Low-dose sodium nitrite vasodilates hypoxic human pulmonary vasculature by a means that is not dependent on a simultaneous elevation in plasma nitrite

Abstract

Inorganic nitrite has recently been recognized to possess vascular activity that is enhanced in hypoxia. This has been demonstrated in humans in the forearm vascular bed. In animal models nitrite reduces pulmonary vascular resistance, but its effects upon the pulmonary circulation of humans have not yet been demonstrated. This paradigm is of particular interest mechanistically since the pulmonary vasculature is known to behave differently to the systemic. To investigate, 18 healthy volunteers were studied in a hypoxic chamber (inspired oxygen, 12%) or while breathing room air. Each received an infusion of sodium nitrite (1 micromol/min) or 0.9% saline. Three protocols were performed: nitrite/hypoxia (n = 12), saline/hypoxia (n = 6), and nitrite/normoxia (n = 6). Venous blood was sampled for plasma nitrite, forearm blood flow was measured by strain-gauge plethysmography, and pulmonary arterial pressure was measured by transthoracic echocardiography. Plasma nitrite doubled and clearance kinetics were similar whether nitrite was infused in hypoxia or normoxia. During hypoxia, nitrite increased forearm blood flow (+36%, P < 0.001) and reduced three separate indirect indexes of pulmonary arterial pressure by 16%, 12%, and 17% (P < 0.01). Pulmonary, but not systemic, arterial effects persisted 1 h after stopping the infusion, at a time when plasma nitrite had returned to baseline. No effects were observed during normoxia. Therefore, in hypoxic but not normoxic subjects, sodium nitrite causes arterial and pulmonary vasodilatation. In addition, hypoxia-induced pulmonary vasoconstriction was attenuated for a prolonged period and not dependent on a simultaneous elevation of plasma nitrite. This finding is consistent with the direct extravascular metabolism of nitrite to nitric oxide to effect hypoxia-associated bioactivity.

Fig. 1.

Schematic diagram of the protocols followed. FiO₂, inspired oxygen.

Fig. 2.

Example traces of the echo surrogate markers of pulmonary arterial pressure used in normoxia (top) and after the hypoxia equilibration period (bottom). Left: peak tricuspid regurgitation (TR) waveform. Middle: pulmonary acceleration time (PAT) measured from the onset of forward pulmonary arterial systolic flow to its peak velocity. Right: the isovolumic relaxation time (IVRT) period of the right ventricle measured at the lateral tricuspid annulus.

Fig. 3.

Biochemical and physiological profiles during each protocol. Top: plasma nitrite concentration. Middle: forearm blood flow (FBF) measured by strain-gauge plethysmography. Bottom: pulmonary arterial systolic pressure, estimated from the velocity of TR. Pre, preinfusion. All statistical comparisons not shown were not significant.

Fig. 4.

Correlation of FBF to plasma nitrite concentration in both a hypoxic (top) and a normoxic (bottom) environment.