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Biomedical subjects

P M Dowd

Publications and source records attributed to P M Dowd.

At least 37 records · Page 2Linked to original sources
PubMed1993

Calcitonin gene-related peptide in treatment of severe peripheral vascular insufficiency in Raynaud's phenomenon.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator that may be involved in the regulation of the peripheral circulation and in its response to cold. There is evidence that CGRP in digital cutaneous perivascular nerves is deficient in Raynaud's phenomenon. Our pilot study of intravenous CGRP suggested that this substance is beneficial in patients with Raynaud's phenomenon; here we have extended our studies. Ten patients with severe Raynaud's phenomenon secondary to connective tissue disease were randomly assigned to groups receiving intravenous CGRP (0.6 micrograms/min for 3 h per day on 5 days) or saline. Hand and digital blood flow and skin temperature were measured by thermocouple and laser doppler flowmetry. Blood flow was significantly (p < 0.05) increased by CGRP in both hands (median blood flow after infusion as percentage of baseline reading 179 [range 100-355]%) and fingers (149 [100-161]%); saline had no effect (hands 102 [84-123]%, fingers 96 [81-113]%). Hand temperature was increased more by CGRP than by saline (2.8 [1.5-4.0] vs 1.0 [-1.0 to 2.5] degrees C, p < 0.05). Digital temperature increased after CGRP but the difference between the treatment groups in temperature rise was not significant, perhaps because saline caused increases in some patients. All ulcers healed in four of five CGRP-treated patients but in no saline-treated patients. Thus intravenous CGRP effectively dilates the compromised digital cutaneous vasculature in severe Raynaud's phenomenon.

Adult↗
PubMed1993

Characterization of endothelin-binding sites in human skin and their regulation in primary Raynaud's phenomenon and systemic sclerosis.

Endothelin (ET), which mediates vasoconstrictor and vasodilator activities via multiple receptor subtypes, has been implicated in the control of blood flow and vascular tone in human skin, and possibly in the abnormal vasoconstrictor response in primary Raynaud's phenomenon and systemic sclerosis. Using in vitro autoradiography we have examined the endothelin-binding characteristics and receptor subtypes of human skin, and sought to provide evidence for endothelin receptor regulation in skin from patients with primary or secondary Raynaud's phenomenon. Specific 125I-ET-1 and 125I-ET-3 binding sites were localized to microvessels of the sub-epidermal plexus and dermal papillae, larger blood vessels, sweat glands, epidermis, and hair follicles. Both ETA and ETB receptors were demonstrated in microvessels and other structures. ET receptor heterogeneity in skin vasculature suggests a role for ET as an autocrine/paracrine regulator of vasoconstrictor and vasodilator pathways in human skin. The presence of binding sites in epidermis and hair follicles suggests a possible mitogenic function for endothelin in human skin. Endothelin-binding density was significantly higher (p < 0.05) in microvessels of skin from patients with systemic sclerosis but not significantly different in Raynaud's phenomenon patients, compared to controls. Lack of down regulation of ET receptors in Raynaud's phenomenon and systemic sclerosis may contribute to the pathogenesis of vasospasm in these diseases.

Adult↗
PubMed1993

Basophil mediator release in atopic dermatitis.

