guinea pig trachea. The two receptors are blocked by the octapeptide antagonists, which are not discriminatory, while undecapeptides are particularly active on the receptor subtype which shows high sensitivity for eledoisin and kassinin .

Animals↗
PubMed1984

Receptors for substance P. I. The pharmacological preparations.

The undecapeptide substance P (SP) is both a potent stimulant of intestinal (guinea pig ileum), vascular venous (rabbit mesenteric vein) and tracheal (guinea pig trachea) smooth muscles, and a relaxant of large arteries (dog common carotid artery, rabbit aorta). SP also decreases the peripheral vascular resistance in the coronary vessels of rabbit isolated hearts. The contractions of the guinea pig ileum in response to SP are partially antagonised by atropine and significantly depressed by indomethacin, while the contractions of the guinea pig trachea are strongly potentiated by indomethacin. Large arteries, but not the veins, are insensitive to SP when the endothelium is removed, and slightly less responsive to the peptide when this is applied in the presence of mepacrine, eicosatetraynoid acid or BW 755C. These results indicate that all myotropic actions of SP, except that on venous smooth muscle, are partially or completely indirect and most of them are due to the release of endogenous agents: these are acetylcholine, prostaglandins and possibly histamine in the guinea pig ileum, prostaglandins and possibly a leukotriene in the guinea pig trachea and a still unidentified factor of endothelial origin in dog and rabbit large arteries. The effect of substance P on the rabbit isolated anterior mesenteric vein appears to be a direct one.

Animals↗
PubMed1984

Receptors for substance P. II. Classification by agonist fragments and homologues.

Substance P (SP), a series of C-terminal fragments, SP-(2-11), SP-(3-11), SP-(4-11), SP-(5-11), SP-(6-11), SP-(7-11) and the homologues physalaemin, eledoisin and kassinin were used to measure the order of potency of agonists in five pharmacological preparations. These are: the guinea pig ileum, the guinea pig trachea, the rabbit mesenteric vein, the dog common carotid artery and the rabbit aorta. Apparent affinities (pD2) and relative activities of SP-related peptides were measured in the absence and presence of antagonists (a mixture of atropine, indomethacin and diphenhydramine) in the guinea pig ileum and the rabbit mesenteric vein, in the absence and presence of indomethacin in the guinea pig trachea and in tissues with intact endothelium (the dog carotid artery and the rabbit aorta). The orders of potency measured in the absence and presence of antagonists in the guinea pig ileum were different, while no major changes were noted in two other preparations, namely the guinea pig trachea and the rabbit mesenteric vein. The order of potency of agonists determined with homologues revealed the existence of three major patterns namely: kassinin greater than eledoisin greater than physalaemin = SP in the guinea pig trachea and the rabbit mesenteric vein, SP = physalaemin greater than eledoisin greater than kassinin in the arterial smooth muscle of the dog carotid artery and the rabbit aorta and physalaemin greater than kassinin greater than eledoisin greater than SP in the guinea pig ileum treated with antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Receptors for substance P. III. Classification by competitive antagonists.

A series of ten octa- and five undecapeptide antagonists of SP have been tested in four isolated smooth muscle preparations in order to characterise the receptors mediating the SP-induced contractions of the guinea pig ileum (G.P.I.), the guinea pig trachea (G.P.T.) and the rabbit mesenteric vein (R.M.V.) and the relaxation of the dog carotid artery (D.C.A.). It has been shown that: (a) Indirect effects by substance P and related peptides, mediated by acetylcholine or prostaglandins reduce the affinity of [pro4,trp7,9,10]SP (4-11) (an SP-antagonist) only in the G.P.I. (b) Octapeptide antagonists are specific for SP, have no agonistic activities and exert a competitive antagonism against SP, its homologues and fragments. (c) Undecapeptide antagonists are weaker than the octapeptides in the G.P.I. and G.P.T. and slightly stronger in the D.C.A. and R.M.V. However these compounds still have variable degrees of agonistic activity in some tissues. Affinity of octapeptide antagonists bearing the basic structure [pro4,trp7,9]SP-(4-11) is increased by the additional replacement of Leu10 with trp, Met11 with Leu, Nle or Phe, but it is slightly reduced by substituting Phe8 with Val. Antagonists containing aliphatic residues at the C-terminal end, for instance [pro4,trp7,9,Nle11]SP-(4-11) are more potent than others in the R.M.V., while those with aromatic residues, for instance [pro4,trp7,9,10]SP-(4-11) are weak on the R.M.V. but fairly active on the G.P.T. These antagonists do not show any selectivity on the G.P.I. and the D.C.A. Comparison of antagonists affinities for receptor characterisation suggest the existence of three different functional sites for SP-related peptides. The site of the G.P.I. and D.C.A., which accepts both the antagonists containing aromatic or aliphatic groups at the C-terminal end; the site of the G.P.T. which prefers the aromatic and that of the R.M.V. which shows high affinity for aliphatic residues. The receptor classification emerging from data obtained with antagonists is compared with the classifications of the literature and with those based on the order of potencies of SP homologues and fragments.

