Hypoxic pulmonary vasoconstriction is unique to pulmonary arteries and serves to match lung perfusion to ventilation. However, in disease states this process can promote hypoxic
pulmonary hypertension. Hypoxic pulmonary vasoconstriction is associated with increased
NADH levels in pulmonary artery smooth muscle and with intracellular Ca(2+) release from
ryanodine-sensitive stores. Because
cyclic ADP-ribose (
cADPR) regulates
ryanodine receptors and is synthesized from beta-
NAD(+), we investigated the regulation by beta-
NADH of
cADPR synthesis and metabolism and the role of
cADPR in hypoxic pulmonary vasoconstriction. Significantly higher rates of
cADPR synthesis occurred in smooth muscle homogenates of pulmonary arteries, compared with homogenates of systemic arteries. When the beta-
NAD(+):beta-
NADH ratio was reduced, the net amount of
cADPR accumulated increased. This was due, at least in part, to the inhibition of
cADPR hydrolase by beta-
NADH. Furthermore,
hypoxia induced a 10-fold increase in
cADPR levels in pulmonary artery smooth muscle, and a membrane-permeant
cADPR antagonist,
8-bromo-cADPR, abolished hypoxic pulmonary vasoconstriction in pulmonary artery rings. We propose that the cellular redox state may be coupled via an increase in beta-
NADH levels to enhanced
cADPR synthesis, activation of
ryanodine receptors, and sarcoplasmic reticulum Ca(2+) release. This redox-sensing pathway may offer new therapeutic targets for hypoxic
pulmonary hypertension.