Basophils have been implicated as a source of histamine and pro-inflammatory eicosanoids in atopic dermatitis. However, mechanisms regulating basophil mediator release are not understood. An H3 receptor involved in the control of histamine synthesis and release has been identified in nervous tissue. In this study we have investigated 1) release of histamine, leukotriene C4, and prostaglandin D2 from anti-immunoglobulin E (IgE)-stimulated basophils of adults with atopic dermatitis and unaffected individuals and 2) specific H3 receptor-dependent basophil mediator release, using an H3 receptor agonist and antagonist. Basophil-rich leukocyte fractions were prepared by dextran sedimentation of venous blood from 19 patients with atopic dermatitis (five male, 14 female, mean age 30.6 years, range 19-59 years) and 15 unaffected individuals (five male, 10 female, mean age 27.6 years, range 19-50 years). Anti-IgE (0.78-78.0 micrograms/ml) stimulation of basophils induced a concentration-dependent release of histamine and leukotriene C4, but not prostaglandin D2. Histamine release was maximally induced by 7.8 micrograms/ml anti-IgE with no significant (Mann-Whitney U test) difference between atopic basophils (n = 17; 43.65 +/- 4.16% mean +/- SEM) and normal basophils (n = 13; 52.23 +/- 4.39%). LTC4 release was maximal from atopic basophils incubated with 2.6 micrograms/ml anti-IgE (n = 5; 0.99 +/- 0.29 pg/10(6) cells) and from normal basophils incubated with 0.78 microgram/ml anti-IgE (n = 5; 25.38 +/- 5.79 pg/10(6) cells). Anti-IgE-stimulated release of leukotriene C4 from atopic basophils was significantly less than from normal basophils at all concentrations (p < 0.05). Basophils were co-incubated with anti-IgE (2.6 and 7.8 micrograms/ml) and either the H3 receptor agonist, (R)alpha-methylhistamine (10(-8) and 10(-7) M), or the H3 receptor antagonist thioperamide (10(-6) and 10(-5) M). Neither drug modulated anti-IgE-induced release of histamine (atopics, n = 10; normals, n = 8). These results indicate 1) that basophils from adults with atopic dermatitis release the same amount of histamine as, but less leukotriene C4 than, basophils of unaffected adults and 2) that H3 receptors are not involved in anti-IgE release of histamine from basophils. These data do not support a role for increased basophil release of histamine as a mediator in the itch and erythema of atopic dermatitis in adults.

Adult↗
PubMed1993

Degos disease and spastic paraplegia.

Malignant atrophic papulosis (Degos disease) is a rare disorder characterized by a vasculopathy of unknown origin. The cutaneous manifestations comprise erythematous papules, which heal to leave scars with a pathognomonic central porcelain-white atrophic area and a peripheral telangiectatic rim. There is usually involvement of the gastrointestinal tract but other organ systems can also be affected, the central nervous system being involved in 20% of cases. It is frequently fatal within 2 or 3 years from onset of systemic involvement, the cause of death usually being intestinal perforation. Our patient is of interest as she has survived an unusually long time despite florid cutaneous and neurological manifestations.

Atrophy↗
PubMed1993

Edothelin-1 in human skin.

Endothelin-1 (ET-1) was originally identified as an endothelium-derived peptide with potent local constrictor and systemic pressor effects. Consequently it was implicated as a mediator in the control of systemic as well as peripheral vascular tone. The intense activity that followed the discovery of ET-1 has shown that endothelium is not the only site of synthesis nor is smooth muscle the sole target. ET-1 is capable of initiating and regulating an array of cellular responses including contraction, proliferation, synthesis of extracellular matrix proteins and induction of proto-oncogene expression. This diversity of function is paralleled by an increasing number of mediators capable of inducing synthesis of ET-1 in an ever increasing array of cell types. ET-1 is also a neuropeptide; mRNA for ET-1 has been identified by in situ hybridization in human spinal cord and dorsal root ganglia, and ET-1 was shown to modulate adrenergic neurotransmission at the neuro-effector junction. This review will highlight some of the recent advances in our understanding of the mechanisms regulating the synthesis of and cellular responses to ET-1 with particular reference to its potential role in the maintenance of cutaneous homeostasis and in the pathophysiology of cutaneous diseases.

Animals↗
PubMed1993

The new H1 antihistamines. Treatment of urticaria and other clinical problems.

The new H1 antihistamines are a major therapeutic advancement in the treatment of allergic disorders such as urticaria and allergic rhinitis. Their efficacy combined with greatly reduced sedating and anticholinergic side effects makes the new class of H1 antihistamines the first-line treatment in the management of urticaria and mild angioedema. The choice of a particular low-sedating H1 antihistamine depends on pharmacokinetic considerations, the severity of the problem (systemic steroids and epinephrine are the first-line treatment for severe angioedema), and the requirement for limiting the frequency of administration. The efficacy of the new H1 antihistamines in the treatment of itch due to atopic eczema and systemic disease remains uncertain, and further controlled clinical trials are needed to elucidate their possible role in these conditions.

Astemizole↗
PubMed1992

Further studies on the actions of endothelin-1 on blood flow in human skin.