Animals↗
PubMed1984

Neurohumoral regulation of precapillary vessels: the kallikrein-kinin system.

Bradykinin and related kinins are potent vasodilators. Inhibition of peripheral vascular smooth-muscle tone may result from actions of kinins at different levels. These include the afferent nociceptive nerve endings (bradykinin being a potent algesic agent); the brain and the spinal cord; and the three basic structural components of resistance vessels, namely, endothelium, smooth-muscle fibers, and autonomic nerve endings. The relative roles and the importance of these various structures and the mechanisms for the vasodilator and hypotensive effects of the kinins are discussed. Attention is focused on data obtained in isolated vascular beds, perfused with physiological media, and in strips or segments of arterial and venous vessels, suspended in vitro. Bradykinin and related kinins are potent vasodilators in the majority of peripheral vascular beds of various species, although they contract some isolated arteries and all the veins. These opposite vascular effects of the kinins appear to be mediated by at least two different receptor types, which have been identified and characterized with a series of kinin agonists and some kinin antagonists. B1-receptors mediate the contraction of arterial and venous smooth muscles, while B2-receptors are involved in the relaxation of arteries, the contraction of veins, and the increase in vascular permeability produced by kinins. Hypotension generally results from activation of B2-receptors, B1-receptors intervening only in special conditions. The relaxing effect of kinins in isolated arteries (B2-receptors) occurs only in the presence of endothelium, whereas all the stimulations do not require endothelium and appear to be owing to the activation of B2- and B1-receptors in the membranes of vascular smooth-muscle cells. It is still unknown whether endothelium is involved in the hypotensive and peripheral vasodilator actions of kinins in vivo.

Animals↗
PubMed1984

New agonist and antagonist analogues of bradykinin.

Three new analogues of bradykinin (BK) have been tested for their agonistic and antagonistic actions on the rabbit jugular vein and the guinea pig ileum (B2 receptors), and six were studied on rabbit aorta strips (B1 receptors). Substitution of Gly4, Phe5, and Phe8 in BK with D-Trp gives analogues with a relative affinity lower than 1.0% as compared with BK. These analogues have no antagonistic properties on the rabbit jugular vein and on guinea pig ileum (B2 receptors). Substitution of Pro7 in des-Arg9-BK by Gly and by D-Ala give compounds that antagonise the effects of kinins on the rabbit aorta strips (B1-receptor system). These new antagonists are fairly potent with a pA2 value of 6.03 to 7.29 and seem competitive because the pA2--pA10 values approximate 0.95. These results suggest that the orientation of Phe8 is critical for the activation of B1 receptors by kinins.

Animals↗
PubMed1984

Substance P--structure-activity studies and the development of antagonists.

Various attempts to developing antagonists for substance P (SP) and related peptides, based on our past experience with angiotensin, kinins, and neurotensin, were unsuccessful. The particular features of SP, namely the high activity of C-terminal partial sequences in some pharmacological tests were used to develop one hexa and several octapeptide antagonists. Weak antagonists were obtained with a single modification, namely the replacement of Leu10 with trp in the sequences SP (6-11), SP (4-11) and SP (1-11). The affinity of octa and undecapeptide antagonists could be increased by using two (in positions 7 and 9 or 7 and 10) or 3 (in position 7, 9 and 10) substitutions of the natural residues with trp. Affinity of antagonists was further increased by replacing Met11 with either Nle or Phe. These new compounds showed some selectivity, [pro4, trp7 ,9, Nle11 ]-SP (4-11) being more potent in the rabbit mesenteric vein than all other octapeptides described in the present study; on the other hand, [pro4, trp7 ,9,10,Phe11]-SP (4-11) was found to be the most potent antagonist of SP and related peptides in the guinea pig ileum and the guinea pig trachea. Both compounds were similarly active in the dog carotid artery. Undecapeptide antagonists, bearing the same structural modifications as the octapeptides, were found to be stimulant in the guinea pig trachea and relaxant in the dog carotid artery. The agonistic property was eliminated by repeated applications of the compounds in guinea pig tracheae, and therefore the compounds could be tested as antagonists. The undecapeptides were found to be much more active antagonists against kasinin and eledoisin than against SP and physalaemin. The data obtained with the octa and undecapeptide antagonists of SP have been used for identification and characterization of SP receptors in various smooth muscles. It appears that SP and related peptides may exert their numerous pharmacological effects by activating more than one receptor type.

Animals↗
PubMed1983

Effects of bradykinin and some of its fragments on smooth muscles and chemotaxis.

