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D Regoli

Publications and source records attributed to D Regoli.

At least 19 recordsLinked to original sources
PubMed1979

Studies on the inhibitory action of somatostatin in the electrically stimulated rat vas deferens.

Somatostatin (SS) inhibits in a dose-dependent manner electrically evoked contractions in the rat vas deferens. This action was not modified by yohimbine, naloxone or a mixture of antagonists containing atropine, phentolamine, methysergide, burimamide, propranolol and indomethacin, but was markedly potentiated by reducing the Ca2+ concentration of the medium from 2.5 to 1.25 mM and greatly inhibited when increasing the Ca2+ concentration of the medium from 2.5 to 5.0 mM. Clonidine (CLO), but not beta-endorphin (ENDO) was affected similarly to SS by changing the Ca2+ concentration of the medium. The contractile effect of norepinephrine in unstimulated rat vas deferens was not altered by SS. These results were taken as an indication that SS produces its inhibitory action in the rat vas deferens by interacting with specific SS and its receptors presumably located in the cell membranes of adrenergic nerve terminals. The interaction between SS and its receptors may provoke a decreased diffusion of Ca2+ ions into the nerve terminals and/or a decreased mobilisation of Ca2+ ions from intraneuronal stores thus leading to a reduction in electrically evoked release of norepinephrine.

Animals↗
PubMed1979

Conformational features of bradykinin. A circular dichroism study of some peptide fragments and structural analogues of bradykinin.

The vasoactive hormone bradykinin, its N-and C-terminal fragments and some structural analogues were studied by Circular Dichroism. Conformational features of the peptide can be detected by comparative analysis of the various CD spectra recorded as a function of aqueous pH, solvent and temperature. It is shown that the two biologically essential arginine residues (Arg1 and Arg9) are important for the specific folded bradykinin conformation. Differences between bradykinin, its fragments and analogues become clearly established in conformational terms, and are discussed in relation to the biological activity of these peptides.

Bradykinin↗
PubMed1979

An analysis of the negative inotropic action of somatostatin.

1 Somatostatin (SS) was evaluated as a chronotropic and inotropic agent in isolated spontaneously beating auricles of rats, rabbits and guinea-pigs.2 SS was completely inactive in rat and rabbit auricles but exerted a dose-dependent, negative inotropic effect in guinea-pig auricles in concentrations between 1.5 x 10(-8) to 1.2 x 10(-6) M.3 The negative inotropic effect of SS (6.0 x 10(-8) and 3.0 x 10(-7) M) was not inhibited by a mixture of antagonists containing practolol (7.9 x 10(-6) M), phentolamine (3.5 x 10(-7) M), methysergide (2.8 x 10(-7) M), diphenhydramine (3.9 x 10(-5) M), cimetidine (4.0 x 10(-5) M) atropine (3.4 x 10(-7) M) and indomethacin (1.4 x 10(-5) M).4 The negative inotropic effect of SS was greatly potentiated by reduction in the Ca(2+) concentration of the medium from 5.0 to 1.25 mM.5 On a molar basis, SS was equipotent with acetylcholine (ACh) as a negative inotropic agent in the guinea-pig auricles.6 SS (6.0 x 10(-8) and 6.0 x 10(-7) M) was found to inhibit selectively the positive inotropic action of neurotensin (NT) in guinea-pig but not in rat auricles.7 The inhibitory action of SS against NT was independent of its negative inotropic action.8 These results suggest that SS produces its negative inotropic action by interacting with specific receptors presumably located in the cell membrane of guinea-pig atria. The interaction between SS and its receptor may cause a decreased Ca(2+) diffusion and/or transport into the atrial cells. The physiological and pharmacological significance of these results is discussed.

Acetylcholine↗
PubMed1979

Immunological and biological activities of fragments and analogs of bradykinin.