When injected into human skin, endothelin-1 produces intense vasoconstriction localized to the site of the injection, but this area of vasoconstriction is surrounded by vasodilatation which spreads several centimetres from the injection site. The vasodilatation induced by intradermal injection of endothelin-1 (63 pmol) into human skin is prevented by local anaesthetic. Pretreatment of human skin with capsaicin also inhibits this response. Pretreatment of subjects with the selective histamine H1-receptor antagonist cetirizine, 10 mg orally 4 h before intradermal injections, inhibited vasodilatation caused by the intradermal injection of histamine (750 pmol), endothelin-1 (63 pmol), and carbachol (750 pmol). Endothelin-1 (0.3-10 microM) and carbachol (1-30 microM) failed to induce histamine release from rat peritoneal mast cells. We conclude that the vasodilatation caused by intradermal injection of endothelin-1 into human skin is neurogenic and is probably mediated by neuropeptide-containing primary afferent neurones. Because neither carbachol nor endothelin-1 cause histamine release from mast cells, our data suggest that histamine release from mast cells at the effector end of the axon reflex is responsible for the carbachol- and endothelin-induced vasodilatation in human skin.

Adult↗
PubMed1992

Characterization of histamine receptor sub-types regulating prostacyclin release from human endothelial cells.

1. The histamine receptor sub-types that are involved in the initiation and maintenance of prostacyclin (PGI2) release from human endothelial cells have been investigated. 2. Endothelial cells cultured from umbilical vein (HUVEC) were incubated with either histamine, the selective H1-receptor agonists, 2-methyl histamine (2-MeHA) or thiazolylethylamine (ThEA), the H1-agonist/H3-antagonist, beta-histidine (beta-His), the selective H2-agonist, dimaprit, the H2-agonist/H3-antagonist, impromidine, the selective H3-agonist, (R)alpha-methylhistamine ((R)alpha-MeHA) and the H3-antagonist, thioperamide. 3. The H1-agonists and the H3-agonist (R)alpha-MeHA induced a concentration (100 nM-1 mM) and time-dependent release of PGI2 as determined by radioimmunoassay for 6-keto-PGF1 alpha, but were less potent than histamine itself. The rank order of potency was the same following 30 min and 24 h incubation, i.e. histamine > ThEA > 2-MeHA >> beta-His > (R)alpha-MeHA. 4. Histamine and 2-MeHA (1 microM-1 mM), ThHEA (10 microM-1 mM) and (R)alpha-MeHA (1 mM), but not beta-His, induced a significantly greater increase in PGI2 release after 24 h incubation than after 30 min incubation (P < 0.05). 5. Neither the selective H2-agonist, dimaprit, nor the H2-agonist/H3-antagonist, impromidine alone induced release of PGI2. 6. The H1-antagonist, mepyramine (10 microM), abolished release of PGI2 induced by histamine, the H1-agonists and (R)alpha-MeHA but the H2-antagonist cimetidine (10 microM) and the H2/H3-antagonist, burimamide (10 microM) did not significantly modulate PGI2 release. 7. Although the H3-agonist (R)alphax-MeHA induced release of PGI2, it failed to modulate PGI2 release in the presence of histamine.8. Low concentrations of the H3-antagonist, thioperamide (100 nM) did not modulate histamine release of PGI2 at all but after 24 h incubation, thioperamide (10-4 M) partially reduced PGI2 release in the presence of histamine.9. These results indicate that PGI2 from HUVEC is initiated and maintained via histamine HI-receptor occupancy. There appears to be no involvement of either H2- or H3-receptors in this particular endothelial cell histaminergic response.

Cells, Cultured↗
PubMed1992

The effect of Mycobacterium tuberculosis on the susceptibility of human cells to the stimulatory and toxic effects of tumour necrosis factor.

It has previously been shown that the inherently tumour necrosis factor-alpha (TNF-alpha)-sensitive L929 murine fibroblast cell line becomes much more sensitive to the cytotoxic effect of this cytokine after exposure to Mycobacterium tuberculosis in culture. In this study it is now shown that normal human cells of types likely to be involved in tuberculous lesions are affected in a similar way. Growth of normal human fibroblasts is usually stimulated by TNF-alpha in vitro, but after exposure to M. tuberculosis or to extracts of this organism, these cells are killed rather than stimulated by subsequent exposure to TNF-alpha. Similarly, human endothelial cells become susceptible to doses to TNF-alpha which do not normally affect viability. Moreover this enhancement of sensitivity to TNF-alpha is not confined to its toxicity. Endothelial cells and HeLa cells exposed to M. tuberculosis express increased levels of ICAM-1 after subsequent exposure to TNF-alpha, implying synergy between the two stimuli. It is suggested that these effects contribute to the ability of M. tuberculosis to distort the normal protective role of TNF-alpha so that the cytokine becomes detrimental to the host.

