PubMed Health⌕ Search

Biomedical subjects

S D Brain

Publications and source records attributed to S D Brain.

106 records · Page 6Linked to original sources
PubMed1989

Endothelin-1: demonstration of potent effects on the microcirculation of humans and other species.

The effect of endothelin-1 (ET-1) on microvessels was investigated by use of intravital microscopy and by measuring microvascular blood flow changes. ET-1 caused a selective constriction of arterioles in the hamster cheek pouch, without affecting venules. A decrease in blood flow was observed at the site of intradermal injection of ET-1 in rabbit and human skin. ET-1, as a consequence of its vasoconstrictor activity, acted in an anti-inflammatory manner to inhibit edema formation and neutrophil accumulation induced by chemotactic agents in rabbit skin. In human skin, a flare, due to increased blood flow, spread for several centimeters around a central constricted area. The flare, the result of an axon reflex, reveals an alternative mechanism through which ET-1 can act to modulate vascular tone.

Animals↗
PubMed1988

Substance P regulates the vasodilator activity of calcitonin gene-related peptide.

The 37-amino-acid calcitonin gene-related peptide (CGRP) occurs as a result of alternative processing of mRNA from the calcitonin gene. The potency of CGRP as a vasodilator and the occurrence of the peptide in nerves associated with blood vessels suggest an important role for CGRP in the regulation of blood flow. The finding that CGRP induces protracted vasodilatation when administered extra-vascularly, to mimic release from nerves, has led us to investigate how the vasodilator activity of CGRP is controlled in vivo. CGRP is often co-localized with substance P in C-fibre nerves. Here, we demonstrate that injection of CGRP with substance P into human skin converts the long-lasting vasodilatation induced by CGRP into a transient response. Experiments in animals reveal that the phenomenon is dependent on the action of proteases from mast cells stimulated by substance P. The results reveal a new regulatory interaction between two neuropeptides and provide evidence for an in vivo role for mast cell proteases.

Animals↗
PubMed1988

Endothelin induces potent microvascular constriction.

Endothelin is a recently discovered peptide produced by endothelial cells. It has been shown to have potent constrictor effects on major arteries in vitro and to raise rat blood pressure in vivo. The present experiments show that endothelin has a potent constrictor action on the microvasculature. Blood flow changes were measured by a xenon clearance technique in rabbit skin. Endothelin, when injected intradermally into rabbit skin, decreased local blood flow in a dose-dependent manner. Endothelin reduced basal skin blood flow and reversed the increased blood flow induced by a vasodilator. These results show that endothelin, administered extravascularly, has potent vasoconstrictor activity. This adds further support to the suggestion that endothelin may have an important role in the physiological control of blood flow and pressure.

Animals↗
PubMed1986

A second form of human calcitonin gene-related peptide which is a potent vasodilator.

A recently predicted form of human calcitonin gene-related peptide, (beta CGRP) exhibits potent vasodilator activity in rabbit skin with a similar potency to the form of human CGRP originally described (alpha CGRP). Both peptides, because of their vasodilator activity, cause a potentiation of inflammatory oedema induced by mediators of increased vascular permeability. The results demonstrate that changes can be made at certain positions in the amino acid sequence of human CGRP without loss of vasodilator activity.

Amino Acid Sequence↗
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↗
PubMed1985

Leukotrienes C4 and D4 in psoriatic skin lesions.

Chemoattractant arachidonate lipoxygenase products have been recovered from the skin lesions of psoriasis, and may play a role in eliciting the intra-epidermal neutrophil infiltrate that characterises this disease. In view of evidence for lipoxygenase activity in psoriasis, the characteristic vasodilation in psoriatic lesions, and the vasodilator properties of leukotriene (LT) C4 and D4 in human skin, the presence of these LTs in psoriatic lesions has been investigated. Skin chamber fluid from abraded psoriatic lesions contained significantly greater amounts of immunoreactive material than that from clinically normal skin, as determined by a double antibody radioimmunoassay (RIA) that uses antiserum cross-reacting with both LTC4 and LTD4. Purification of lesional chamber fluid and scale extracts by high performance liquid chromatography (HPLC) and RIA of fractions showed immunoreactivity which co-eluted with standard LTC4 and LTD4. These findings suggest that LTC4 and LTD4 may play a role in mediating the vasodilation and increased blood flow that characterise psoriatic skin lesions.

Adolescent↗
PubMed1985

Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability.

The potent vasodilator calcitonin gene-related peptide (CGRP, human synthetic), when mixed with histamine and injected intradermally in the rabbit, induced a marked potentiation of local oedema. CGRP also potentiated oedema induced by other mediators of increased microvascular permeability in the rabbit; bradykinin, platelet-activating factor (Paf), C5a des Arg, N-formylmethionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4). Substance P alone, or mixtures of substance P and CGRP, failed to induce oedema in rabbit skin. In rat skin, however, substance P induced oedema and this was potentiated by CGRP. CGRP had a protracted potentiating action following intradermal injection in the rabbit. The time for half loss of activity for CGRP was 40.1 +/- 7.5 min compared to 18 +/- 1 min for prostaglandin E2 (PGE2). No loss of potentiating activity was detected after incubation of CGRP in rabbit plasma or blood for 60 min. We postulate that endogenous CGRP, if released locally from nerve endings, could have a marked enhancing effect on oedema induced by other mediators in an inflammatory reaction.

