Non-epithelial endothelin-A receptors activate adenylate cyclase in rat trachea: biochemical mechanisms and physiological implications.
In the present study, we investigated the mechanisms underlying the differential effects of endothelins (ETs) in the rat trachea. Sarafotoxin-S6c (SRTX-c) and ET-3 were more potent spasmogens to rat tracheal strips than ET-1. The EC50 values were 12, 14.1 and 89.1 nM, respectively. Tension responses to ET-1 and ET-3, but not to SRTX-c, were enhanced by either indomethacin or the ET(A) blocker, BQ-610 (1 microM). In epithelium-intact tracheal rings, both ET-1 and ET-3 activated adenylate cyclase (AC) in a concentration-dependent manner. The activation by ET-1 of AC was significantly higher than that of ET-3. Thus, EC50 values for ET-1 and ET-3 were 71 and 200 nM, and maximal cAMP increments were 196% and 62% above baseline, respectively. SRTX-c, up to 1 microM, did not alter basal cAMP level. Mechanical removal of the epithelium neither had an effect on AC activation by ET-1 or ET-3, nor did it alter the inability of SRTX-c to modulate AC activity. Conversely, pre-incubation of tracheal strips with indomethacin (1 microM) virtually ablated the increments in cAMP by the ETs. Likewise, BQ-610 attenuated AC activation, concentration-dependently (IC50=28.2 nM). Taken together, the present study suggests that ET(A) receptors, from non-epithelial source, are functionally-linked to AC activation via a prostanoid-dependent pathway. This ET(A)-initiated cascade acts to negatively regulate muscle contraction. Such a cross-talk between ET signals most likely accounts for variation of tension responses to ET homologs.
El-Mowafy
A M
AM
Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt. Elmowafy@FRCU.EUN.EG
Abou-Mohamed
G A
GA
D000262:Adenylyl Cyclases / Q000187:drug effects*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*; D014132:Trachea / Q000187:drug effects* / Q000201:enzymology; D014757:Viper Venoms
D016232:Endothelins; D010455:Peptides; D017466:Receptors, Endothelin; D014757:Viper Venoms; C089502:sarafotoxin-c; D000242:Cyclic AMP; D000262:Adenylyl Cyclases