Cell Adhesion Molecules↗
PubMed1991

Image analysis quantification of peptide-immunoreactive nerves in the skin of patients with Raynaud's phenomenon and systemic sclerosis.

Image analysis quantification was used to assess the results of immunocytochemistry for a neuronal marker and neuropeptides in digital skin biopsies from Raynaud's phenomenon (RP) and systemic sclerosis (SS) patients, to verify the possibility of a selective quantitative abnormality of immunoreactive nerves. The field area of specific immunostaining and nerve counts were evaluated on coded specimens, and the data compared by statistical analysis. Nerves immunoreactive for protein gene product 9.5 (PGP), a marker for neuronal elements, were decreased significantly in epidermal and subepidermal layers of digital skin in RP patients (P less than 0.0001). This change was paralleled by a decrease of calcitonin gene-related peptide (CGRP) immunoreactive nerves in the epidermis and around capillaries in the dermal papillae (P = 0.005). In the skin of RP patients, these changes were readily demonstrated by image analysis, although they were not always apparent on visual screening. In digital skin of SS patients, there was a generalized and very significant decrease of PGP, CGRP, and VIP immunoreactivities in all areas (P less than 0.0001). These results demonstrate that neuropeptide-containing nerves are involved in the digital pathology of RP and SS, and that image analysis quantification is an accurate and sensitive method for assessing morphological changes in pathological samples.

Adult↗
PubMed1991

The effect of capsaicin application on mast cells in normal human skin.

Peptides released from sensory nerves during an axon reflex are thought to cause mast cell degranulation, histamine (Hi) release and Hi-induced vasodilatation leading to the flare of the triple response. Capsaicin stimulates peptide release from sensory neurones and causes flare in vivo but does not cause Hi release from mast cells in vitro. The effects of capsaicin on mast cell degranulation in human skin in vivo has been studied by histological examination of skin biopsies after topical capsicin (1%) treatment of stratum corneum-denuded forearm in four volunteers. The results show a significant reduction in the visible numbers of mast cells and the appearance of degranulated mast cells ghosts in the skin six hours after capsaicin application. Since capsaicin itself does not release Hi from mast cells, these data suggest that capsaicin-induced release of peptides from neurones could cause mast cell degranulation.

Adult↗
PubMed1991

Vascular responses to histamine at low temperatures in normal digital skin and Raynaud's phenomenon.

A defective histaminergic dilating system in the digital vasculature has been proposed for the pathophysiology of Raynaud's phenomenon but this is not supported by studies of digital intradermal responses to histamine or agents which cause histamine release. The vascular responses (measured by planimetry and laser Doppler flowmetry) of digital skin over the middle phalanx to intradermal histamine, compound 48/80 and Substance P have now been studied at low temperatures (because it is in the cold that Raynaud's phenomenon occurs) in normal controls and patients with primary Raynaud's phenomenon. A cold-related attenuation of mast cell histamine release by compound 48/80 was observed in both normal and Raynaud's subjects. These results do not support a major histaminergic defect in the pathogenesis of Raynaud's phenomenon.

Adult↗
PubMed1991

Digital cutaneous vascular responses to histamine and neuropeptides in Raynaud's phenomenon.

The pathophysiology of Raynaud's phenomenon is not well defined, but active cutaneous microvascular vasoconstriction and emptying must occur to account for the pallor and are reasons for studying the microvasculature. It has been proposed that there may be a defect in a local histamine vasodilator mechanism. The role of the peptidergic nervous system in Raynaud's phenomenon has not been previously investigated. To study the histaminergic and peptidergic axes in Raynaud's phenomenon, we measured the cutaneous microvascular responses of patients with Raynaud's phenomenon to digital intradermal injections of saline, histamine, the histamine-releasing agent, compound 48/80, substance P, and calcitonin gene-related peptide. We compared these results with those obtained in normal subjects. Intradermal cutaneous microvascular blood flow responses were quantified by planimetry and laser Doppler flowmetry. The results show: a) that in primary Raynaud's phenomenon there is no evidence of local deficiency in histamine release or insensitivity to histamine in the cutaneous microvasculature; and b) that patients with Raynaud's phenomenon react normally to the neuropeptides calcitonin gene-related peptide and substance P, providing a rationale for treating Raynaud's phenomenon with vasoactive peptides.

Adolescent↗