K+ CHANNELS AND HYPOXIC PULMONARY VASOCONSTRICTION

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Our understanding of the cellular mechanisms of tissue oxygen sensing remains incomplete. In contrast to most other vascular beds, the pulmonary arterial (PA) bed constricts during mild to moderate hypoxia in a phenomenon known as hypoxic pulmonary vasoconstriction (HPV). When airway hypoxia is localized, HPV performs the useful function of matching regional perfusion to ventilation. However, in diseases associated with generalized airway hypoxia, such as chronic obstructive lung disease and neonatal respiratory distress, HPV causes an increase in pulmonary artery pressure (pulmonary hypertension) with significant associated morbidity and mortality. The mechanism of HPV is poorly understood, although it appears that HPV is an intrinsic property of the PA which does not require transduction by the nervous system or circulating blood components. Extensive investigation has failed to identify either a non-vascular oxygen-sensing cell or a diffusible mediator of HPV. Recent studies in our laboratory and others have demonstrated that isolated segments of PA show hypoxic contraction similar to HPV, suggesting that oxygen-sensing is an intrinsic property of the PA. Several lines of investigation have led us to propose the working hypothesis that oxygen directly affects the function of PA smooth muscle cell (SMC) ion channels, causing membrane depolarization, calcium influx and vasoconstriction. This hypothesis is based on the observations: 1) that hypoxia causes PA SMC membrane depolarization; 2) that pharmacologic inhibitors of potassium channels cause pulmonary vasoconstriction; and 3) that an oxygen-sensitive potassium channel is present on another oxygen sensing cell, the carotid body type I cell. The proposed studies will use patch clamp and fluorescence microscopy to measure the effects of oxygen tension on PA SMC potassium and calcium channels, intracellular calcium ion concentration, and contraction. The specific hypotheses to be tested are: 1) hypoxia causes PA SMC membrane depolarization by decreasing potassium conductance; 2) oxygen- sensing is an intrinsic property of a subset of potassium channels; 3) differences between pulmonary and systemic artery responses to hypoxia (vasoconstriction vs vasodilation) are due to intrinsic differences in the effect of oxygen on SMC potassium channels; and 4) transfer of genetic information coding for oxygen-sensitive channels can confer oxygen-sensing to a non-sensitive cell. While the primary hypotheses focus on the potassium channel as the sensor for HPV, two alternative hypotheses will also be tested: 1) oxygen directly affects the function of a calcium channel; and 2) oxygen indirectly affects ion channel function through an intracellular signalling process.