Effects of phosphodiesterase isoenzyme inhibitors on cutaneous inflammation in the guinea-pig.
1. Inflammation is central to the pathophysiology of asthma. The recent findings that different inflammatory cells may express different phosphodiesterase (PDE) isoenzymes have centered attention on inhibitors of these isoenzymes as new drugs for the treatment of asthma. In this study, we investigated the effect of different PDE isoenzyme inhibitors on the accumulation of 111In-labelled eosinophils and local oedema formation at sites of allergic- and mediator-induced inflammation in guinea-pig skin. 2. Systemic treatment with SK&F 94120, a type III PDE inhibitor, or zaprinast, a type V PDE inhibitor, had no effect on the 111In-eosinophil accumulation and oedema formation induced by i.d. injection of zymosan-activated plasma (ZAP), PAF, histamine or in a passive cutaneous anaphylaxis (PCA) reaction. 3. Systemic treatment with rolipram, a type IV PDE inhibitor, effectively inhibited 111In-eosinophil accumulation induced by ZAP, PAF, histamine and in a PCA reaction. However, oedema formation measured in the same sites was not affected. Systemic administration of higher doses of theophylline produced similar results. In contrast, 111In-neutrophil accumulation induced by ZAP or in a PCA reaction was not altered by systemic treatment with rolipram. 4. Locally-injected rolipram had little effect on 111In-eosinophil accumulation and oedema formation induced by histamine, PAF and in a PCA reaction. 5. These data show that systemic, but not local, treatment with rolipram effectively inhibits allergic- and mediator-induced 111In-eosinophil accumulation but not oedema formation or 111In-neutrophil accumulation. This, taken together with the potent inhibitory effects of PDE type IV inhibitors on eosinophil function in vitro, suggest that this class of drugs may be beneficial in disease states such as asthma where eosinophils are thought to play a major pathophysiological role.
Department of Applied Pharmacology, National Heart and Lung Institute, London.
M M
MM
Teixeira
A G
AG
Rossi
T J
TJ
Williams
P G
PG
Hellewell
D000818:Animals; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002316:Cardiotonic Agents / Q000494:pharmacology; D003872:Dermatitis / Q000188:drug therapy* / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007205:Indium Radioisotopes; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D012867:Skin / Q000378:metabolism / Q000473:pathology
D002147:Calmodulin; D002316:Cardiotonic Agents; D007205:Indium Radioisotopes; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011719:Pyrazines; D011760:Pyrrolidinones; C048350:5-(4-acetamidophenyl)pyrazin-2(1H)-one; C011145:zaprinast; D020889:Rolipram