Response of fetal rabbit ductus arteriosus to bradykinin: Role of nitric oxide, prostaglandins, and bradykinin receptors

Nitric oxide plays a major role in vascular tone control. Increased blood l evels of bradykinin (BK), which stimulates nitric oxide biosynthesis, occur at birth. BK effects on ductus arteriosus (DA) tone were investigated in f etal rabbit under fetal (2.5% O-2 "low Po-2") and neonatal (30% O-2 "high P o-2") conditions using in vitro isometric tension studies. Intact and endot helium-denuded DA, contracted with norepinephrine (ED75-90) showed a biphas ic 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 fro m baseline tension, with greater contraction under high Po-2. The B-2-recep tor antagonist D-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-BK (HOe-140, 10(-7) M) abolished relaxation, but not contraction, to BK in intact and denuded DA. The B-1-receptor antagonist des-Arg(9)-[Leu(8)]-BK (10(-7) M) reduced BK-i nduced contraction but not relaxation in intact DA only. Nitric oxide synth ase inhibitors, N-omega-nitro-L-arginine methyl ester (10(-4) M) and N-omeg a-monomethyl-L-arginine (10(-4) M) partially inhibited relaxation to BK in intact DA, with L-arginine (3 x 10(-4) M) reversing N-omega-monomethyl-L-ar ginine inhibition. N-omega-nitro-L-arginine methyl ester (10(-4) M) caused a small but significant inhibition of relaxation to BK in denuded DA. Indom ethacin (2.8 X 10(-6) M), a cyclooxygenase inhibitor, abolished relaxation but not contraction to BK in intact and denuded DA. BK-induced relaxation o f the DA acts through B-2-receptors. releasing both nitric oxide and prosta glandins, whereas endothelial B-1-receptors may mediate contraction. BK act ion on isolated DA changes from relaxation to contraction as its concentrat ion increases, with greater contraction at neonatal Po-2. Thus increased BK levels at birth may aid functional closure of the DA.