REGULATION OF CORONARY ARTERY MYOGENIC TONE BY PKG

维持充足的冠状动脉血流对生命至关重要。一氧化氮（NO）可能通过抑制血管平滑肌（VSM）收缩和限制冠状动脉张力的发展而在血流调节中发挥关键作用。事实上，从冠状动脉内皮中增强一氧化氮的强补性释放被认为至少部分地解释了绝经前妇女循环雌激素的心脏保护作用。人们普遍认为NO的血管扩张作用主要是通过平滑肌细胞中cGMP依赖性蛋白激酶（PKG）的作用介导的。然而，主要由于缺乏足够的选择性抑制剂，PKG对血管张力调节的贡献尚不清楚。佛蒙特大学Wolgang Dostmann博士的实验室最近开发了新的PKG肽抑制剂，可能提供识别PKG依赖性所需的选择性工具。这些肽是由有效的、底物竞争的PKG抑制剂序列与促进细胞摄取的载体序列（通常被称为“特洛伊木马”肽）相连接组成的。最近的初步研究表明，新的PKG抑制剂肽DT-3可以有效地渗透培养的血管平滑肌细胞并选择性地抑制PKG活性。在这个项目中，包括DT-3在内的特定PKG抑制剂将被用来评估PKG作用的作用，随后将被解决，主要集中在PKG依赖的Ca2+敏感钾通道（K/Ca）的激活。这项研究的发现将为确定心脏血流的基本机制提供有价值的见解。

Maintenance of adequate coronary artery blood flow is essential for life. Nitric oxide (NO) may play a critical role in the regulation of flow by opposing vascular smooth muscle (VSM) contraction and restricting the development of coronary artery tone. In fact, enhanced tonic release of NO from coronary endothelium is believed to account, at least in part, for the cardioprotective effect of circulating estrogen in premenopausal women. It is widely believed that the vasodillatory influence of NO is mediated predominantly through the action of cGMP dependent protein kinase (PKG) in smooth muscle cells. However, due primarily to the lack of adequately selective inhibitors, the contribution of PKG to the regulation of vascular tone remains unclear.. New peptide inhibitors of PKG, recently developed in the laboratory of Dr. Wolgang Dostmann at the University of Vermont, may provide the selective tools needed to discern PKG dependence. These peptides are composed of potent, substrate-competitive PKG inhibitor sequences linked to carrier sequences (often referred to as "Trojan horse" peptides) that facilitate cellular uptake. Recent preliminary studies have revealed that the novel PKG inhibitor peptide, DT-3, effectively permeates cultured vascular smooth muscle cells and selectively inhibits PKG activity. In this project, specific PKG inhibitors including DT-3 will be employed to assess the role of PKG action will subsequently be addressed, primarily focusing on PKG dependent activation of Ca2+ sensitive potassium channels (K/Ca). The findings of this study will provide valuable insights into the fundamental mechanisms that determine cardiac blood flow.