Using a number of analogs and fragments of a short-chain peptide bradykinin, a series of experiments have been carried out to assess the effect of modifications to the basic structure of the parent molecule on its myotropic and immunoreactive properties. Binding kinetics of both an antibody raised against the authentic nonapeptide and its specific biological receptor found in the guinea pig ileum were used to study these alteration effects. Peptide derivatives of bradykinin with an extension at the N-terminal (Lys- and Met-Lys-bradykinin) cross-react with the antibody raised to bradykinin 59 and 70% respectively. On the other hand, internal fragments with intact C-termini (2-9 and 3-9 bradykinin) react with this same antibody to an extent of 250 and 875% respectively, indicating that they are more potent antigens than the vasopressor molecule itself. Other internal fragments, as well as 9-substituted analogs effectively and not interact. These results indicated that the C terminal arginine of bradykinin is indeed essential in the binding mechanism with its antibody. This in turn illustrates the role of the carrier ovalbumin in the development of antiserum to the ovalbumin-toluene-diisocyanate-bradykinin complex. The physiological experiments with the guinea pig bioassay preparations lead to similar conclusions. Most internal fragments of bradykinin are devoid of activity, whereas N-terminal fragments (2-9, 3-9, and 5-9 bradykinin) have retained some activity again indicating a need for an intact arginine residue at the C-terminus of the molecule. Any modification in position 9 results in severe impairment of biological activity. Thus, the C-terminal residue of bradykinin must be conserved in order that the molecule may retain its immunological and physiological activities. Any extensions, deletions, or modifications of this site will severely retard these functions.

Amino Acid Sequence↗
PubMed1979

Synthesis of peptides by the solid-phase method. IV. Des-Arg(9)-bradykinin and analogs.

We have synthesized a series of 19 analogs of the octapeptide fragment of bradykinin (BK), des-Arg 9-bradykinin, in order to perform a structure-activity study of this peptide on the newly discovered B1 receptor of bradykinin. The first time, each residue of the octapeptide was replaced by L-alanine to pinpoint biologically important residues. Thereafter, both phenylalanine residues in positions 5 and 8 were substituted by L-tyrosine methyl ether, L-cyclohexylalanine, D-phenylalanine, and L-leucine. This paper describes the synthesis of the analogs by the solid phase method. A Beckman peptide synthesizer was used to assemble the peptides on the resin support. Couplings were performed by the symmetrical anhydribe procedure. After cleavage with liquid HF, the peptides were purified by ion-exchange chromatography on carboxymethyl-cellulose and by gel filtration on Bio-Gel P2 resin. The purity of the octapeptides was then checked by tic, paper electrophoresis, amino acid analysis, and elemental analysis. The new peptides were tested on the rabbit aorta in order to evaluate their kinin-like activities and to see if they act as antagonist. The results of the biological assays are discussed in terms of structure-activity relationships.

Amino Acids↗
PubMed1979

Cardiovascular actions of kinins in the rabbit.

The hypotensive action of bradykinin (BK) and congeners was measured in anesthetized rabbits by administering the peptides intravenously and intraarterially in order to evaluate their pulmonary inactivation. A systematic study of the distribution of receptors for BK in the cardiovascular system of the rabbit was approached: (a) by measuring the myotropic effects of several peptides related to BK in strips of large arteries and veins; (b) by recording the changes of tension and rate of isolated atria; and (c) by evaluating the changes of perfusion pressure in isolated hearts, kidneys, and ears. This investigation was extended to strips of aortae of various mammals and to isolated atria of guinea pigs, for comparison. Receptors for BK were classified into two main types, B1 and B2, using the order of potency of these agonists [Tyr(Me)8]-BK, BK, and [des-Arg9]-BK, and an antagonist, specific and competitive for the B1 receptors, the octapeptide [Leu-OMe8,des-Arg9]-BK. The results obtained in this study indicate that the complex cardiovascular effect of BK in vivo may result from direct actions on vascular smooth muscles, presumably mediated by at least two types of receptors, as well as from the release of endogenous prostaglandins. BK and congeners exert a direct action on vascular smooth muscle by stimulating specific receptors both of the B1 type (in the aorta, the large arteries, and the mesenteric vein) and of the B2 type (in the jugular vein); and these vascular tissues provide useful preparations for pharmacological studies of bradykinins. Isolated organs perfused through their main arteries with physiological medium respond to BK by an increase of perfusion pressure (vasoconstriction in isolated ears and kidneys) or by a decrease (vasodilation in the rabbit heart). The vascular effects of BK in the heart and the kidney depend in part on the release of endogenous prostaglandins and on the activation of receptors that appear to be of the B2 type. Like other endogenous hypotensive agents, BK appears to reduce the tonus of the peripheral vessels, while contracting large arteries and veins. The results obtained in vitro are discussed with respect to the hypotensive effect in vivo and to the role of kinins in inflammation and oedema.

