Hypoxic pulmonary vasoconstriction (HPV) is unique to pulmonary arteries, and aids ventilation/perfusion matching. However, in diseases like emphysema HPV can promote hypoxic pulmonary hypertension. Our previous investigations have demonstrated that the calcium mobilising second messenger cyclic adenosine diphosphate ribose (cADPR) is an important mediator of HPV (Wilson et al. 2001; Dipp & Evans, 2001). We describe here the relationship between the degree of hypoxia, cADPR levels and HPV in isolated rabbit pulmonary arteries. (Male New Zealand White rabbits were killed humanely by cervical dislocation.) In intact pulmonary arteries HPV was reproducible when stepping from a gas mixture containing 20 % O₂ to one containing 2 % O₂. Under these conditions a typical biphasic constriction was observed: an initial transient constriction followed by a slow tonic constriction. When we stepped from 20 % O₂ to 0 % O₂, however, the transient constriction increased in magnitude by approximately 10 % (n = 4). Surprisingly, however, phase 2 of HPV was abolished (Fig. 1).

In arteries without endothelium, stepping from 20 % O₂ to 2 % O₂ induced an initial transient constriction followed by a maintained cADPR-dependent plateau constriction. Once again, stepping from 20 % O₂ to 0 % O₂ augmented the initial transient constriction whilst abolishing the maintained plateau constriction (n = 4). The relationship between P_O2 and cADPR accumulation in the smooth muscle was also bell-shaped, consistent with the view that the plateau constriction by hypoxia is mediated by cADPR-dependent SR Ca²⁺ release. Thus hypoxia (16-21 Torr) increased cADPR content from 1.8 ± 0.04 pmol (mg protein)^-1 (mean ± S.E.M.) to 19.7 ± 1.1 pmol (mg protein)^-1 (n = 3), which returned to 1.91 ± 0.06 pmol (mg protein)^-1 in near-anoxic conditions (5-8 Torr; n = 3). We conclude that there is a P_O2 window within which cADPR accumulation in pulmonary artery smooth muscle and maintained HPV may be induced by hypoxia. Our previous findings suggested that an increase in β-NADH levels by hypoxia may result in inhibition of cADPR hydrolase activity and thereby promote, in part, cADPR accumulation (Wilson et al. 2001). However, we now propose that anoxia promotes a further reduction in β-NAD⁺ availability, leading to a situation where the supply of substrate (β-NAD⁺) for cADPR synthesis becomes rate limiting. As a consequence, increased β-NADH formation under anoxic conditions will result in a fall in cADPR accumulation and reversal/attenuation of HPV.