ET(B) receptor activates adenylyl cyclase via a c-PLA(2)-dependent mechanism: a novel counterregulatory mechanism of ET-induced contraction in airway smooth muscle.
Endothelin-1 (ET-1) contracted the rabbit tracheal smooth muscle (RTSM), yielding a bell-shaped tension-concentration curve. Moreover, ET-1 induced concentration- and time-dependent increases in cAMP concentrations in RTSM (EC(50), 58 nM; t(1/2), 2.4 min). Pretreatment with the AC inhibitors, SQ-22536, or 2'-5'-dideoxyadenosine, enhanced contraction to ET-1 and converted its bell-shaped tension curve into a sigmoidal one, but left contraction to carbachol and KCl unaltered. The potent ET(B)-receptor agonists, ET-3 or sarafotoxin-c, mimicked ET-1's effects on cAMP levels (EC(50) values 55 and 50 nM). Further, cAMP formation by ETs was inhibited by BQ-788 (selective ET(B) receptor blocker; IC(50), 8 nM), but not by BQ-610 (selective ET(A) receptor blocker). Removal of the epithelium did not prevent ET-induced increases in cAMP levels. Unlike isoproterenol, ETs failed to activate AC in membrane fractions from RTSM. In intact RTSM, the c-PLA(2) inhibitor, AACOCF3, and the cyclooxygenase inhibitor, indomethacin, blocked ET-induced increases in cAMP levels. These findings reveal a novel, nonepithelial, c-PLA(2)-mediated, regulatory mechanism downstream from ET(B) receptors.
El-Mowafy
A M
AM
Department of Applied Therapeutics, Kuwait University, Safat, 13110, Kuwait. aelmowafy@hsc.kuniv.edu.kw
Biggs
D F
DF
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D046508:Culture Techniques; D000242:Cyclic AMP / Q000096:biosynthesis; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D019334:Endothelin-3 / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000502:physiology*; D011817:Rabbits; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D015398:Signal Transduction; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014757:Viper Venoms
D000067956:Adenylyl Cyclase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D004791:Enzyme Inhibitors; D010455:Peptides; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014757:Viper Venoms; C089502:sarafotoxin-c; D000242:Cyclic AMP; D010741:Phospholipases A; D000262:Adenylyl Cyclases