Hypoxic pulmonary vasoconstriction and nitric oxide

Abstract

Hypoxia causes pulmonary vasoconstriction (HPV), improving oxygenation by redistribution of the pulmonary blood flow to better oxygenated lung regions. HPV is intrinsic to the pulmonary vascular smooth muscle cell, but can be modulated by several vasoactive substances, as for example endothelium derived nitric oxide (NO) and endothelin-1 (ET-1). A stimulus-response relationship between alveolar oxygen tension and pulmonary vascular resistance (PVR) has been observed in animals. The degree of hypoxia has also been shown to be of importance for endogenous NO production in the lung, but results are conflicting. We hypothesized that the fraction of inhaled oxygen (FIO2) is of importance for the active regulation of pulmonary vascular tone by hypoxia, NO and ET-1. We tested whether the strength of HPV in human lungs is related to FIO2 and if regional hypoxia influences the endogenous enzymatic and non-enzymatic production of NO in pig lungs, and circulating ETI levels in plasma in humans and pigs. We also studied the mechanism of action for inhaled NO (INO) in relation to hyperoxic and hypoxic lung regions in humans and pigs. The studies were conducted in anesthetized, lung-healthy patients or pigs, which were double-lumen intubated, enabling separate and synchronous mechanical ventilation of the right and left lung (Patients), or the left lower lobe (LLL) and the other lung regions (Pigs). Regional pulmonary blood flow was measured by inert gas elimination technique (Patients), or by ultrasonic flow probes (Pigs).

We found a stimulus-response relationship between F102 and blood flow diversion, in the normal human lung. Exhaled NO concentration (NOE) from, and NO synthase (NOS) activity in hypoxic lung regions were significantly higher, than in hyperoxic lung regions. No significant changes were detected in plasma levels of ET-1-like immunoreactivity (ET-1-LI) during acute global or regional hypoxia. NOE was very low during NOS-blockade, but consistently higher in hypoxic than in hyperoxic lung regions. Infusion of nitrite during ongoing NOS-blockade increased NOE in a concentration-dependent manner, and much more in hypoxic than in hyperoxic lung regions. F102 was also shown to be of importance for the mechanism of action for NO. INO to hyperoxic lung regions, augmented the vaso-constriction in hypoxic lung regions, causing a further redistribution of pulmonary blood flow to hyperoxic lung regions in both Patients and Pigs. No such redistribution of pulmonary blood flow was observed in the absence of regional hypoxia. INO to hyperoxic lung regions, significantly decreased NOE from, and NOS activity in hypoxic lung regions, indicating a decreased endogenous enzymatic NO production in hypoxic lung regions. The mediator, or mediators causing this distant down-regulation of NO production was shown to be bloodborne, in a cross-circulation pig model. PVR increased and NOE decreased, predominantly in hypoxic lung regions, when pigs with regional LLL hypoxia received blood from pigs with INO, but not when they received blood from pigs without INO.

Conclusions: A stimulus-response relationship exists between F102 and blood flow diversion in the healthy human lung. Acute hypoxia increases endogenous enzymatic NO production, but not ET- I -LI in plasma. Non-enzymatic NO production from nitrite can occur in hypoxic lung regions. INO has dual effects, dilating vessels in lung regions directly reached by INO, and constricting vessels in lung regions not directly reached by INO. This distant effect is blood-borne, and more prominent in hypoxic, than in hyperoxic lung regions.