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D Regoli

Publications and source records attributed to D Regoli.

426 records · Page 24Linked to original sources
PubMedDate not supplied

Characterization of pre- and postjunctional receptors for neurokinins and kinins in the rat vas deferens.

Neurokinins and kinins are potent stimulants of the rat vas deferens: they increase both the twitch response to electrical stimulation by facilitating transmitter release and the basal tone of the preparation by activating smooth muscle receptors. The two sites of action have been studied separately in the present experiments by using the prostatic for the prejunction site and the epididymal section of the vas deferens for the postjunction site. Receptors for neurokinins, characterized by the order of potency of agonists, appear to be of the NK-A type both at the pre- and postjunction level. Receptors for kinins are present also at both sites and are probably of the B2 type: they have been characterized by the use of agonists and, the B2 postjunction type has been convalidated with antagonists. These compounds could not be used for the prejunction receptor characterization, because they act as agonists. Receptor for angiotensin at the prejunction level are of the same type as in the cardiovascular and other systems.

Animals↗
PubMedDate not supplied

Substance P and neurokinins as stimulants of the human isolated urinary bladder.

Neurokinins are active stimulants of the human isolated urinary bladder. In a preliminary study, performed on bladders taken from four donors, we attempted the characterization of neurokinin receptors. It was shown that neurokinin A is more active than neurokinin B and substance P. Neurokinin receptors selective agonists were also tested and it was found that the most active compound was the NK-A selective agonist, [Nle10]NKA 4-10: A substance P antagonist was able to reduce the effect of neurokinin A but its affinity was rather low. This suggests that the receptor mediating the contraction of the human urinary bladder to neurokinins is of the NK-A (NK2) type. The action of neurokinins on the human urinary bladder appears to be a direct one and mediated by specific receptors different from those of other agents. On the contrary, kinins were found to be active through a new mechanism which was not influenced by either anti-B1 or anti-B2 receptor antagonists.

Adult↗
PubMedDate not supplied

Comparison of binding assay and biological activity on a NK-1 system with new selective agonists.

Binding sites for the [125I]Bolton-Hunter labeled substance P (BH.SP) were studied in homogenates of rat brain. Binding at 4 degrees C was much lower than at 25 degree C or 37 degrees C, but degradation of the peptide was very important at 37 degrees C. A mixture of peptidases inhibitors (bacitracin 4 x 10(-5) M), chymostatin (2 x 10(-6) M), leupeptin (4 x 10(-6) M), phosphoramidon (4 x 10(-6) M) was needed to stabilize the binding conditions, which were established as follows: BH.SP 40 pM, membrane preparation 1.25 mg/ml, incubation 20 min, temperature 25 degrees C and pH 7.4, in the presence of peptidase inhibitors. Binding occurred rapidly and was maximum at 20 min: it increased linearly with the amount of membranes added. It was saturable and readily reversible. Kd and receptor concentration were respectively 0.4 +/- 0.2 nM and 17 +/- 1 fmol/mg protein. Kd value measured in kinetic studies (0.2 nM) was similar to the one measured by saturation experiments (0.6 nM). Several analogues, homologues or fragments of SP were shown to inhibit BH.SP binding: their relative affinities were compatible with an interaction on a binding site of the type NK-1. This was confirmed with new selective agonists. [Sar9,Met(O2)11]SP, the NK-1 selective ligand was very potent, while [Nle10]NKA (4-10) (NK-2 selective) and [MePhe7]NKB (NK-3 selective) were nearly inactive. The present results confirm the findings of other similar studies and stress the importance of using (a) peptidase inhibitors for obtaining stable binding conditions and (b) selective agonists for characterizing NK-1 receptor sites in rat brain.

Animals↗
PubMedDate not supplied

Structure-activity studies of neurokinin A.

A structure-activity study on neurokinin A and its C-terminal fragment NKA (4-10) has been performed in order to find selective agonists for the NK-2 receptor and identify chemical modifications suitable for protecting the peptides from degradation, while maintaining activity. Five series of compounds have been prepared and tested: 1. the complete series of the L-Ala monosubstituted analogues of NKA; 2. a series of NKA fragments from the C- or N-terminal; 3. the complete series of NKA (4-10) analogues monosubstituted with beta-Ala; 4. a series of NKA (4-10) analogues with monosubstitutions in pos. 4, 8, 10 or multisubstitutions in two or more of the same positions; and 5. a series of 6 NKA (4-10) analogues monosubstituted with 1-amino,1-cyclohexane carboxylic acid residue. It has been found that the most selective agonists for the NK-2 receptor system are [beta Ala8]NKA (4-10) and [Nle10]NKA (4-10). Protection from aminopeptidase may be obtained by acetylation of the N-terminal amide of NKA (4-10), while partial protection from endopeptidases should be expected from the presence of beta-Ala in position 8. Conformational constraints induced with 1,amino,1-cyclohexane carboxylic acid residue gave weakly active compounds. Multiple substitutions reduce rather than potentiating the favorable effects of the corresponding monosubstituted compounds.