Animals↗
PubMed1979

Receptors for angiotensin: a critical analysis.

Angiotensin exerts numerous contractile and secretory effects by activating specific receptors. Recent pharmacological findings obtained with this peptide in various laboratories are analyzed, using the order of potency of agonists and the affinity of competitive antagonists as criteria for the classification of receptors for angiotensin in several systems. The analysis is restricted to experiments in which biological effects have been measured. Desensitization (the third criterion for classification of receptors) is discussed and a new protocol is proposed for its utilization. The analysis reveals that receptors for angiotensin in intestinal and vascular smooth muscles, in the heart, and in the vas deferens are all of the same type, while the receptors mediating the release of catecholamines from the adrenal medulla and those subserving the steroidogenic action on the adrenal cortex remain still unidentified. The recently proposed role of ATI as mediator of renin in the adrenal medulla is not substantiated by pharmacological findings with decapeptide antagonists. Moreover, the utilization of ATI as an agonist to determine the order of potency of angiotensins and the use of SQ 20881 as an inhibitor of the converting enzyme have shown serious limitations and should be reconsidered. The hypothetical role of ATIII as mediator of the renin-angiotensin system in the adrenal cortex, at least in other species than the rat, appears to be supported by the high affinity of heptapeptide antagonists for the adrenocortical receptor. However, these antagonists have generally been compared with [Sar1,Ala8]-ATII, A compound which is definitely inadequate for evaluating the affinities of octapeptides in the adrenal cortex. Therefore most of the data supporting the role of ATIII in this system have to be carefully reconsidered. Analogues of ATII are proposed for using as agonists and as antagonists instead of the natural angiotensins (for determining the order of potency of agonists) and instead of [Sar1,Ala8]-ATII (for measuring the affinities of competitive antagonists).

Animals↗
PubMed1979

Receptors for bradykinin and kallidin.

In order to establish if bradykinin (BK) and Lys-bradykinin (Lys-BK), alias kallidin, act on the same or on different receptors, experiments were performed on strips of cat terminal ileum and of rabbit aorta. The first preparation contains receptor B2 and the second has the newly identified receptor B1. The criterion used for establishing the identity of receptors for BK and Lys-BK in the cat ileum (receptor B2) was desensitization, while for the rabbit aorta (receptor B1) we measured the apparent affinity (pA2 value) of a competitive and specific inhibitor of BK, [Leu-OMe3,des-Arg9]-BK. Since cat ileum desensitized with BK or Lys-BK shows a significant decrease or a complete disappearance of the response to the other agent, while maintaining full sensitivity for histamine, and since the pA2 values of [Leu-OMe8,des-Arg9]-BK against BK and Lys-BK are identical in the rabbit aorta, we conclude that the two kinins act on the same types of receptors.

Animals↗
PubMed1979

Structure-activity studies of [des-Arg9]-bradykinin on the B1 receptor of the rabbit aorta.

Eight L-alanine analogues of [des-Arg9]-bradykinin and a few other compounds substituted in positions 5 and (or) 8 have been tested on rabbit aortic strips in order to identify the group(s) responsible for binding and (or) stimulation of the B1 receptor. The results obtained with the L-Ala series have shown that the active group is located at the C-terminal end and it is probably Phe8, while the middle part and the N-terminal end of the peptide molecule are primarily involved in binding the agonist to the receptor. An aromatic ring is required in position 8 for activation of receptors, since the elimination or aromaticity (as in [Leu8,des-Arg9]-bradykinin and in [cyclohexylalanine8,des-Arg9]-bradykinin) brings about pure and competitive antagonists. Some compounds exert an angiotensin-like effect when applied at very high concentrations.

