M.W. Greaves

Mast cell population density, blood vessel density and histamine content in normal human skin

Mast cell population density was determined in normal skin from two regions of the arm of several healthy men and compared with blood vessel density and histamine concentration in the same sites. Mast cell and hlood vessel counts were made in 1–1.5 μm thick plastic sections, by light microscopy and tissue‐histamine concentrations were determined by automated fluorimetric analysis.

Symptomatic dermographism: Natural history, clinical features, laboratory investigations and response to therapy§

Fifty patients with a history of symptomatic dermographism were investigated. The mean age of onset was 25·75 years (range: ‘from birth’ to 52 years) and the peak age of onset was in the second and third decades. The mean duration at last follow‐up was 5–1 years (range: 3 months to 47 years). The duration was longer than 5 years in 22%, and longer than 10 years in 10% of the patients. Ninety‐two percent of patients, but not a single member of an age‐matched group of sixty control subjects, produced measurable wealing at a pressure of 3·5 × 105 Pa or less applied with a calibrated dermographometer. The incidence of the atopic diathesis was not increased in patients with symptomatic dermographism, and no associations with systemic diseases, food allergens or medications were established‐ Routine haematological, biochemical, microbiological and intradermal screening tests were not found to be helpful in the management of this condition. Protease inhibitor profiles revealed a significant reduction in the level of circulating a i‐antitrypsin inhibitor which was not the result of a genetic difference between the patient and control groups. In a double‐blind randomized controlled trial of eight different antihistamine regimes in twelve patients, a combination of hydroxyzine (10 mg qds) and cimetidine (400 mg qds) proved significantly superior to all other treatments in reducing dermographometer‐induced wealing, and was associated with fewest side‐effects.

Tests to establish the diagnosis in cholinergic urticaria

Methods for establishing the diagnosis in cholinergic urticaria are reviewed and compared. Provocation by exercise or hot bath is more effective than local provocation by intradermal tests. Of the intradermal tests, responses to nicotine acid tartrate and acetyl β methylcholine chloride are positive only in patients with the more severe, readily induced eruptions. Furthermore, intradermal testing is not always reproducible in the same patient. In our patients, exercise proved the simplest, most effective diagnostic test.

Vascular responses of human skin to injection of substance P and mechanism of action

The mechanism of cutaneous inflammation caused by substance P in human skin was assessed in five subjects receiving i.d. injections (5-405 pmol) at pH 7.2 as compared to histamine (0.08-1.6 nmol), compound 48/80 (100 ng) and solvent control. Both substance P and histamine produced sigmoid dose-response curves for the following parameters: 1 min and 5 min planimetrically measured areas of erythema, and mean diameter of weal. Substance P pretreatment induced tachyphylaxis, as assessed by standard methods with adequate controls, to both histamine and to substance P and vice versa. Erythema following substance P i.d. was not blocked by a constricting band. Diphenhydramine, and to a lesser extent doxantrazole, (but not cimetidine or indomethacin) when assessed as inhibitors after oral pretreatment, did shift dose response curves for histamine and substance P to the right. Light and electron microscopic assessment of mast cells was compared in substance P and solvent control injected human skin. These results support a possible role for substance P in cutaneous inflammation acting either directly or via histamine release from mast cells.

Adenosine triphosphate-evoked vascular changes in human skin: Mechanism of action

Adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenosine, adenine and inosine were injected intradermally into the backs of human volunteers. ATP, ADP and AMP evoked weal and flare responses in the skin in a dose dependent manner. The rank order of potency was ATP greater than ADP greater than AMP; other metabolites were apparently inactive. The potency of ATP was approximately 0.002 times that of histamine. In the forearm, cross tachyphylaxis was demonstrated between ATP and histamine weals; also the flare due to injected ATP spread beyond a band which was applied to prevent diffusion, indicating that the flare is neurogenic. Injections of ATP and high doses of ADP produced a sensation of persistent pain, unlike histamine which produced transient pain or itch on some occasions, and saline which was without effect. The possible involvement of histamine, mast cells and prostaglandins in the response was examined. The inhibitory actions of systemic pretreatment with diphenhydramine suggests that the erythema and wealing responses to ATP are at least partly due to ATP-evoked histamine release. Indomethacin, doxantrazole and cimetidine did not alter the ATP reaction.

Cimetidine in chronic idiopathic urticaria: a randomized double-blind study.

Ash & Schild (1966) demonstrated the existence of two subclasses of histamine receptors subsequently termed Hi and H2 (Black et al, 1972). Recently studies of the responses of human skin blood vessels to the synthetic Hi agonist 2-methyl histamine and the H2 agonist 4-methyl histamine led Robertson & Greaves (1978) to conclude that these vessels possessed both classes of receptor. Further support for this view arose from studies of the inhibitory action of the selective H2 receptor antagonist cimetidine (Brimblecombe et al., 1975). Cimetidine caused suppression of erythema and wealing due to three doses of histamine. In combination with the Hi antagonist chlorpheniramine, cimetidine caused a significantly greater inhibition of histamine erythema than either drug alone (Marks & Greaves, 1977). These findings raise the possibility that combination therapy using cimetidine and chlorpheniramine might have advantages over conventional (Hi) antihistamine treatment in skin disorders involving histamine release. Patients with chronic idiopathic urticaria are usually treated with conventional Hi antihistamines, but the response is good in no more than about 1/3 of patients (Champion et al, 1969). Furthermore, the use of higher doses of antihistamines is limited by troublesome atropine and hyoscine-like sideeffects. We have therefore explored the possibility that combination therapy with a conventional Hi antihistamine (chlorpheniramine) and the specific H2 antihistamine cimetidine might be more effective than chlorpheniramine alone in the treatment of chronic urticaria.

