Effects of chronic pulmonary overcirculation on pulmonary vasomotor tone.
BACKGROUND
A model of shunt-induced pulmonary hypertension was used to study the effects of pulmonary overcirculation on endothelial nitric oxide synthase (eNOS) and cytochrome P450-4A (cP450-4A) vasodilatory mechanisms and related hemodynamic responses.


METHODS
An aortopulmonary shunt was constructed in 6-week-old piglets (n = 7, sham-operated controls n = 8). Hemodynamic measurements were made 4 weeks later under serial experimental conditions: baseline (fractional concentration of oxygen, 0.4); inhaled nitric oxide, 25 ppm (INO); hypoxia (fractional concentration of oxygen, 0.14); hypoxia + INO; N(omega)-nitro-L-arginine methylester (L-NAME 30 mg/kg intravenously, competitive NOS inhibitor); and L-NAME + INO. Lung protein levels of eNOS and cP450-4A and NOS activity were compared between groups.


RESULTS
Shunted animals had a higher baseline pulmonary artery pressure (p < 0.05). L-NAME resulted in a greater increase in pulmonary vascular resistance in shunted animals (150% +/- 26% shunt versus 69% +/- 14% control; p = 0.01). The INO administered during baseline conditions decreased pulmonary vascular resistance only in control animals (p < 0.05). Protein levels of eNOS and NOS activity were similar in both groups; however, cP450-4A protein levels were decreased in the shunted group (p = 0.02).


CONCLUSIONS
The NO production was preserved in shunted animals but they demonstrated greater vasodilatory dependence on NO, evidenced by an exaggerated increase in pulmonary vascular resistance after NOS inhibition. Loss of the cP450-4A vasodilatory system may be the driving force for NO dependency in the shunted pulmonary circulation.
Parviz
M
M
Department of General Surgery, Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee 53226, USA.
Bousamra
M
M
Chammas
J H
JH
Birks
E K
EK
Presberg
K W
KW
Jacobs
E R
ER
Nelin
L D
LD
D000818:Animals; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000097:blood*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology*; D006899:Mixed Function Oxygenases / Q000097:blood*; D019001:Nitric Oxide Synthase / Q000097:blood*; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D011669:Pulmonary Wedge Pressure / Q000502:physiology; D013552:Swine; D014655:Vascular Resistance / Q000502:physiology; D014666:Vasomotor System / Q000473:pathology / Q000503:physiopathology*
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019001:Nitric Oxide Synthase; D042926:Cytochrome P-450 CYP4A