Cellular mechanisms regulating tone in the chronically hypoxic pulmonary circulating are poorly defined. A growing body of evidence suggests alterated endothelial control of pulmonary vascular tone plays a critical role in pulmonary hypertension (PHT). We found inhibition of endothelial nitric oxide synthase (NOS) unmasks a potent vasoconstrictor stimulus in the hypoxic/hypertensive rat lung which is largely mediated by ET-1. These inhibitor studies also suggest that ET-1 is acting by stimulating Ca2+ influx through Ca2+ channels than the L-type channel, possibly low threshold voltage-gated Ca2+ channels. However, the mechanisms linking ET- 1, PA smooth muscle cells (SMC) membrane potential and Ca2+ influx in the hypertensive pulmonary circulation at the cellular level have not been defined. Additionally in question is the effect of chronic hypoxia on PA SMC ion channel expression and regulation. While it is known that chronic hypoxic PHT reduces macroscopic on PA SMCs, which might render the cells more depolarized, the full effect of chronic hypoxia on PA SMC ion channels and the mechanisms through which ion channel activation is altered are unknown. Results with NOS inhibitors in the hypertensive lung establish an important role for NO in modulating PA tone. While it has been generally assumed that NO acts through SMC cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG) to phosphorylate target proteins, including ion channels, the majority of prior work has been done studying SMC from the normotensive circulation. Our preliminary data suggests that in the hypertensive pulmonary circulation a novel mechanisms of action for NO, independent of PKG-mediated phosphorylation, may play in important role in modulating basal vascular tone. Our four specific aims are to test the hypotheses that: 1) ET-1 causes membrane depolarization of hypertensive PA SMCs via inhibition of delayed rectifier K+ channels and activation of PA SMC non-selective cation channels. 2) Novel routes of Ca2+ entry in response to ET-1 and hypoxia develop, including low threshold voltage operated Ca2+ channels. 3) NO and cGMP modulate the activity of ET-1 regulated channels, including cyclic nucleotide gated (CNG) channels, in hypertensive resistance PA SMCs. And 4) The stimulus for alterations in PA SMC channel regulation (decreased K+ channels and novel Ca2+ channels) is either for both hypoxia and hemodynamic stress.
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