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Biomedical subjects

J R Tippins

Publications and source records attributed to J R Tippins.

At least 37 records · Page 2Linked to original sources
PubMed1987

Platelet activating factor-mediated leukotriene biosynthesis in rat lungs: effect of prostaglandins E1 and F1 alpha.

The effect of prostaglandins E1 and F1 alpha on peptidoleukotriene biosynthesis/release from rat chopped lung stimulated with platelet activating factor was studied. Prostaglandin E1, known to stimulate adenylate cyclase in airways, inhibited the biosynthesis of leukotrienes C4, D4 and E4 and total peptidoleukotrienes whereas prostaglandin F1 alpha, which has no effect on adenylate cyclase, did not exert any effect on total peptidoleukotriene release, though a small inhibition was found for leukotriene D4. Cyclic AMP itself inhibited peptidoleukotriene release from platelet activating factor-stimulated lung, suggesting that the effect of prostaglandin E1 is mediated by cyclic AMP.

Alprostadil↗
PubMed1987

Neuropeptides and leukotriene release: effect of peptide histidine isoleucine and secretin in platelet activating factor-stimulated rat lung.

We have previously demonstrated that vasoactive intestinal peptide and calcitonin gene-related peptide inhibit leukotriene release from platelet activating factor-stimulated rat lung. We now report evidence that Peptide Histidine Isoleucine and Secretin, two naturally occurring peptides which are structurally homologous to vasoactive intestinal peptide, show a significant ability to inhibit leukotriene release in the same animal model. A preliminary hypothesis about the mechanism of this inhibition by the neuropeptides is discussed.

Animals↗
PubMed1987

Leukotriene release by endometrium and myometrium throughout the menstrual cycle in dysmenorrhoea and menorrhagia.

Endometrium and myometrium were collected at hysterectomy from 21 women with measured menstrual blood loss. Eight women complained of dysmenorrhea and the remaining 13 had pain-free periods. Specimens were obtained throughout the menstrual cycle (menstrual, n = 5; follicular, n = 4; early luteal, n = 3; mid-luteal, n = 5; late luteal, n = 4). Leukotriene C4, leukotriene D4 and leukotriene E4 release were examined using a short-term incubation technique. Endometrial leukotriene release, which was always significantly greater than myometrial release, changed throughout the menstrual cycle and the highest concentrations were found during menstruation. Endometrial, but not myometrial, leukotriene concentrations were significantly higher in tissues obtained from women with a complaint of dysmenorrhoea compared with those in tissue from pain-free women. No correlation was found between leukotriene release in either endometrium or myometrium and menstrual blood loss (range 15-457 ml).

Adult↗
PubMed1986

Investigation of the structure/activity relationship of human calcitonin gene-related peptide (CGRP).

The biological activities of calcitonin gene-related peptide (CGRP) enzymic digest fragments, chemically modified products and beta-CGRP have been compared to that of intact alpha-CGRP on rat isolated paired atria. Tryptic and chymotryptic digests both produced inactive fragments. Acetylation of the N-terminal amino acid (Alanine) or either of Lys 24 or Lys 35, resulted in reduced, but measurable, biological activity. Destruction of the disulphide bridge between Cys 2 and Cys 7 abolished biological activity. Substitution of several amino acids, Asp 3, Val 22 and Asn 25, with Asn, Met and Ser respectively (beta-CGRP), produced a peptide with similar biological activity to alpha-CGRP.

Amino Acids↗
PubMed1986

Potent vasodilator activity of calcitonin gene-related peptide in human skin.

We have recently shown that the novel neuropeptide calcitonin gene-related peptide, CGRP, is a potent vasodilator. In this paper we report a detailed study of the effects of CGRP in human skin. CGRP induces a clearly defined, long-lasting erythema. We have measured the effect of CGRP on blood flow in human skin using a laser Doppler technique and have demonstrated increased local blood flow that persists for a number of hours. We compared the response of CGRP with other known vasodilators [histamine, prostaglandin (PG) E2, PGI2, substance P, and vasoactive intestinal peptide (VIP)] in the skin, and in all subjects the erythema induced by CGRP was more persistent than that induced by the other mediators tested. Except at high doses the local vasodilatation induced by CGRP was not associated with a wheal and flare as seen with histamine, substance P, and VIP. CGRP is an extremely potent vasodilator and if released into the circulation, or locally from peripheral nerve endings, it could have a role in the regulation of blood flow in both physiologic and pathologic conditions; CGRP may be the endogenous mediator of the flare in the triple response. A deficiency in CGRP secretion or action could be an important component of peripheral vascular disease. Some flushing reactions (e.g., those associated with medullary thyroid carcinoma) may result from circulating CGRP.

Adult↗
PubMed1986

The effect of vasoactive intestinal peptide and calcitonin gene-related peptide on peptidoleukotriene release from platelet activating factor stimulated rat lungs and ionophore stimulated guinea pig lungs.

The effect of four neuropeptides and acetylcholine on the release of leukotrienes LTC4, LTD4 and LTE4 from platelet activating factor-stimulated rat lung and ionophore A23187-stimulated guinea pig lung, as detected by the combined use of HPLC and radioimmunoassay, was studied. Both vasoactive intestinal peptide and calcitonin gene-related peptide were found to inhibit the release of leukotrienes in both preparations. This effect was most marked in platelet activating factor-stimulated rat lung, where inhibition of LTC4 release was more pronounced than either inhibition of LTD4 or LTE4 production. The effect of vasoactive intestinal peptide on LTC4 biosynthesis was dose-related in rat lung. Neither substance P nor beta-endorphin were found to inhibit leukotriene release in rat lung. Vasoactive intestinal peptide inhibition of leukotriene release is independent from its actions on the muscarinic receptor, since acetylcholine was found to have no effect in the same preparation.

