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(Circulation Research. 2001;89:77.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Cyclic ADP-Ribose Is the Primary Trigger for Hypoxic Pulmonary Vasoconstriction in the Rat Lung In Situ

Michelle Dipp, A. Mark Evans

From the School of Biology (A.M.E.), University of St Andrews, Fife, and the University Laboratory of Physiology (M.D.), Oxford University, Oxford, UK.

Correspondence to A. Mark Evans, School of Biology, Bute Building, University of St Andrews, Fife, KY16 9TS, UK. E-mail ame3{at}st-and.ac.uk

Abstract

Abstract—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, Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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.

Key Words: cADP-ribose • pulmonary artery • hypoxia

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