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Involvement of ET A receptors in the facilitation by endothelin‐1 of non‐adrenergic non‐cholinergic transmission in the rat urinary bladder
Author(s) -
Donoso M.V.,
Salas C.,
Sepúlveda G.,
Lewin J.,
Fournier A.,
HuidobroToro J.P.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14761.x
Subject(s) - guanethidine , endocrinology , medicine , chemistry , long term potentiation , stimulation , cholinergic , endothelin receptor , acetylcholine , endothelins , endothelin 1 , bradykinin , receptor , biology
1 Endothelin‐1 (ET‐1; 3–10 n m ) raised the tone of rat bladders bathed in buffer containing atropine (1 μ m ) plus guanethidine (3.4 μ m ). In addition, ET‐1 potentiated, in a concentration‐dependent fashion (1–10 n m ), 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 n m ). 3 The ET‐1‐induced increase in basal tension reached its maximal effect within 60–90 s. In contrast, the 7.8 μ m ATP‐induced contractions increased by 50% within the first minute following incubation with 10 n m 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 n m ET‐1, recovery required 30 min; applications of 10 n m 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 F 2α 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 n m ) was inactive. AGETB‐9 and AGETB‐89, two ET B receptor agonists, were also inactive (up to 100 n m ). 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 n m ). 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 ET A receptors in the rat bladder, which mediate both actions of ET‐1. The interaction of ET‐1 with purinergic mechanisms is discussed.