RECEPTORS FOR HISTAMINE IN HUMAN SKIN BLOOD VESSELS: A REVIEW

Histamine was one of the first of the drugs occurring naturally in man to be discovered, and it is surprising that even now the pharmacological characterization of such a simple, abundant and ubiquitous amine still remains incomplete. Histamine was first identified by Dale & Laidlaw (1910; 1911) in extracts of ergot. They emphasized its oxytocic actions but also drew attention to its inhibitory properties. The identification of histamine in animal tissues had to await studies of lung and liver extracts by Best, Dale, Dudley & Thorpe (1927) who also highlighted the inhibitory and vasodilator actions of histamine. At about the same time Lewis (1927) adduced considerable indirect evidence that histamine was liberated from human skin following injury and was an important mediator of skin inflammation. However direct evidence of the release of histamine from skin following injury had to await skin perfusion studies (Greaves & Sondergaard 1970; Sondergaard & Greaves, 1971) in which increased amounts of histamine were recovered in perfusates from urticated skin. More recently increased histamine concentrations have been found in venous blood draining cold-challenged skin in cold urticaria (Bentley-Phillips, Black & Greaves, 1976). The frequent failure of conventional antihistamine given systemically to produce reliable suppression of urticarial reactions has led to the suggestion that histamine may be only one of several mediators responsible for the observed vascular changes. However an alternative explanation is now afforded by the discovery of the existence of subclasses of histamine receptors. Ash & Schild (1966) by studying the responses ofa wide range of preparations to analogues of histamine were able to delineate two subclasses of receptors. Subsequent work by Black et al. (1972) defined H|-receptors which were involved in actions of histamine antagonized by conventional (H,) antihistamines and H, receptors which were unaffected by H,-antihistamines, but were antagonized by burimamide which was thus defined as an H2-receptor antagonist. Actions of histamine involving Hj-receptors include stimulation of gastric acid secretions, the chronotropic action of histamine on the heart and inhibition of contraction of the rat uterus The possibility that further subclasses of histamine receptors exist has not been excluded. Exploration of the possibility that human skin blood vessels possess both classes of receptor was prompted hy the observation that the vascular flushing in skin of human volunteers who had received histamine intravenously could be suppressed by administration of H2-receptor antagonists (Wyllie, Hesselbo & Black, 1972; Burland et ah, 1975) and by the identification of two synthetic analogues of histamine, 2-methyl histamine and 4-methyl histamine with predominantly H,-agonist and Hiagonist activity respectively (Black et al., 1972). 2-Methyl histamine evokes a weal and a bright red surrounding fiare due at least in part to an axon refiex. 4-Methyl histamine also causes a weal but the surrounding erythema is less bright and does not involve an axon reflex. The magnitude of the erythema response, but not the weal, is dose-related for each drug. Itching and pain are variable and occur in response to both compounds (Robertson & Greaves, 1977). These observations suggest that the axon refiex and vasodilator actions of histamine are predominantly due to H, and H2 receptors respectively. The actions of chlorpheniramine, an H,-antihistamine, and cimetidine, a highly selective Hiantihistamine (Brimblecombe et al, 1975), on erythema and wealing due to three doses of both agonists are of great interest (Figs i and 2). Chlorpheniramine inhibited erythema due to 2-methyl histamine but cimetidine had no effect on this reaction. By contrast the erythema reaction due to 4-

Factitious urticaria (dermographism): treatment by cimetidine and chlorpheniramine in a randomized double-blind study

The Hi‐antihistamine chlorpheniramine and the H2‐antihistarnine cimetidine, given alone and in combination, have been compared with placebo in twenty patients with factitious urticaria (dermographism), in a double‐blind, randomized cross‐over trial. Of these regimes, the combination was the only treatment which significantly reduced weal size, flare size and duration of weal, compared with placebo, although other treatments approached statistical significance. Continuation of the most effective of the four treatments in nineteen of the patients for a further 3 months without breaking the randomization code provided further evidence of the greater effectiveness of combined cimetidine and chlorpheniramine. No significant side effects were noted.

Trimethylaminuria: the use of choline as an aid to diagnosis

Trimethylamine metabolism can be studied by means of choline loading. The value and some limitations of the method are illustrated by results obtained in normal subjects, a patient with the Fish Odour syndrome and his kindred.

Cholinergic urticaria with associated angio‐oedema

Three patients are described who developed angio‐oedema and urticaria after a hot bath challenge and physical exercise. In one patient this was accompanied by a fall in peak expiratory flow rate. Blood levels of smooth muscle biological activity, measured using a bio‐assay, increased in all patients after experimental challenge. The association of angio‐oedema with cholinergic urticaria is emphasized and possible mechanisms discussed.