Mechanisms of oxygen sensing: a key to therapy of pulmonary hypertension and patent ductus arteriosus.
Specialized tissues that sense acute changes in the local oxygen tension include type 1 cells of the carotid body, neuroepithelial bodies in the lungs, and smooth muscle cells of the resistance pulmonary arteries and the ductus arteriosus (DA). Hypoxia inhibits outward potassium current in carotid body type 1 cells, leading to depolarization and calcium entry through L-type calcium channels. Increased intracellular calcium concentration ([Ca+ +]i) leads to exocytosis of neurotransmitters, thus stimulating the carotid sinus nerve and respiration. The same K+ channel inhibition occurs with hypoxia in pulmonary artery smooth muscle cells (PASMCs), causing contraction and providing part of the mechanism of hypoxic pulmonary vasoconstriction (HPV). In the SMCs of the DA, the mechanism works in reverse. It is the shift from hypoxia to normoxia that inhibits K+ channels and causes normoxic ductal contraction. In both PA and DA, the contraction is augmented by release of Ca+ + from the sarcoplasmic reticulum, entry of Ca+ + through store-operated channels (SOC) and by Ca+ + sensitization. The same three 'executive' mechanisms are partly responsible for idiopathic pulmonary arterial hypertension (IPAH). While vasoconstrictor mediators constrict both PA and DA and vasodilators dilate both vessels, only redox changes mimic oxygen by having directly opposite effects on the K+ channels, membrane potential, [Ca(++)]i and tone in the PA and DA. There are several different hypotheses as to how redox might alter tone, which remain to be resolved. However, understanding the mechanism will facilitate drug development for pulmonary hypertension and patent DA.
Weir
E K
EK
Department of Medicine, VA Medical Center and University of Minnesota, Minneapolis, MN 55417, USA. weirx002@umn.edu
Obreztchikova
M
M
Vargese
A
A
Cabrera
J A
JA
Peterson
D A
DA
Hong
Z
Z
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002344:Carotid Body / Q000166:cytology / Q000378:metabolism; D015687:Cell Hypoxia; D015195:Drug Design; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism
D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D010100:Oxygen; D002118:Calcium