Development of endothelin receptors in perinatal rabbit pulmonary resistance arteries

Abstract

1. Contractile responses to endothelin-1 (ET-1) and sarafotoxin S6c (S6c) were studied in pulmonary resistance arteries (∼320 μm 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 (pK_b: 6.4 in 4 day rabbits). BQ-788 inhibited responses to ET-1 at all age points except for 7 days (pK_b: 6.7 at 0–24 h; 6.2 at 4 days). BQ-788 inhibited responses to S6c at all age points (pK_b: 8.5 at 4 days). SB 209670 inhibited responses to ET-1 and S6c at 0–24 h and 4 days (pK_b for ET-1: 8.3 and 8.0 respectively; pK_b for S6c: 9.2 and 10.2 respectively).

3. Acetylcholine (1 μM) induced vasodilation at all age points (inhibited by 100 μM L-N^ω-nitroarginine methylester) although the degree of vasodilation was significantly reduced (∼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.

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