Subsequent studies in cat small pulmonary artery smooth muscle cells, showed that intracellular Ca2+ increased during hypoxia but decreased in cells from large pulmonary and cerebral arteries (55). The Ca2+ increase was due to Ca2+ release from ryanodine-sensitive intracellular stores and Ca2+ influx from the extracellular fluid.
Patch-clamping and immunofluorescent microscopy combined with ever more selective pharmacologic agents further elucidated the roles of Ca2+, K+, and other ions in regulating vascular tone. Closely linked to the study of changes in cellular Ca2+ during hypoxia were studies of the role of K+ channels, particularly the Kv channels (4). However, it is still not certain whether hypoxia directly inhibits Kv channels, and the resulting depolarization leads to increased intracellular Ca2+, or if Kv channel inhibition is secondary to Ca2+ release from the sarcoplasmic reticulum (42). The presence of distinct subpopulations of pulmonary artery myocytes each with distinct distributions of K+ channels lends further intrigue to the isolated cell story (6). Recently, it has been shown that like the graded contractile response to hypoxia in lungs and arteries, pulmonary artery smooth muscle cells show a graded response of K+ current, membrane potential and intracellular Ca2+ (39).
With the ability to study mechanisms at the cellular and subcellular level, investigations into the redox theory of HPV have burgeoned and may offer the best chance yet to identify the elusive 02 sensor (49). Most theories suggest that reactive oxygen species (ROS) such as H202 and superoxide are involved. Kv channels, ADP-ribosyl cyclase, and cyclic ADP-ribose hydrolase, the mitochondria or more specifically, the electron transport chain, have all been nominated as candidates for the sensor. Whether ROS species increase or decrease during hypoxia is controversial. Different preparations (tissue versus cell) and limitations of current detection methods may affect the validity and/or the interpretation of the results and lead to discrepant reports.
The role ofpH as modulator of HPV was discussed earlier but the possibility that pH; might also mediate HPV is suggested by studies in isolated arteries and cells. During hypoxia, pHj increased in small pulmonary artery cells but decreased in large pulmonary artery cells. These changes were not dependent upon the pHj before hypoxia (28). In large diameter pig pulmonary arteries, pH; also decreased during hypoxia (23). In HC03~-containing solutions, pulmonary artery smooth muscle cells from cats and guinea pigs showed evidence for the major ion exchangers, Na+/H+ and the Na+ dependent and independent C1"/HC03~ ion transporters. In the catthe CI'/ HC03~ exchanger appeared to be more active in regulating pHi; but in the guinea pig the Na+/H+ exchanger appeared to play more of a role (44). These differences further underscore the idea that different species may have different elaborations upon the same mechanism.
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