Animals↗
PubMedDate not supplied

The actions of neurokinins and substance P in canine pylorus, antrum and duodenum.

Analogues highly selective for receptors for substance P [beta-Ala4,Sar9,Met(02)11]-SP(4-11), for neurokinin A, [Nle10]-NKA(4-10), and for neurokinin B, [beta-Asp4,MePhe7]-NKB(4-10), were administered intraarterially before and after atropine or tetrodotoxin, to characterize the locations on nerve and muscle of the different receptor subtypes in the canine antrum, pylorus and duodenum. Circular muscle strips from each region were also studied in vitro. The NK-2 receptors in the antrum and the pylorus were located postsynaptically on smooth muscle. The NK-3 receptors, on the other hand, were located on neuronal sites in the antrum and duodenum. NK-1 receptors were located on neuronal and nonneuronal sites in the antrum, pylorus and duodenum. Only nonneural receptors could be activated in vitro.

Animals↗
PubMedDate not supplied

Structure-activity studies of bradykinin analogues on rat mast cell histamine release.

Bradykinin (BK), kallidin (KD), and various analogues induced histamine release from rat mast cells. The results obtained with substituted analogues of BK indicated that: 1) the presence of both Arg residues at position 1 and 9 of kinins was favorable to confer histamine-releasing activity, 2) acetylation of the N-terminal amino acid residue led to a drastic reduction of this activity, 3) addition of a D-Arg residue at the N-terminus reduced their activity, as well as trans-4-hydroxyproline (Hyp) substitutions at position 2 or 3,4) D-Arg0 addition and Hyp3 substitution were synergistic in lowering activity, and 5) D-Phe7 substitution led to enhanced histamine-releasing activity.

Amino Acid Sequence↗
PubMedDate not supplied

Neurokinin A. A pharmacological study.

Discovered in 1983, the decapeptide neurokinin A has been shown to occur in several peripheral organs and to exert a variety of biological effects. In this article, we review the most sensitive and selective in vivo and in vitro tests which have been used in various laboratories to evaluate naturally occurring or synthetic neurokinin A. A comparison of the effects of neurokinin A and those of its mammalian homologues, substance P and neurokinin B as well as those of tachykinins and related peptides is presented in the frame of a study directed toward characterization of neurokinin receptors. Indeed, neurokinin A has been shown to be particularly active on a neurokinin receptor subtype, the NK-2. Structure-activity studies performed with neurokinin A and its fragments as well as with several analogues of both the decapeptide and the heptapeptide NKA(4-10) have brought to the identification of the minimum structure required for activation of NK-2 receptors. Selective agonists for this receptor have been identified, in particular [Nle10]-NKA(4-10) and [beta-Ala8]-NKA(4-10).

Animals↗
PubMedDate not supplied

Structure-activity studies on nociceptin/orphanin FQ: from full agonist, to partial agonist, to pure antagonist.

A heptadecapeptide (Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln) was identified from rat brain and from porcine brain as a ligand for OP4, a new G-protein coupled receptor that is similar in sequence to opioid receptors. The OP4 receptor is widely expressed in the nervous system where it mediates a broad range of physiological functions. The new peptide, nociceptin (NC), has a primary sequence recalling that of opioid peptides. Despite the homologies (a) of the OP4 receptor with known opioid receptors, especially the OP2 (kappa) receptor, and (b) of NC with opioid peptides, particularly dynorphin A, the two biological systems have different anatomical locations and chemical requirements for activation. NC does not bind to opioid receptors, and mammalian opioid peptides do not interact with the OP4 receptor. The presence of Phe in position 1 and Arg in position 8, appear to be instrumental to exclude NC from interacting with the opioid receptors. Contrary to opioid peptides which strikly require Tyr in position 1, the active core that activates the OP4 appears to be towards the centre of the peptide molecule and includes Phe4. Based on the message/address model, several changes have been made in the N-terminal tetrapeptide Phe-Gly-Gly-Phe (message) and a few also in the C-terminal of the template NC(1-13)-NH2, a fragment that acts as a full agonist both in vitro and in vivo. Subtle changes of the N-terminal sequence, especially at Phe1, led to the discovery of peptide antagonists ([Phe1 psi (CH2-NH)Gly2[-NC(1-13)-NH2 and [Nphe1[-NC(1-13)-NH2). The first compound has been widely used to characterize NC actions in the periphery and in the central nervous system. It has been shown to act mainly as an antagonist outside the brain and as an agonist in the central nervous system. [Nphe1[-NC(1-13)-NH2- on the contrary, acts as antagonist both in the periphery and in the brain. These first peptide prototypes may soon be followed by non-peptide compounds, some of which, are already described in patient literature.