Acetylcholine↗
PubMed1986

CGRP: a novel neuropeptide from the calcitonin gene is the most potent vasodilator known.

The calcitonin gene has been shown to give rise to another peptide, calcitonin gene-related peptide (CGRP). The structure of human CGRP has been determined by mass spectrometry. Calcitonin gene-related peptide-containing neurons have been detected in a number of species, particularly in association with heart and blood vessels. Pharmacological studies have shown that CGRP is a potent vasodilator in a number of vessels and vascular beds, including the skin and coronary circulation. Investigations in humans have also reported the potent vasodilator action of CGRP. The evidence from these studies suggests that CGRP is an important regulator of vascular tone and blood flow.

Animals↗
PubMed1984

Leukotriene biosynthesis and metabolism detected by the combined use of HPLC and radioimmunoassay.

A radioimmunoassay for leukotriene D4 (LTD4) has been developed which exhibits sufficiently high sensitivity to be useful in conjunction with RP-HPLC in the detection of LTC4, LTD4 and LTE4 in physiological samples. The detection limit of the assay was approximately 240 amoles, using antiserum TG1 at a dilution of 6 X 10(3), with 50% displacement at 70 fmoles. Antiserum NW1, also at a dilution of 6 X 10(3), displayed a detection limit of 9 fmoles with 50% displacement at 100 fmoles. The two antisera have similiar crossreactivities, both manifesting useful affinities for LTE4 and LTC4, and low or negligible affinities for other arachidonic acid metabolites, or their derivatives. The radioimmunoassay was used to detect 1) LTC4, LTD4 and LTE4 released from perfused rat lung in response to platelet-activating factor (PAF) stimulation, 2) conversion of exogenous LTD4 to LTE4 in human blood, and 3) endogenous leukotrienes in human blood samples.

Animals↗
PubMed1984

The myotropic and plasma-calcium modulating effects of calcitonin gene-related peptide (CGRP).

Human and rat calcitonin gene-related peptides cause a dose-related contraction of guinea pig ileum, which is antagonised by an anti-histamine, mepyramine, and an anticholinergic compound, hyoscine. Both peptides also cause a positive inotropic and a positive chronotropic effect in the rat isolated auricle and these responses are antagonised by propranolol, a B adrenoceptor blocker. Further, the peptides lower plasma calcium levels in both rats and rabbits in a dose-related manner resembling calcitonin; in the rabbit, but not in the rat, the initial calcium lowering effect is succeeded by hypercalcaemia at higher doses, while in the chick, only the parathyroid hormone-like calcium-raising effect is seen.

Animals↗
PubMed1982

Preparation, purification, and structure elucidation of slow-reacting substance of anaphylaxis from guinea pig lung.

The work that we have described had originally three main aims: (a) to design a new purification system for SRS-A from which we would obtain pure material for the structural analysis: (b) to define the functional groups in the pure material by spectrophotometric, chemical, and enzymic inactivation methods; and (c) to deduce the complete covalent structure by an accepted spectroscopic method capable of defining structure in atomic detail. These aims have been achieved. The structure of SRS-A, the physiologically more relevant example of the SRSs that were studied, because it was derived immunologically from an animal model of an acute hypersensitivity reaction, has been rigorously defined. Of paramount importance in the determination of this structure was the mass spectrometric analysis of the intact molecule. Degradative and comparative studies are not capable of unequivocally defining structure. For example, the mass spectrum clearly showed the absence of an amide or similar C-terminal blocking groups or, as has been suggested, a sulfone in the molecule; such conclusions could not be drawn from comparative chromatographic data even on multiple systems. Mass spectrometric analysis of the intact molecule could overcome these problems by allowing the complete covalent structure to be collated from the information obtained from each fragmentation. The use of stable isotopes and accurate mass measurement removed possible ambiguities in the interpretation, and the sensitivity and specificity of mass spectrometry made it the method of choice for the structural analysis.

Animals↗
PubMed1982

Slow reacting substances (leukotrienes): enzymes involved in their biosynthesis.

Slow reacting substances (leukotrienes C4, D4, E4) are synthesized in vivo by a combination of two previously unrelated pathways: lipoxygenase oxygenation of arachidonic acid and the glutathione detoxification pathway. Enzymes involved in the latter pathway (glutathione transferase [RX: glutathione R-transferase, EC 2.5.1.18]; gamma-glutamyltransferase [(5-glutamyl)-peptide: amino acid 5-glutamyltransferase, EC 2.3.2.2] ) have been investigated in guinea pig lung and rat basophilic leukemia (RBL-1) cells. We report data on levels of enzymic activity both before and during the release of slow reacting substances. Both glutathione transferase and gamma-glutamyltransferase are present in significant quantities in guinea pig lung and RBL-1 cells. A model for the changes in gamma-glutamyltransferase during leukotriene release is proposed for the cell line, and differences from the guinea pig lung system are reported. Leukotriene C4 is converted to the more potent leukotriene D4 by the action of gamma-glutamyltransferase on guinea pig ileum during bioassay. gamma-Glutamyltransferase may represent a control feature in the biosynthesis of leukotriene D4, and thus be involved in leukotriene-induced bronchoconstriction in the lung.

Animals↗