5-(N-ethylcarboxamido)adenosine desensitizes the A2b-adenosine receptor in lung circulation.
The adenosine agonist 5-(N-ethylcarboxamido)adenosine (NECA) induces vasodilation in the pulmonary circulation via A2-adenosine-receptor activation. We addressed whether prolonged treatment with NECA desensitizes in A2-adenosine- receptor function in isolated lung and pulmonary artery smooth muscle cells (PASMC). In lung microcirculation preconstricted with a hypoxic gas, initial administration of NECA caused a 57% vasodilatory response after 3-4 min. Readministration of NECA after 45 min resulted in minimal vasodilation. The highest accumulation of PASMC cAMP occurred 3-5 min after NECA, coincident with NECA-induced vasodilation. In PASMCs treated with NECA for 45 min, cAMP did not increase. Isoproterenol- and indolidan-induced vasodilation remained intact in NECA-desensitized lungs. In NECA-desensitized PASMCs, isoproterenol-induced cAMP accumulation was decreased, suggesting a common mechanism of desensitization. cAMP accumulation was decreased in cholera toxin-treated NECA-desensitized PASMCs compared with cholera toxin-treated control PASMCs, demonstrating that Gsalpha-adenylyl cyclase signaling contributes to desensitization. The A2a-adenosine-receptor agonist CGS-21680C neither increased cAMP accumulation in PASMCs nor attenuated NECA-induced vasodilation. These data support that the A2b-adenosine receptor is responsible for pulmonary vasodilation and desensitization through mechanisms(s) involving Gsalpha-adenylyl cyclase signaling.
Haynes
J
J
Pulmonary and Critical Care Division, Departments of Medicine, Physiology, Pathology, and Pharmacology, University of South Alabama College of Medicine, Mobile, Alabama 36688, USA.
Obiako
B
B
Babal
P
P
Stevens
T
T
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000097:blood* / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D010627:Phenethylamines; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000241:Adenosine; D007545:Isoproterenol