Amino Acid Sequence↗
PubMedDate not supplied

Plasma extravasation induced by neurokinins in conscious rats: receptor characterization with agonists and antagonists.

The purpose of the present experiments was to study the effects of various neurokinin related peptides, such as substance P, [beta Ala8]NKA(4-10), and [MePhe7]NKB, which are selective for NK-1, NK-2, and NK-3 functional sites, respectively, to induce plasma extravasation in rats and the effectiveness of RP 67580 and CP-96,345 (two nonpeptide NK-1 receptor selective antagonists) and SR 48968 (a nonpeptide NK-2 receptor selective antagonist) to prevent such an effect. Bolus intravenous injection of substance P (1.0 nmol/kg) into conscious rats induced extravasation of Evans blue dye (EB), a selective marker of albumin vascular permeability, in the duodenum, the stomach, the pancreas, and the urinary bladder by 50, 40, 58, and 312%, respectively; a slight increment occurred also in the ileum and the kidney but was not significant. [beta Ala8]NKA(4-10) (1.0 nmol/kg) increased EB extravasation in the stomach and the urinary bladder by 52 and 99%, respectively, while [MePhe7]NKB (1.0 nmol/kg) did the same in the stomach, the ileum, and the urinary bladder by 58, 50, and 79%. Pretreatment with RP 67580 (250 nmol/kg) blocked the albumin extravasation mediated by substance P in the duodenum, the pancreas, and the urinary bladder by 100, 100, and 78%, respectively. CP-96,345 (250 nmol/kg) also inhibited EB extravasation mediated by substance P in the duodenum and the pancreas by 100 and 100%, respectively, but was ineffective in the urinary bladder. Neither RP 67580 nor CP-96,345 prevented the substance P mediated extravasation in the stomach. RP 67580 and CP-96,345 did not antagonize the effects of NK-2 and NK-3 selective agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMedDate not supplied

Vascular reactivity to angiotensin and noradrenaline following nephrectomy in rats.

Angiotensin II (AT II), but not noradrenaline (NA) provoked greater pressor effects in anaesthetized rats which have been bilaterally nephrectomized for 24-48 h than in control animals which underwent the same surgical procedure 2-3 h previously. Perfused hindquarters and isolated portal veins derived from bilaterally nephrectomized rats did not exhibit supersensitivity to AT II or NA. Aorta strips removed from rats nephrectomized 48 h before showed a selective decrease of sensitivity to AT II. The results of these in vitro assays suggest that the well known increased pressor effect to AT II, observed in nephrectomized rats cannot be accounted for by an increased sensitivity or large arterial and venous vessels or of the femoral vascular bed.

Angiotensin II↗
PubMedDate not supplied

[Kinin B1 and B2 receptor antagonists and therapeutic perspectives].

Physiological and pathological effects of kinins result from the activation of specific receptors which are present in various organs. Kinin receptors have been characterized through studies on isolated organs in vitro and have been classified as B1 and B2. A careful analysis of B2 receptors led to the identification of two subtypes, namely B2rb (in the rabbit) and B2gp (in the guinea-pig). The distinction between B2rb and B2gp receptors is primarily based on differences in the activities of selective agonists and particularly on differences in affinities of competitive antagonists, namely DArg[Hyp3,DPhe7,Leu8]BK and the non-peptide compound, WIN 64338. The non-competitive antagonist, HOE 140, has shown the same affinity on B2rb and B2gp. The potential role of B1 and B2 receptors in physiopathology is analysed on data obtained with specific and selective antagonists of the B1 (desArg9[Leu8]BK) and B2 (HOE140) receptors. The therapeutic potential of endogenous kinins as mediators of the therapeutic beneficial effects of the angiotensin-converting enzyme inhibitors or the potential of the use of exogenous kinins in the vascular permeability are discussed together with the therapeutic potential of B1 and B2 receptor antagonists.

Animals↗