Developmental changes in endothelium-dependent vasodilation and the influence of superoxide anions in perinatal rabbit pulmonary arteries.
ACh-induced vasodilation was investigated in pulmonary arteries from 8 and 2 day pre-term foetal, neonatal (0-12 h and 4 day old) and adult rabbits. The effects of superoxide anion generation [with hypoxanthine (HX, 0.1 mM)/xanthine oxidase (XO, 15 mu ml(-1))], endogenous superoxide dismutase (SOD) inhibition [with the Cu-Zn SOD inhibitor triethylenetetramine (TETA, 1 mM)], endogenous superoxide anion scavenging [by superoxide dismutase (SOD, 50 u ml(-1))] and inhibition of endothelial nitric oxide synthase (eNOS) [with, Nomega-nitro-L-arginine methylester (L-NAME, 0.1 mM)], on basal and ACh-induced NO activity were studied by examining phenylephrine-induced contraction and ACh-induced vasodilation respectively. L-NAME and endothelium removal abolished all ACh-induced vasodilation and 1 microM sodium nitroprusside fully dilated all vessels. ACh-induced vasodilation was absent in the 8 day pre-term foetus and 0-12 h neonate but present at all other ages. L-NAME itself contracted 2 day pre-term foetal vessels. At 0 12 h, SOD, but not the phosphodiesterase 5 inhibitor zaprinast (1 microM), uncovered ACh-induced vasodilation. At this age SOD reduced phenylephrine-induced contraction which was not influenced by TETA, L-NAME or HX/XO, and L-NAME itself did not cause contraction. This suggests both ACh-induced and basal NO activity are compromise in these vessels by endogenous superoxide anion production and deficiencies in endogenous SOD activity. In 4 day vessels, but not adult vessels, L-NAME, TETA and HX/XO augmented contractions to phenylephrine, and L-NAME itself induced vasoconstriction, suggesting that basal NO and SOD activities were present by 4 days but were not evident in the adult. ACh-induced NO activity, and the influence of endogenous SOD on this, were present in the adult (and 4 day) vessels as superoxide generation with HX/XO significantly reduced ACh-induced vasodilation and this effect was inhibited by SOD and augmented by TETA. Increased oxygen tensions > 500 mmHg attenuated ACh-induced vasodilation in the foetal but not neonatal rabbits. Raising the oxygen tension from approximately 20 to approximately 120 mmHg revealed ACh-induced vasodilation in the 8 day pre-term vessels. In summary, superoxide anion accumulation combined with deficiencies in SOD activity may transiently compromise basal and ACh-induced NO activity at birth. Experimental oxygen tensions markedly influence ACh-induced vasodilation in foetal rabbit pulmonary arteries.
Morecroft
I
I
Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, Glasgow University.
MacLean
M R
MR
D000109:Acetylcholine; D000818:Animals; D000831:Animals, Newborn; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000254:growth & development / Q000502:physiology*; D011688:Purinones / Q000494:pharmacology; D011817:Rabbits; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D013481:Superoxides; D009569:Nitric Oxide; D013482:Superoxide Dismutase; C011145:zaprinast; D000109:Acetylcholine; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester