Bjorn R Lindgren, MD PhD; Ulf Rosen...

Bjorn R Lindgren, MD PhD; Ulf Rosenquist, MD; Tommy Ekstrom MD; Reidar Gronneberg, MD PhD FCCP; [unkeyable] Bengt E Karlberg, MD Ph.D.,[unkeyable] and Rolf G G Andersson, PhD Section

The aim of this research was to investigate whether ACE-inhibitors could influence bronchial reactivity and interfere with inflammatory skin answers Ten hypertensive subjects, who had reacted with cough during ACE-inhibitor therapy, were treated in a double-blind crossover fashion for pair weeks with enalapril and with placebo. Enalapril reduc the [PCsub20] value for histamine and augmented the dermal replication Circulating eosinophilic leukocyte on a level in venous blood dropped markedly after the histamine bronchoprovocation performed during enalapril treatment. Plasma substance P was reduc after histamine provocation performed during placebo treatment, whereas this reduction was abolished according to enalapril. In this meditation we have demonstrated ACE-inhibitor-induction of moderately increased bronchial reactivity in controls with suspected ACE-inhibitor-elicited coughs. It is refer toed that coughing during ACE-inhibitor therapy is to be paid to an increased inflammatory state in the airways. (Chest 1989;95:1225-30)

[PCsub20] = histamine concentration causing a 20 percent reduction of [FEVsub1]; PRA = plasma renin activity

After the discovery and isolation of teprotide, the first known ACE inhibitor, from the venom of the Brazilian pit viper Bothrop jararaca, synthesized ACE inhibitors have become widely used in the treatment of hypertension and congestive heart failure. In addition to inhibiting the conversion of angiotensin I to II, ACE inhibitors have been demonstrated to decrease the metabolism of bradykinin[1,2] and substance P[3-5] which are important proinflammatory mediators. Adverse skin and mucosal reactions are associated with ACE-inhibitor treatment.[6-8] Lately, interest has been focused upon ACE inhibitor-induced coughs which appear to be to occur more frequently than was previously believed, possibly because of difficulties the one and the other patients and doctors have in relating this symptom to the antihypertensive therapy. Several studies have reported suspected ACE inhibitor-induced cough in about 10 to 30 percent of studied subjects[9-16] It has been moveed that cycloxygenase products might be involved in the pathogenesis of this cough since the cyclooxygenase inhibitor sulindac relieved symptoms in a patients[17] and since ACE inhibition is known to interfere with the production of prostaglandins.[18]

Capsaicin is a naturally occurring substance derived from plants of the Solanaceae family and known as the piquant of chilies. Its custom of action is not completely understood, unless capsaicin causes an initial release as well as a depletion of neuropeptides, eg substance P from primary sensory neurons[1920] The capsaicin-induced cough bent back has been demonstrated to be augmented following ACE-inhibitor treatment.[11,21] Bronchial reactivity to histamine and bradykinin was not changed in six enslaves with mild asthma given individual dose of ramipril.[22]

A useful correlation exists between bronchial and dermal inflammatory responses[23] and ACE inhibitor-induced adverse reactions in the airways and the skin occasionally have been observ to be accompanied by the agency of eosinophilia.[13,24,25] Infiltration of inflammatory lonely dwellings eg, eosinophils, into allergen-treated example sites in sensitized guinea pigs was increased by dint of ACE inhibition as well as the wheal and flare reactions evok at allergen, capsaicin, and bradykinin.[26,27]

The aim of the near study was to investigate whether ACE inhibition could influence bronchial reactivity and anti-human IgE-evoked skin answers in subjects with coughs previously earnestly suspected of being ACE inhibitor-induced. The consideration was approved by the ethical committee of Linkoping University Hospital. [TABULAR DATA OMITTED]

MATERIALS AND METHODS

make liables and Treatment

cogitation subjects were ten hypertensive patients, three men and seven women (Table 1) who had previously reacted with persistent cough during ACE-inhibitor therapy. The controls were skin tested with anti-human IgE and histamine bronchoprovocation, at the cessation of two-week-long treatment periods, with enalapril (10 mg twice a day) and placebo. remedys were administered in a randomized, double blind cross-over manner and given quite through the four-week-long study. All antihypertensive medication was suspended during a three-week run-in period. single in kind subject (No. 5) had stable bronchial asthma and continued with regular inhalations of corticosteroids twice daily in every part the study.

Intradermal Skin Testing

Intradermal skin testing was performed between days 13 and 27 and the inflammatory answer was followed for 24 h At the beginning of each exhibition 15[unkeyable]L of diluted (1/200 vol/vol ratio) heterologous whole anti-human IgE, raised in rabbits against a mixture of isolated Fc fragments from the epsilon chain from a human IgE myeloma protein, was injected intradermally.[28] This was done by way of means of an Agla micrometer syringe outfit (Wellcome Reagents Ltd Beckenham, England) in sum of two units skin sites in the volar area of the forearms. single injection was given in the distal half of undivided arm, and the other in the proximal half of the other arm. pair weeks later tests were performed onward the half of the forearm that had not previously been used in order to avoid the riddle of the skin being in a refractory phase.[29] sum of two units perpendicular diameters of the roughly circular flare/erythema reaction areas were measured 025 05 1 3 6 12 and 24 h after the intradermal injections of anti-IgE. The mean diameter area was calculated, assuming a circular shape, according to the formula: