Development of endothelin receptors in perinatal rabbit pulmonary resistance arteries.
1. Contractile responses to endothelin-1 (ET-1) and sarafotoxin S6c (S6c) were studied in pulmonary resistance arteries (approximately 320 microm i.d.) from fetal, 0-24 h, 4 day and 7 day rabbits. The effects of the ET(A)-selective antagonist FR139317, the selective ET(B) receptor antagonist BQ-788 and the non-selective ET(A)/ ET(B) receptor antagonist SB 209670, on these responses, were determined. Acetylcholine-induced vasodilation and noradrenaline-evoked contractions were also examined. 2. ET-1 potency was in the following order (pEC50 values): fetal (8.7) = 0-24 h (8.8) = 4 day (8.6) > 7 day (8.0). The order of potency for S6c was 7 days (11.1) = 4 days (10.8) > 0-24 h (9.7) > fetal (8.6). Hence, S6c and ET-1 were equipotent in the fetus but S6c was increasingly more potent than ET-1 with increasing age, being some 1000 times more potent by 7 days. By 7 days, responses to ET-1 were also resistant to both FR139317 and BQ-788. FR139317 inhibited responses to ET-1 in vessels from 0-24 h and 4 day, but not fetal, rabbits (pKb: 6.4 in 4 day rabbits). BQ-788 inhibited responses to ET-1 at all age points except for 7 days (pKb: 6.7 at 0-24 h; 6.2 at 4 days). BQ-788 inhibited responses to S6c at all age points (pKb: 8.5 at 4 days). SB 209670 inhibited responses to ET-1 and S6c at 0-24 h and 4 days (pKb for ET-1: 8.3 and 8.0 respectively; pKb for S6c: 9.2 and 10.2 respectively). 3. Acetylcholine (1 microM) induced vasodilation at all age points (inhibited by 100 microM L-N(omega)-nitroarginine methylester) although the degree of vasodilation was significantly reduced (approximately 75%) at 0-24 h. Noradrenaline induced contraction at all age points except 7 days and its response was significantly enhanced at 0-24 h. 4. Over the first week of life, the potency of S6c increases whilst that to ET-1 decreases suggesting differential development of responses to ET-1 and S6c and heterogeneity of ET(A)- or 'ET(B)-like' receptor-mediated responses. There is no synergism between ET(A) and ET(B) receptors at birth but this is established by 7 days. Immediately after birth rabbit Pulmonary Resistance Arteries are hyperresponsive to ET-1 and noradrenaline but exhibit impaired nitric-oxide dependent vasodilation.
Docherty
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Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow.
MacLean
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MR
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D011817:Rabbits; D017466:Receptors, Endothelin / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*; D014757:Viper Venoms / Q000494:pharmacology
D001381:Azepines; D019332:Endothelin-1; D007189:Indans; D007211:Indoles; D009842:Oligopeptides; D010880:Piperidines; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; C079574:FR 139317; D012701:Serotonin; C086539:BQ 788; D011189:Potassium Chloride; D000109:Acetylcholine; D009638:Norepinephrine