Inhibition of hypoxic pulmonary vasoconstriction by carbon monoxide in dogs

Objective: We tested the hypothesis that carbon monoxide might participate in the modulation of hypoxic pulmonary vasoconstriction (HPV) by prostacycl in (PGI(2)) and nitric oxide. Design: Prospective, interventional study. Setting: University laboratory. Subjects: Nineteen intact anesthetized mongrel dogs. Interventions: Right heart catheterization for the measurements of mean pul monary artery pressure (Ppa), left atrial pressure estimated from occluded Ppa (Ppao), pulmonary capillary pressure (Pcp) calculated from the Ppa deca y curve after balloon occlusion, and cardiac output (Q); inferior vena cava balloon for the control of Q by manipulation of venous return; ventilation in hyperoxia (fraction of inspired O-2, 0.4) or in hypoxia (F-IO2, 0.1); i nhibition of cyclooxygenase by indomethacin (Indo); inhibition of nitric ox ide synthase by N-G-nitro-L-arginine (L-NA); inhibition of heme oxygenase b y mesoporphyrin IX (SnMP); inhalation of nitric oxide (20 ppm); and inhalat ion of carbon monoxide (100 ppm). Measurements and Main Results: The first seven dogs were weak responders to hypoxia as assessed by a hypoxia-induced increase in the gradient between Ppa and Ppao, measured at one level of Q kept constant, by an average of on ly 2 mm Hg (p = NS). This HPV was markedly increased by the combined admini stration of Indo and L-NA. A further enhancement of HPV was observed after the addition of SnMP, leading to severe pulmonary hypertension with an aver age increase in Ppa to 39 mm Hg. Inhaled nitric oxide inhibited HPV only af ter the combined administration of Indo, L-NA, and SnMP. Inhaled carbon mon oxide had no effect. The next 12 dogs were stronger responders to hypoxia, as assessed by a hypo xia-induced increase in the gradient between Ppa and Ppao, measured at seve ral levels of Q, by an average of 3 mm Hg (p <.05). This HPV was of the sam e magnitude after administration of placebo (n = 6) or SnMP (n = 6). Additi on of Indo enhanced HPV to the same extent in the placebo and in the SnMP g roups. Addition of L-NA induced a further enhancement of HPV, which was, ho wever, greater in the SnMP group. There was a slight increase in the capill ary-venous segment relative to the arterial segment in hypoxic conditions, but the partitioning of pulmonary vascular resistance was otherwise unaffec ted by nitric oxide, carbon monoxide, or PGI(2). Conclusions: Endogenous carbon monoxide modulates canine HPV only in the ab sence of nitric oxide. The vasodilation mediated by nitric oxide, PGI(2), o r carbon monoxide is essentially distributed between proximal and distal si tes proportionally to the degree of constriction produced during hypoxia.