Action of carbon dioxide on hypoxic pulmonary vasoconstriction in the rat lung: evidence against specific endothelium-derived relaxing factor-mediated vasodilation.
OBJECTIVE
The effect of hypercapnia on pulmonary vascular tone is controversial with evidence for both a vasoconstrictor and vasodilator action. The objective of this study was to investigate the possibility that this dual response to CO2 could be explained by a direct constrictor action on smooth muscle and an indirect dilator action via the release of endothelium-derived relaxing factor. The effect of ventilation with hypercapnia (FICO2 0.15) on pulmonary pressor response to hypoxia (FIO2 0.3) was investigated.


METHODS
Prospective, randomized study.


METHODS
The National Heart and Lung Institute, UK.


METHODS
The isolated, blood-perfused rat lung.


METHODS
Angiotensin-II and a blocker of endothelium-derived relaxing factor synthesis, NG-monomethyl-L-arginine (L-NMMA).


RESULTS
The vasomotor effect of hypercapnia depended on pulmonary arterial pressure. Under resting tone, CO2 acted as a mild constrictor (change in mean pulmonary arterial pressure from 14 +/- 2 to 15 +/- 2 mm Hg, n = 4; p < .05. At increased tone, induced either by hypoxia or Angiotensin-II, CO2 was a vasodilator. Thus, hypoxia increased mean pulmonary arterial pressure from 17 +/- 2 to 32 +/- 2 mm Hg (n = 8; p < .01), but simultaneous ventilation with hypoxia and hypercapnia reduced this by 16 +/- 1% (p < .01). Angiotensin-II (1 microgram) increased pulmonary arterial pressure from 14 +/- 2 to 39 +/- 5 mm Hg (n = 8; p < .01), but with hypercapnia, this angiotensin-induced pulmonary vasoconstriction was reduced by 18 +/- 6% (p < .001). The reduction in hypoxic pulmonary vasoconstriction induced by hypercapnia was not significantly different from that seen with Angiotensin-II hypercapnia. Blocking endothelium-derived relaxing factor synthesis using 30 microM NG-monomethyl-L-arginine did not significantly change either basal pulmonary arterial pressure or the response to hypercapnia, but increased hypoxic pulmonary vasoconstrictor by 24 +/- 4% (n = 4; p < .01). There was no significant difference between the change in hypoxic pulmonary vasoconstriction induced by hypercapnia after saline control (21 +/- 8% decrease) and the change in hypoxic pulmonary vasoconstriction caused by CO2 after 30 microM L-NMMA (25 +/- 10% decrease, p < .05, n = 8).


CONCLUSIONS
Endothelium-derived relaxing factor seems unlikely to specifically modulate CO2-induced vasodilation in the rat pulmonary circulation.
Baudouin
S V
SV
Department of Anaesthesia and Intensive Care, National Heart and Lung Institute, London, UK.
Evans
T W
TW
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D001784:Blood Gas Analysis; D002245:Carbon Dioxide / Q000494:pharmacology*; D003251:Constriction, Pathologic / Q000139:chemically induced / Q000503:physiopathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006935:Hypercapnia / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D000860:Hypoxia / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012121:Respiration, Artificial; D014655:Vascular Resistance / Q000187:drug effects*; D019323:omega-N-Methylarginine
D000804:Angiotensin II; D002245:Carbon Dioxide; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine