Elevated leukocyte phosphodiesterase as a basis for depressed cyclic adenosine monophosphate responses in the Basenji greyhound dog model of asthma.
The BG dog manifests various characteristics of human asthma, including airway hyperreactivity to low concentrations of methacholine. Studies have suggested that airway hyperreactivity in asthma is related to inadequate intracellular cAMP responses. We studied cAMP characteristics in MNL from 19 BG and 14 mongrel dogs. beta-Adrenergic receptors were assessed by 125I CYP in the presence and absence of propranolol. The responses of cAMP to ISO were measured by radioimmunoassay. Adenylate cyclase activity was determined in homogenized MNL preparations by cAMP generation. PDE activity was quantitated by radioenzyme assay. Mongrel dog leukocyte ISO-stimulated cAMP levels doubled, whereas there were negligible increases in MNL from BG dogs. Basal PDE levels were higher in BG dogs than in mongrel dogs. The PDE inhibitor Ro 20-1724 restored ISO-stimulated cAMP responses in MNL of BG dogs. Adenylate cyclase activity was not lower in MNL homogenates from BG dogs than in mongrel dogs. Cells from both BG and mongrel dogs demonstrated similar receptor numbers and affinities of saturable, specific beta-adrenergic binding over a 10 pM to 400 pM range. Our results suggest that depressed cAMP responses in BG dogs are due to high PDE activity rather than to a defect in the beta-adrenergic receptor adenylate cyclase system.
Chan
S C
SC
Hanifin
J M
JM
Holden
C A
CA
Thompson
W J
WJ
Hirshman
C A
CA
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000276:immunology / Q000662:veterinary*; D000242:Cyclic AMP / Q000502:physiology*; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000201:enzymology*; D004285:Dogs; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol; D007962:Leukocytes / Q000201:enzymology*; D008214:Lymphocytes / Q000145:classification; D008688:Methacholine Compounds / Q000494:pharmacology; D009000:Monocytes / Q000201:enzymology; D010727:Phosphoric Diester Hydrolases / Q000097:blood*; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism
D007457:Iodine Radioisotopes; D008688:Methacholine Compounds; D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D010869:Pindolol; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases