title: Involvement of ETA receptors in the facilitation by endothelin-1 of non-adrenergic non-cholinergic transmission in the rat urinary bladder.
abstract: 1. Endothelin-1 (ET-1; 3-10 nM) raised the tone of rat bladders bathed in buffer containing atropine (1 microM) plus guanethidine (3.4 microM). In addition, ET-1 potentiated, in a concentration-dependent fashion (1-10 nM), the contractions evoked by both transmural nerve stimulation and applications of exogenous adenosine 5'-triphosphate (ATP). 2. The threshold concentration of ET-1 required to facilitate non-adrenergic non-cholinergic (NANC) transmission and potentiate ATP-induced contractions, was about 10 fold lower than that required to increase the bladder tone (3 nM). 3. The ET-1-induced increase in basal tension reached its maximal effect within 60-90 s. In contrast, the 7.8 microM ATP-induced contractions increased by 50% within the first minute following incubation with 10 nM ET-1 but required about 5 min to develop the maximal effect. 4. The ET-1-induced potentiation of NANC or ATP responses was long-lasting and persisted in spite of extensive washing. The recovery of the bladder excitability depended on the concentration of ET-1. Following the application of 3 nM ET-1, recovery required 30 min; applications of 10 nM ET-1 required at least 60 min for full recovery. 5. The ET-1-induced potentiation of responses was selective for ATP and related structural analogues. ET-1 did not modify the contractions induced by acetylcholine, 5-hydroxytryptamine, prostaglandin F2 alpha or bradykinin. 6. The potency of ET-2 was similar to that of ET-1. ET-3 and ET-C-terminal hexapeptide were inactive up to 100 M. Sarafotoxin S6b was 2 to 3 fold less potent than ET-1 whereas sarafotoxin S6c (100 nM) was inactive. AGETB-9 and AGETB-89, two ETB receptor agonists, were also inactive (up to 100 nM). 7. Removal of one or both disulphide bonds in ET-1 and tryptophan-21 formylation of ET-1, resulted in inactive peptides (up to 100 nM). 8. The ET-1 receptor antagonists, BE-18257B and FR 139317, blocked both the ET-1-induced rise in tone and the potentiation of ATP responses in a concentration-dependent fashion. FR 139317 was at least 30 fold more potent than BE-18257B. Both antagonists blocked at lower concentrations the ET-1 increase in bladder tone as compared to the ATP potentiation. The antagonism was slowly reversible. 9. Results are consistent with the presence of ETA receptors in the rat bladder, which mediate both actions of ET-1. The interaction of ET-1 with purinergic mechanisms is discussed.
authors.affiliation: Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago.
authors.forename: M V
authors.initials: MV
authors.lastname: Donoso
authors.forename: C
authors.initials: C
authors.lastname: Salas
authors.forename: G
authors.initials: G
authors.lastname: Sepúlveda
authors.forename: J
authors.initials: J
authors.lastname: Lewin
authors.forename: A
authors.initials: A
authors.lastname: Fournier
authors.forename: J P
authors.initials: JP
authors.lastname: Huidobro-Toro
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D001381:Azepines / Q000494:pharmacology; D004558:Electric Stimulation; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects*; D011983:Receptors, Purinergic / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation*
chemical_list: D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007211:Indoles; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D011983:Receptors, Purinergic; C069764:cyclo(glutamyl-alanyl-isoleucyl-leucyl-tryptophyl); C079574:FR 139317; D000255:Adenosine Triphosphate