J.C. Foreman

Calcitonin gene-related peptide, endothelin-1, the cutaneous microvasculature and Raynaud's phenomenon

It has been argued that the digital cutaneous microvasculature is the site of the anomaly which causes Raynauds phenomenon (RP). Both endothelin‐1 (ET‐1), a potent vasoconstrictor peptide present in the digital cutaneous microvasculature. and calcitonin gene‐related peptide (CGRP). a powerful vasodilator present in digital cutaneous perivascular nerves, have been implicated in the pathogenesis of RP. Circulating ET‐1 levels are raised, and there is a diminution of CORP‐containing perivascular nerves in linger skin in RP

Cutaneous responses to vasoactive intestinal polypeptide in chronic idiopathic urticaria.

Cutaneous wheal and flare responses to increasing concentrations of calcitonin gene-related peptide, substance P, neurokinin A, vasoactive intestinal polypeptide (VIP), compound 48/80, and phosphate-buffered saline were measured in 10 patients with chronic idiopathic urticaria and 10 healthy controls. A significant increase in VIP-induced wheal, but not flare or cutaneous blood flow, was seen in urticarial patients compared with controls (p less than 0.001). No significant differences in responses to other tested compounds were found between these groups. These data point to an increased sensitivity of microvasculature to VIP in patients with chronic idiopathic urticaria.

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 flarein vivo but does not cause Hi release from mast cellsin vitro. The effects of capsaicin on mast cell degranulation in human skinin vivo has been studied by histological examination of skin biopsies after topical capsaicin (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 cell 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.

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

Summary 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‐l (0.3–10 μm) and carbachol (1–30 μm) 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.

Raynaud's phenomenon, calcitonin gene-related peptide, endothelin, and cutaneous vasculature

I tested this hypothesis in 63 women consecutively having ELA for treatment of menorrhagia. A Weck-Baggish hysteroscope was used (Weck, ER Squibb, New Jersey). This hysteroscope had separate inflow, outflow, and laser fibre channels allowing a satisfactory fluid infusion system to be established. A standard laser regimen with a ’Surgical Laser Technology CL100 Nd-YAG’ laser (Malvern, USA)8 was used. In 30 women (group A) fluid was infused continuously by means of a simple roller pump. In the other 33 women (group B) fluid was pumped into the cavity with a ’Hamou Hysteromat’ (Karl Stortz, Tuttinglheim, Germany), consisting of a roller pump connected to a pressure transducer that allows control of intrauterine pressure. If the preset level is reached the roller pump is progressively slowed until the predetermined limit is regained. The closed pressure-controlled infusion system (group B) was associated with a reduction of 21% in treatment time, 39% in the volume of fluid infused, 86% in the volume absorbed, and 82% in the rate of fluid absorption: Mean Mean Mean Rate treatment volume volume fluid No with time infused absorbed absorbed fluid Group (min) (ml) (ml) (ml/min) balance A 28 5326 1537 57 z%) ) B 22 3245 219* 10* 18 (SS % )*

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 Raynauds 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 Raynauds phenomenon occurs) in normal controls and patients with primary Raynauds phenomenon. A cold-related attenuation of mast cell histamine release by compound 48/80 was observed in both normal and Raynauds subjects. These results do not support a major histaminergic defect in the pathogenesis of Raynauds phenomenon.

Calcitonin-gene-related-peptide in the treatment of severe Raynaud's phenomenon

In placebo-controlled studies, both intravenous Iloprost and oral nifedipine have been shown to reduce Raynauds phenomenon secondary to systemic sclerosis. Which is better? During winter 1986/1987, 23 patients with systemic sclerosis were randomized, doubleblind, to either Iloprost with oral placebo (three 8-h infusions on 3 consecutive days with a further infusion after 8 weeks), or oral nifedipine (10 mg t.i.d. for 4 weeks then 20 mg t.i.d. for 12 weeks) with placebo infusion (NaCl). Patients were assessed by daily diary card, clinical examination and blood-flow measurements pretreatment and after 4, 8, 12 and 16 weeks. The number of Raynauds attacks fell from 12/week (mean duration 38 min) before treatment to 8/week (Iloprost) and 9/week (nifedipine) (P < 005) (mean duration fell 30% with Iloprost and 14% with nifedipine); the number of skin lesions (4/patient) fell to 0-5/patient (Iloprost) and I/patient (nifedipine) by week 4. Digital blood flow was consistently increased with Iloprost but was significantly reduced from baseline at weeks 4 and 8 (P<005) following nifedipine (between-treatment difference (P<o-O5) at weeks 4 and 8). Microcirculatory fiow was consistently increased by Iloprost (P<o-O5) but not by nifedipine. Iloprost reduced digital peripheral vascular resistance (PVR) until week 16; the effect of nifedipine was once again inconsistent. Nifedipine increased forearm blood flow and decreased forearm PVR at weeks 12 and 16 (P<005). Mean blood pressure was reduced significantly in both treatment groups. Although the improvement in digital blood flow was more marked following Iloprost, the reduction in symptoms was equal with both drugs. This can be explained by the different modes of action ofthe two drugs: nifedipine is a general vasodilator with little effect on damaged bloodvessels (it probably acts by preventing platelet aggregation), while Iloprost may produce specific effects that increase flow in these damaged vessels (i.e. by promoting vascular endothelial healing). It may be beneficial to use both drugs.

Stimulation and release of interleukin-1 from peritoneal macrophages of the mouse

Lipopolysaccharide (LPS) caused a concentration-dependent increase of released and cell-associated interleukin-1 (IL-1) in resident peritoneal macrophages from the mouse. LPS was about 30 times more potent at stimulating the level of cell-associated IL-1 than it was at stimulating the release of IL-1. Human recombinant tumour necrosis factor-α (TNF-α) and the calcium ionophores A23187 and ionomycin induced a concentration-dependent increase of cell-associated IL-1 but failed to cause release of IL-1 at concentrations producing maximal stimulation of cell-associated IL-1. The phorbol ester, 4β-phorbol dibutyrate, stimulated the release of IL-1 from mouse macrophages but failed to induce an increase in cell-associated IL-1. Substance P, neurokinin A, neurokinin B, calcitonin gene-related peptide and platelet-activating factor did not increase the released or cell-associated IL-1 in mouse macrophages. These agents also failed to alter released or cell-associated IL-1 stimulated by LPS, 1 μg ml−1. It appears that a calcium signal is sufficient for the transcription and translation of IL-1 mRNA but does not result in the secretion of biologically active forms of IL-1. Our data also indicate that different intracellular signals may control the release and the cell accumulation of IL-1. We conclude that inflammatory mediators may independently increase either the release of, or the cell accumulation of IL-1.

The action of a calcitonin gene-related peptide antagonist in human skin

The CGRP antagonist, CGRP8-37, antagonized the ability of CGRP to increase blood flow in human skin and cause erythema. The mechanism of the antagonist effect of CGRP8-37 on the CGRP-induced erythema was an increase by the antagonist of the rate of decay of the CGRP-induced erythema. Since CGRP8-37 activates rat peritoneal mast cells to release their granular contents, we conclude that the degradation of CGRP by protease released from skin mast cells by CGRP8-37. It was not possible to demonstrate any antagonistic effect of CGRP8-37 on the CGRP receptor mediating increased blood flow in human skin.