Pulmonary vasoconstriction during regional nitric oxide inhalation: Evidence of a blood-borne regulator of nitric oxide synthase activity

Background: Inhaled nitric oxide (INO) is thought to cause selective pulmonary vasodilation of ventilated areas. The authors previously showed that INO to a hyperoxic lung increases the perfusion to this lung by redistribution of blood flow, but only if the opposite lung is hypoxic, indicating a more complex mechanism of action for NO. The authors hypothesized that regional hypoxia increases NO production and that INO to hyperoxic lung regions (HL) can inhibit this production by distant effect. Methods: Nitric oxide concentration was measured in exhaled air (NO_E), NO synthase (NOS) activity in lung tissue, and regional pulmonary blood flow in anesthetized pigs with regional left lower lobar (LLL) hypoxia (fraction of inspired oxygen [F10₂] = 0.05), with and without INO to HL (F10₂ = 0.8), and during cross-circulation of blood from pigs with and without INO. Results: Left lower lobar hypoxia increased exhaled NO from the LLL (NO_ELLL) from a mean (SD) of 1.3 (0.6) to 2.2 (0.9) parts per billion (ppb) (P < 0.001), and Ca²⁺-dependent NOS activity was higher in hypoxic than in hyperoxic lung tissue (197 [86] vs. 162 [96] pmol · g^-1 · min^-1, P < 0.05). INO to HL decreased the Ca²⁺-dependent NOS activity in hypoxic tissue to 49 [56] pmol · g^-1 · min^-1 (P < 0.01), and NO_ELLL to 2.0 [0.8] ppb (P < 0.05). When open-chest pigs with LLL hypoxia received blood from closed-chest pigs with INO, NO_ELLL decreased from 2.0 (0.6) to 1.5 (0.4) ppb (P < 0.001), and the Ca²⁺-dependent NOS activity in hypoxic tissue decreased from 152 (55) to 98 (34) pmol · g^-1 · min^-1 (P = 0.07). Pulmonary vascular resistance increased by 32 (21)% (P < 0.05), but more so in hypoxic (P < 0.01) than in hyperoxic (P < 0.05) lung regions, resulting in a further redistribution (P < 0.05) of pulmonary blood flow away from hypoxic to hyperoxic lung regions. Conclusions: Inhaled nitric oxide downregulates endogenous NO production in other, predominantly hypoxic, lung regions. This distant effect is blood-mediated and causes vasoconstriction in lung regions that do not receive INO.