Alanine↗
PubMed1979

Biological activities of kinins modified at the N- or at the C-terminal end.

A series of analogues of des-Arg9-bradykinin, modified at the N- or C-terminal end, were tested on rabbit aorta strips (receptor B1) and on cat ileum strips (receptor B2) in an attempt to find long-acting agonists and antagonists. It was found that the methylation or the amidation of the C-terminal carboxyl reduces the affinity and (only the amidation) the intrinsic activity of the agonists, while not changing significantly the duration of action of both agonists and antagonists. The addition of a Lys at the N terminal is accompanied by a marked increase of affinity, no changes of intrinsic activity, and a prolongation of the duration of action of agonists. Antagonists behave in a similar way as the agonists and show increased affinity; the time required for inducing full inhibition as well as the duration of action are significantly increased. The pharmacological and physiopathological implications of these results are discussed.

Amides↗
PubMed1978

A new bioassay for glucagon.

1 The relaxant action of glucagon has been studied in strips of rabbit renal arteries partially contracted by a low concentration (1 ng/ml) of noradrenaline.2 The preparation was relaxed in a dose-dependent manner by concentrations of glucagon varying between 25 ng/ml and 420 ng/ml.3 The relaxant effect of glucagon (0.1 mug/ml approximately ED(60)) on this preparation was not affected by propranolol (5.0 mug/ml), cimetidine (10 mug/ml), diphenhydramine (10 mug/ml), indomethacin (5.0 mug/ml), phentolamine (1.2 mug/ml), atropine (10 mug/ml) and 8-Leu-AT(II) (1.0 mug/ml) but was slightly potentiated by Des-Arg(9) Leu-OMe(8)-Bk (25 mug/ml) and indomethacin (50 mug/ml).4 The dose-response curve to glucagon remained parallel in the presence of papaverine (2.5 mug/ml) but was shifted to the left by a factor of 2.5 to 2.8. Theophylline (250 mug/ml) also potentiated the vascular relaxation induced by glucagon.5 Insulin (10 mug/ml) did not influence the relaxant effect of glucagon.6 The removal of the N-terminal amino acid (His) of glucagon reduced by 89% the biological activity of this fragment on the vascular preparation. The removal of the C-terminal amino acids Met-27, Asn-28 and Thr-29 of glucagon resulted in a fragment which was inactive either as an agonist or as an antagonist when tested at concentrations as high as 925 ng/ml.7 It is concluded that the relaxation of partially contracted strips of rabbit renal arteries by glucagon constitutes a simple, sensitive, relatively specific and reliable bioassay which may be useful for the determination of glucagon in biological materials and for structure-activity relationship studies with this hormone.

Animals↗
PubMed1978

Rat vas deferens: a specific bioassay for endogenous opioid peptides.

The electrically-evoked contractions of the rat vas deferens were selectively inhibited by beta-endorphin, the preparation being much less sensitive to enkephalins and narcotic analgesic drugs. However, introduction of D-Ala in position 2 of [Leu]-enkephalin enhanced the activity of the opioid peptide to the order of that of beta-endorphin. It is concluded that the rat vas deferens preparation constitutes a specific bioassay for endogenous opioid peptides and related compounds.

Animals↗
PubMed1978

Synthesis of peptides by the solid-phase method. III. Bradykinin: fragments and analogs.

The natural sequence of bradykinin (BK) and 55 fragments or analogs of this peptide were perpared via the solid-phase method. The peptides were purified using ion-exchange (O-carboxymethyl(CM) and partition (Sephadex G-25) chromatography. The purity of each peptide was established by paper and thin-layer chromatography, paper electrophoresis, amino acid analysis, and biological assays. The compounds were tested in anesthetized rats (tested in vivo) and in two smooth-muscle preparations (rabbit aorta strip, cat ileum strip) in which BK produces contraction by stimulating specific receptors of different types. Some of the new peptides are interesting in that they either resist pulmonary inactivation, or are more potent than BK itself, or antagonize the myotropic effect of BK in rabbit aorta strips.

Animals↗