Bradykinin (BK) and two of its C-terminal fragments, namely H-Phe-Ser-Pro-Phe-Arg-OH and H-Ser-Pro-Phe-Arg-OH were found to be potent inhibitors of the chemotaxis of rat polymorphonuclear neutrophils (PMN). The activity of the three peptides was significantly enhanced by SQ 14225, a rather specific inhibitor of kininase II. A shorter C-terminal sequence of BK (Phe-Arg-OH) was inactive. The whole peptide (BK) exerted potent actions on blood pressure and on isolated organs, e.g. the rabbit mesenteric vein or the guinea pig ileum, but none of its fragments showed similar effects. The present findings suggest that rat PMN possess membrane receptors which cannot be considered identical to B1- and B2-receptors, previously characterized on isolated smooth muscles.

Animals↗
PubMed1982

Substance P antagonists active in vitro and in vivo.

[Pro4, Trp7,9]SP-(4-11) and a newly developed compound, [Pro4, Trp7,9,10]SP-(4-11) were shown to be potent antagonists of substance P (SP). They inhibited the hypotensive effect of SP in the anesthetised rats, the vasodilator effect in the rabbit perfused heart and the relaxation induced by SP in dog carotid arteries contracted with noradrenaline. Stimulatory actions of SP in the guinea pig ileum and the guinea pig trachea were also inhibited by the two antagonists, which were shown to be specific for substance P and related peptides in all the pharmacological preparations utilised in the present study.

Animals↗
PubMed1982

Kininases and vascular responses to kinins.

We have utilized several inhibitors to assess the effects of kininases on the contractile activity of bradykinin (BK), kallidin (KD), des-Arg9-BK and des-Arg10-KD on two isolated blood vessels, the rabbit aorta and mesenteric vein. The response of the two vessels to kinins are mediated by B1-receptors, implying that fragments of kinins without the C-terminal arginine are much more active on these tissues than the whole kinin sequences. Blockers of carboxypeptidase B-like enzymes, such as SQ24798 and pivalyl-L-arginine decrease the apparent affinity of BK and KD on the two vessels, while not changing those of des-Arg9-BK and des-Arg10-KD; this suggests that a major part of the contractile activities of BK and KD are mediated by des-Arg metabolites formed in situ at the tissue level by a kininase I. The block of kininase II by captopril or desacetylated MK-421 bring about a complex pattern of activity changes that include the potentiation of BK and KD and the depression of des-Arg10-KD. These results, in conjunction with those obtained with the non-specific inhibitors of metallopeptidases, thioglycolic acid and EDTA, suggest that the relative contribution of kininase I and kininase II to the degradation of kinins in arterial and venous vessels may be different. The implications of these findings on the pharmacology of B1-receptors are discussed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1982

Synthesis of peptides by the solid-phase method. 7. Substance P and analogues.

Substance P and 21 related peptides containing isosteric or isofunctional groups were prepared by the solid-phase method. After purification by gel filtration and ion-exchange chromatography, the compounds were characterized by thin-layer chromatography, paper electrophoresis, and amino acid and elemental analysis. The biological activities of the peptides were evaluated in vitro on the guinea pig ileum, the rabbit mesenteric vein, and the dog common carotid artery and in vivo on the rat blood pressure. It is shown that the replacement of some residues in the undecapeptide substance P causes variable losses of apparent affinity with a little or no change in the intrinsic activity. All the analogues used in the present study were found to be inactive as antagonists.

Animals↗
PubMed1982

Synthesis and biological activities of photoaffinity labeling analogues of substance P.

Substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-MetNH2, SP) is an undecapeptide with important properties as a neurotransmitter and with other functions. No specific antagonists and no long-acting analogues of this peptide hormone are known to date. In order to reach these goals, analogues of SP have been prepared which contain potential affinity, as well as photoaffinity labeling functions, suitable for irreversible attachment to SP receptors. We report here the synthesis of SP analogues which have the Phe residues in positions 7 or 8 replaced with (4'-NO2)Phe, (4'-NH2)Phe, (4'-N2+)Phe, and (4'-N3)Phe. Some of these peptides are used for photoaffinity labeling studies using various bioassays. The synthesis of the (NO2)Phe-containing peptide was carried out on solid phase using Nle instead of Met and the Boc strategy up to residue 4; the remaining amino acids were added using an Fmoc strategy. The protected undecapetide was cleaved by ammonolysis, purified by chromatography on silica gel with chloroform/methanol and deprotected afterwards. The amino, diazonium, and azido peptides were obtained in this sequence by chemical modification of the nitro peptides. On guinea pig ileum the modified peptides in position 8 had close to maximal activity, whereas modifications in position 7 produced some reduced activity, especially the nitro modification. No diazonium peptide produced any irreversible effects on guinea pig ileum. Photoinactivation studies were carried out on strips of guniea pig trachea, but no irreversible effects have been observed, neither permanent stimulation nor permanent inactivation. The biological activities and effects are discussed in view of the molecular properties of the synthesized analogues.

Affinity Labels↗