Cardiopulmonary effects of chronic administration of the NO synthase inhibitor L-NAME in the chick embryo.
BACKGROUND
Experimental observations in mammalian models suggest that endothelial nitric oxide (NO) synthase (NOS) content and activity are decreased in persistent pulmonary hypertension of the newborn.


OBJECTIVE
To test the hypothesis that disruption of NO signaling in the developing chick embryo lung may contribute to pulmonary hypertension.


METHODS
We analyzed pulmonary arterial reactivity and structure and heart morphology of 19-day chick embryos (incubation time 21 days) that received a daily injection of the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 20 mug per gram egg) or vehicle from day 12 until day 18.


RESULTS
Exposure to L-NAME did not affect embryonic survival or body mass of the embryos. The contractile responses to KCl, endothelin-1, the thromboxane A2 mimetic U46619, noradrenaline, and electrical-field stimulation were not affected by exposure to L-NAME. In contrast, in ovo L-NAME exposure reduced the sensitivity of pulmonary arteries to acetylcholine (pD2: 6.53 +/- 0.14 vs. 6.96 +/- 0.13; p < 0.05) and this effect was reversed by the NOS substrate L-arginine. Relaxations induced by sodium nitroprusside or forskolin were not altered by chronic L-NAME. Pulmonary vessel density was not different, but the percentage medial wall area of small pulmonary arteries (external diameter 10-50 microm) was slightly but significantly increased in the embryos exposed to L-NAME. In addition, hearts of L-NAME-exposed embryos showed an increase in right and left ventricular wall area.


CONCLUSIONS
Chronic inhibition of NOS produced, in the chick embryo, impairment of endothelium-dependent relaxation, structural remodeling of the pulmonary vascular bed and biventricular cardiac enlargement.
Villamor
Eduardo
E
Department of Pediatrics, Research Institute Growth and Development (GROW), University of Maastricht, Maastricht, The Netherlands. eiv@paed.azm.nl
Kessels
Carolina G A
CG
van Suylen
Robert J
RJ
De Mey
Jo G R
JG
Blanco
Carlos E
CE
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002642:Chick Embryo / Q000187:drug effects*; D004558:Electric Stimulation; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000196:embryology*; D008168:Lung / Q000187:drug effects / Q000196:embryology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000196:embryology; D013928:Thromboxane A2 / Q000031:analogs & derivatives; D013997:Time Factors
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D013928:Thromboxane A2; D011189:Potassium Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine