Nitric oxide-endothelin-1 interactions after surgically induced acute increases in pulmonary blood flow in intact lambs.
Several congenital heart defects require surgery that acutely increases pulmonary blood flow (PBF). This can lead to dynamic alterations in postoperative pulmonary vascular resistance (PVR) and can contribute to morbidity and mortality. Thus the objective of this study was to determine the role of nitric oxide (NO), endothelin (ET)-1, and their interactions in the alterations of PVR after surgically induced increases in PBF. Twenty lambs underwent placement of an aortopulmonary vascular graft. Lambs were instrumented to measure vascular pressures and PBF and studied for 4 h. Before and after shunt opening, lambs received an infusion of saline (n = 9), tezosentan, an ETA- and ETB -receptor antagonist (n = 6), or Nomega-nitro-L-arginine (L-NNA), a NO synthase (NOS) inhibitor (n = 5). In control lambs, shunt opening increased PBF by 117.8% and decreased PVR by 40.7% (P < 0.05) by 15 min, without further changes thereafter. Plasma ET-1 levels increased 17.6% (P < 0.05), and total NOS activity decreased 61.1% (P < 0.05) at 4 h. ET-receptor blockade (tezosentan) prevented the plateau of PBF and PVR, such that PBF was increased and PVR was decreased compared with controls at 3 and 4 h (P < 0.05). These changes were associated with an increase in total NOS activity (+61.4%; P < 0.05) at 4 h. NOS inhibition (L-NNA) after shunt placement prevented the sustained decrease in PVR seen in control lambs. In these lambs, PVR decreased by 15 min (P < 0.05) but returned to baseline by 2 h. Together, these data suggest that surgically induced increases in PBF are limited by vasoconstriction, at least in part by an ET-receptor-mediated decrease in lung NOS activity. Thus NO appears to be important in maintaining a reduction in PVR after acutely increased PBF.
Oishi
Peter
P
Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143-0106, USA.
Azakie
Anthony
A
Harmon
Cynthia
C
Fitzgerald
Robert K
RK
Grobe
Albert
A
Xu
Jie
J
Hendricks-Munoz
Karen
K
Black
Stephen M
SM
Fineman
Jeffrey R
JR
D000818:Animals; D001783:Blood Flow Velocity; D019332:Endothelin-1 / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D011651:Pulmonary Artery / Q000503:physiopathology / Q000601:surgery; D011652:Pulmonary Circulation; D012756:Sheep; D014652:Vascular Diseases / Q000209:etiology* / Q000503:physiopathology*; D014656:Vascular Surgical Procedures / Q000009:adverse effects*
D019332:Endothelin-1; D009569:Nitric Oxide