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 mm i.d.) from fetal, 0 ± 24 h, 4 day and 7 day rabbits. The eects of the ET Aselective 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 (pEC 50 values): fetal (8.7) = 0 ± 24 h (8.8) = 4 day (8.6) 4 7 day (8.0). The order of potency for S6c was 7 days (11.1) = 4 days (10.8) 40 ± 24 h (9.7) 4 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 mM) induced vasodilation at all age points (inhibited by 100 mM L-N o -nitroarginine methylester) although the degree of vasodilation was signi®cantly reduced (*75%) at 0 ± 24 h. Noradrenaline induced contraction at all age points except 7 days and its response was signi®cantly enhanced at 0 ± 24 h. 4 Over the ®rst week of life, the potency of S6c increases whilst that to ET-1 decreases suggesting dierential development of responses to ET-1 and S6c and heterogeneity of ET A -or`ET B -like' receptormediated 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.

5‐Hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries

“…This suggests variable developmental changes in 5-HT receptor sensitivity or changes in the coupling of the second messenger system with the contractile apparatus. We have recently reported a similar phenomenon for ET-1 induced contraction in the same preparations (Docherty & MacLean, 1998).…”

“…However, we have previously shown that noradrenaline itself is a very poor vasoconstrictor of perinatal rabbit pulmonary resistance arteries and actually fails to contract pulmonary resistance arteries from adult rabbits (Docherty & MacLean, 1998). In addition, preliminary experiments in adult vessels failed to demonstrate any e ect of a 1 -adrenoceptor antagonists on responses to 5-HT in rabbit pulmonary arteries (unpublished observations).…”

“…Vessels were contracted with endothelin-1 (ET-1) (0.1 ± 1 nM) as it reliably induces a maintained contraction in these vessels (Docherty & MacLean, 1998). Vessels were precontracted to give a contraction approximately half the maximal contractile response to this ET-1 as preliminary studies indicated that contraction above this level actually decreased the sensitivity of vasodilators including 5-CT. We studied vasodilation in responses to 5-CT as preliminary results showed that 5-HT gave a variable vasodilator response with a tendency to cause contraction at higher concentrations in preconstricted PRAs.…”

Postnatal changes in pulmonary vein responses to endothelin-1 in the normal and chronically hypoxic lung

“…Experimental studies have shown that the contractile response to ET-1 decreases with increasing age in rabbit pulmonary arteries (7). The effect of age on the pharmacological responses of the porcine pulmonary veins to ET-1 has not been reported; however, as the threshold for ET-1-induced contraction is lower in pulmonary veins than in pulmonary arteries in the fetal lamb (29) and human (4), it is likely that the veins may also exhibit developmental changes in response to ET-1.…”

Endothelial Modulation of Vasoconstrictor Responses in the Perfused Rabbit Ovarian Vascular Bed

“…It was also important to pursue the possibility that the endothelium may release endothelin-1 in response to NA. The nonselective endothelin antagonist SB209670 [20] did not modulate the vasoconstrictor response to NA. Thus, the possibility that the vascular endothelium in this preparation releases endothelins in response to NA was excluded.…”