Hypoxic pulmonary vasoconstriction (HPV) is unique to pulmonary arteries, and it
aids ventilation/perfusion matching. However, in diseases such as
emphysema, HPV can promote hypoxic
pulmonary hypertension. We recently showed that
hypoxia constricts pulmonary arteries in part by increasing
cyclic ADP-ribose (
cADPR) accumulation in the smooth muscle and, thereby, Ca(2+) release by
ryanodine receptors. We now report on the role of
cADPR in HPV in isolated rat pulmonary arteries and in the rat lung in situ. In isolated pulmonary arteries, the membrane-permeant
cADPR antagonist,
8-bromo-cADPR, blocked sustained HPV by blocking Ca(2+) release from smooth muscle
ryanodine-sensitive stores in the sarcoplasmic reticulum. Most importantly, we showed that
8-bromo-cADPR blocks HPV induced by alveolar
hypoxia in the ventilated rat lung in situ. Inhibition of HPV was achieved without affecting (1) constriction by membrane depolarization and voltage-gated Ca(2+) influx, (2) the release (by
hypoxia) of an endothelium-derived
vasoconstrictor, or (3) endothelium-dependent vasoconstriction. Our findings suggest that HPV is both triggered and maintained by
cADPR in the rat lung in situ.