title: New aspects on inflammatory reactions and cough following inhibiton of angiotensin converting enzyme.
abstract: The first inhibitor of angiotensin converting enzyme (ACE) was found in and isolated from the venom of the South American pit viper Bothrops jararaca. This was done after it was discovered that bites of the pit viper inhibit the breakdown of a proinflammatory peptide, bradykinin, in prey. Treatment with newly developed orally active ACE-inhibitors has been reported to cause symptoms such as adverse skin reactions, angioneurotic oedema, coughs and, in asthmatics, rapidly decreasing lung function. In this thesis the ACE-inhibitor MK 422 (active parent diacid of enalapril) was demonstrated to potentiate wheal and flare reactions induced by allergens, bradykinin or capsaicin, and to increase infiltration of "inflammatory cells", like eosinophils and neutrophils, into inflammatory dermal test sites in sensitized guinea pigs. MK 422 also augmented spontaneous and allergen-triggered histamine release in vitro from guinea pig skin and lung tissue. Capsaicin "desensitization" of guinea pig skin markedly reduced the wheal and flare reactions to allergens and attenuated the proinflammatory effect of the ACE-inhibitor. The histamine release in vitro from capsaicin-pretreated skin was also decreased, and no clear potentiating effect of MK 422 was demonstrated. In man, enalapril augmented anti-IgE-induced wheal and flare responses and increased bronchial reactivity to histamine. The drop of circulating eosinophils in venous blood was more pronounced after the provocations performed during enalapril treatment, and plasma substance P tended to increase. The alpha 2-adrenoceptor agonist clonidine, known to attenuate "neurogenic inflammation", reduced the wheal and flare reactions in guinea pig skin and decreased infiltration of neutrophils and eosinophils into inflammatory test sites. Furthermore, clonidine abolished the proinflammatory effect of MK 422 on the allergen- evoked wheal and flare reactions in guinea pig skin without counteracting the blood pressure lowering effect of the ACE-inhibitor. Contrarily, an additive hypotensive effect was demonstrated when clonidine was combined with MK 422. It is suggested that the proinflammatory properties demonstrated by ACE-inhibitors is due to augmentation of "neurogenic inflammation".
authors: Department of Zoophysiology, Uppsala University, Sweden.
authors: B R
authors: BR
authors: Lindgren
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage; D002211:Capsaicin / Q000008:administration & dosage; D003371:Cough / Q000139:chemically induced* / Q000276:immunology; D003875:Drug Eruptions / Q000209:etiology* / Q000276:immunology; D004656:Enalapril / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D015773:Enalaprilat; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007271:Injections, Intradermal; D010047:Ovalbumin / Q000008:administration & dosage; D012867:Skin / Q000276:immunology*; D012882:Skin Tests
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D010047:Ovalbumin; D015773:Enalaprilat; D002211:Capsaicin; D001920:Bradykinin