Animals↗
PubMed1984

The effect of etretinate on the cyclo-oxygenase and lipoxygenase products of arachidonic acid metabolism in psoriatic skin.

Eight psoriatic patients were treated with etretinate (50 mg daily) for 6 weeks. Skin chamber exudates from involved and uninvolved skin were assayed for arachidonic acid, 12-HETE, PGE2 and for neutrophil chemokinetic activity co-chromatographing with leukotriene B4, before and at weekly intervals during therapy. Pre-treatment concentrations of arachidonic acid, 12-HETE and leukotriene B4-like chemokinetic activity but not of PGE2 were elevated in involved skin when compared to uninvolved skin. The concentrations of arachidonic acid and 12-HETE declined during therapy but changes in PGE2 were minimal. LTB4-like activity was detectable in involved skin both before and after etretinate treatment. Clinically, scaling and infiltration improved but erythema was still evident.

Adult↗
PubMed1984

Leukotriene B4-like material in scale of psoriatic skin lesions.

Acidic lipid extracts of scale from the lesions of the skin disease, psoriasis, were purified by straight phase high performance liquid chromatography (h.p.l.c.). Assay of fractions by an agarose microdroplet chemokinesis method showed the presence of biologically active material that coeluted with standard leukotriene B4 (LTB4). LTB4-like chemokinetic activity was also detected in fractions collected on reversed phase h.p.l.c. of psoriatic scale extracts that were initially purified by straight phase h.p.l.c. No LTB4-like activity was detected after similar purification of scale obtained by abrasion of large areas of normal skin. The LTB4-like material found in extracts of psoriatic scale may play a role in the pathogenesis of the neutrophil infiltrate which characterizes psoriasis.

Cell Movement↗
PubMed1983

The identification of hydroxy fatty acids in psoriatic skin.

Psoriasis is a common chronic inflammatory and proliferative skin disease characterised by epidermal neutrophil infiltration which may be induced by chemotactic substances in the involved epidermis. Superficial psoriatic scale was shown to contain biologically active amounts of leukotriene B4 and monohydroxy-eicosatetraenoic acid (HETE)-like material as determined by assay for chemokinetic activity in high performance liquid chromatography (HPLC) fractions of scale extracts. Extracts of scale and chamber fluid from abraded lesional and uninvolved psoriatic skin were purified by HPLC and appropriate fractions were analysed by gas chromatography - mass spectrometry (GC-MS). The following monohydroxy metabolites of arachidonic, linoleic and 11,14-eicosadienoic acids were identified: 15-HETE, 12-HETE, 11-HETE, 9-HETE, 8-HETE, 5-HETE, 13-hydroxy-octadecadienoic acid (13-HODD), 9-HODD and 15-hydroxy-eicosadienoic acid (15-HEDE). The results suggested that 12-HETE, 13-HODD and 9-HODD are the most abundant monohydroxy fatty acids in the psoriatic skin extracts described above. Assays of 13-HODD, 9-HODD and 15-HEDE for chemokinetic activity were negative with concentrations up to 10(-4)M. The biological significance of these three compounds in not known, but some of the hydroxylated metabolites of arachidonic acid may, by virtue of their chemotactic properties, be relevant to the pathogenesis of the psoriatic neutrophil infiltrate.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

The modulation by nedocromil sodium of proteases released from rat peritoneal mast cells capable of degrading vasoactive intestinal peptide and calcitonin gene-related peptide.

Tryptase and chymase released from activated mast cells degrade the neuropeptides calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) to peptide fragments. We have examined whether nedocromil sodium can modulate the ability of rat activated peritoneal mast cells to degrade 125I-CGRP and 125I-VIP. Mast cell-dependent degradation of both 125I-CGRP and 125I-VIP was observed with compound 48/80 (0.03-1 microgram/ml) and in the case of 125I-VIP with anti-IgE (1-20 micrograms/ml). Nedocromil sodium (10(-6)-10(-4) M) caused significant inhibition of neuropeptide degradation, with the most effective inhibition observed against anti-IgE-induced degradation of 125I-VIP. Nedocromil sodium had no inhibitory effect on the ability of lysed mast cells, bovine trypsin or chymotrypsin to breakdown 125I-VIP. These results suggest that nedocromil sodium inhibits mast cell-dependent degradation of neuropeptides, such as VIP, as a secondary consequence of inhibiting the release of mast cell proteases.

Animals↗
PubMedDate not supplied

Calcitonin gene-related peptide is a potent vasodilator.

A novel peptide, calcitonin gene-related peptide (CGRP), has been predicted to result from alternative processing of the primary RNA transcript of the calcitonin gene in the rat. Several lines of evidence suggest that CGRP is a transmitter in the central and peripheral nervous system. Human CGRP has been isolated and characterized, and shown to have potent effects on the heart. The observations presented here indicate that human and rat CGRP also have potent effects on blood vessels. Intradermal injection of CGRP in femtomole doses induces microvascular dilatation resulting in increased blood flow, which we have detected in the rabbit by using a 133Xe clearance technique. In human skin, CGRP induces persistent local reddening. Microscopic observation of the hamster cheek pouch in vivo revealed that topical application of CGRP induces dilatation of arterioles. Furthermore, CGRP relaxes strips of rat aorta in vitro by an endothelial cell-dependent mechanism. Therefore, we suggest that local extravascular release of CGRP may be involved in the physiological control of blood flow and that circulating CGRP may contribute to hyperaemia in certain pathological conditions.

Amino Acid Sequence↗