Response of Fetal Rabbit Ductus Arteriosus to Bradykinin: Role of Nitric Oxide, Prostaglandins, and Bradykinin Receptors

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Nitric oxide plays a major role in vascular tone control. Increased blood levels of bradykinin (BK), which stimulates nitric oxide biosynthesis, occur at birth. BK effects on ductus arteriosus (DA) tone were investigated in fetal rabbit under fetal (2.5% O2 "low PO2") and neonatal (30% O2 "high PO2") conditions using in vitro isometric tension studies. Intact and endothelium-denuded DA, contracted with norepinephrine (ED75-90), showed a biphasic response to BK, with relaxation at 10-9 to 10-7 M BK and contraction at 10-6 to 10-5 M BK. BK (10-6 to 10-5 M) contracted intact DA from baseline tension, with greater contraction under high PO2. The B2-receptor antagonist d-Arg-[Hyp3,Thi5,d-Tic7,Oic8]-BK (Hoe-140, 10-7 M) abolished relaxation, but not contraction, to BK in intact and denuded DA. The B1-receptor antagonist des-Arg9-[Leu8]-BK (10-7 M) reduced BK-induced contraction but not relaxation in intact DA only. Nitric oxide synthase inhibitors, Nω-nitro-L-arginine methyl ester (10-4 M) and Nω-monomethyl-L-arginine (10-4 M) partially inhibited relaxation to BK in intact DA, with L-arginine (3 × 10-4 M) reversing Nω-monomethyl-L-arginine inhibition. Nω-nitro-L-arginine methyl ester (10-4 M) caused a small but significant inhibition of relaxation to BK in denuded DA. Indomethacin (2.8 × 10-6 M), a cyclooxygenase inhibitor, abolished relaxation but not contraction to BK in intact and denuded DA. BK-induced relaxation of the DA acts through B2-receptors, releasing both nitric oxide and prostaglandins, whereas endothelial B1-receptors may mediate contraction. BK action on isolated DA changes from relaxation to contraction as its concentration increases, with greater contraction at neonatal PO2. Thus increased BK levels at birth may aid functional closure of the DA.

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