ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase act as a redox sensor - A primary role for cyclic ADP-ribose in hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction is unique to pulmonary arteries and serv es to match lung perfusion to ventilation. However, in disease states this process can promote hypoxic pulmonary hypertension. Hypoxic pulmonary vasoc onstriction is associated with increased NADH levels in pulmonary artery sm ooth muscle and with intracellular Ca2+ release from ryanodine-sensitive st ores. Because cyclic ADP-ribose (cADPR) regulates ryanodine receptors and i s synthesized from beta -NAD(+), we investigated the regulation by beta -NA DH of cADPR synthesis and metabolism and the role of cADPR in hypoxic pulmo nary vasoconstriction. Significantly higher rates of cADPR synthesis occurr ed in smooth muscle homogenates of pulmonary arteries, compared with homoge nates of systemic arteries. When the beta -NAD(+):beta -NADH ratio was redu ced, the net amount of cADPR accumulated increased. This was due, at least in part, to the inhibition of cADPR hydrolase by beta -NADH. Furthermore, h ypoxia induced a 10-fold increase in cADPR levels in pulmonary artery smoot h muscle, and a membrane-permeant cADPR antagonist, 8-bromo. cADPR, abolish ed 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 Ca2+ release. This redox-sensing pathway may offer new therapeutic targets for hypoxic pulmonary hypertension.