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

Circulation Research - Tập 89 Số 1 - Trang 77-83 - 2001
Michelle Dipp1, Allan M. Evans2
1Michelle Dipp 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.
2A. 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.

Tóm tắt

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, 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.

Từ khóa


Tài liệu tham khảo

10.1111/j.1748-1716.1946.tb00389.x

Voelkel NF. Mechanisms of hypoxic pulmonary vasoconstriction. Am Rev Respir Dis. 1986;133:1186–1195.

10.1152/ajpcell.1992.262.4.C882

10.1038/sj.bjp.0701075

Cornfield D, Stevens T, McMurty I, Abman S, Rodman D. Acute hypoxia causes membrane depolarization and calcium influx in fetal pulmonary artery smooth muscle cells. Am J Physiol. 1993;265:L53–L56.

10.1152/ajpcell.1993.264.2.C323

Kovitz KL, Aleskowitch JT, Sylvester JT, Flavahan NA. Endothelium-derived contracting and relaxing factors contribute to hypoxic responses of pulmonary arteries. Am J Physiol. 1993;260:L516–L521.

Robertson TP, Aaronson PI, Ward JPT. Hypoxic vasoconstriction and intracellular Ca2+ in pulmonary arteries: evidence for PKC-independent Ca2+ sensitization. Am J Physiol. 1995;268:H301–H307.

Dipp M Nye PCG Evans AM. Hypoxia induces sustained sarcoplasmic reticulum calcium release in rabbit pulmonary artery smooth muscle in the absence of calcium influx. Am J Physiol. In press.

10.1038/sj.bjp.0701326

10.1161/circ.96.10.3647

10.1016/S0021-9258(18)94230-4

10.1016/0167-4889(91)90032-S

10.1126/science.1909457

Wilson HL, Dipp M, Thomas JM, Lad C, Galione A, Evans AM. ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase act as a redox sensor: a primary role for cADPR in hypoxic pulmonary vasoconstriction. J Biol Chem. 2000;276:11180–11188.

10.1161/res.41.1.862138

10.1074/jbc.272.26.16358

Leach RM, Robertson TP, Twort CHC, Ward JPT. Hypoxic vasoconstriction in rat pulmonary and mesenteric arteries. Am J Physiol. 1994;266:L223–L231.

10.1111/j.1469-7793.2000.t01-1-00669.x

10.1038/sj.bjp.0703537

10.1152/ajplung.2000.278.2.L294

Nye PCG, Robertson BA, Warren H. Inhibition of nitric oxide production enhances hypoxic pulmonary vasoconstriction of the isolated rat lung. J Physiol. 1990;422:94P.

10.1172/JCI113757

Johns RA, Linden JM, Peach MJ. Endothelium-dependent relaxation and cyclic GMP accumulation in rabbit pulmonary artery are selectively impaired by moderate hypoxia. Circ Res. 1993;65:1508–1515.

10.1165/ajrcmb.11.4.7522486

Higenbottam T, Cremona G. Acute and chronic hypoxic pulmonary hypertension. Eur Respir J. 1993;6:1207–121.

10.1146/annurev.pa.15.040175.001515

Thông tin
Thông tin xuất bản

Circulation Research

Tập 89 Số 1

77-83

Thông tin tác giả