Pulmonary hypertension is a severe and progressive disease for which there is no cure. Current therapies only slow the progression of the disease, and none directly target the problem of lost K+ efflux in pulmonary arterial smooth muscle cells (PASMCs). The loss of sarcolemmal K+ efflux in PASMCs contributes to the abnormal constriction and proliferation of PASMCs during pulmonary hypertension (PH). Thus, one potential therapeutic strategy for PH involves restoring K+ efflux to the affected PASMCs by pharmacological activation of sarcolemmal K+ channels. In initial screening studies, we identified the high conductance, Ca2+-activated K+ (BK) channel as an abundant therapeutic target in PASMCs of small pulmonary arteries. Thus, the first aim of this dissertation research was to define important electrophysiological properties of BK channels in PASMCs of normal (N) rats, and in PASMCs of rats exposed to chronic hypoxia (CH) for three weeks to induce PH. Important findings were verified in PASMCs isolated from human lungs of organ donors, with the intention of evaluating BK channels as pharmacological targets of vasodilator drugs for the treatment of clinical forms of PH. The second aim was to evaluate the potential of BK channels as a therapeutic target for PH by using pharmacological BK channel openers (BKCO). The third aim was to conduct pilot studies to evaluate a gene therapy -based strategy, which was designed to express exogenous BK channels in pulmonary arteries (PA) of CH rats to attenuate the progression of PH.
|Advisor:||Rusch, Nancy J.|
|Commitee:||Johnson, Larry G., Post, Steven R., Rhee, Sung W., Yuan, Jason X.-J., Zheng, Fang|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 76/09(E), Dissertation Abstracts International|
|Keywords:||Bk channel, Cardiovascular, Patch clamp, Pulmonary artery, Pulmonary hypertension, Vascular electrophysiology|
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