REGULATION OF PULMONARY VASCULAR TONE

候选人的长期职业目标是了解 调节肺血管张力， 最终改善肺动脉高压患者的治疗。 他 研究已经从对患者和清醒动物的研究发展到 研究分离的血管和细胞。这一变化是由 确信目前的肺动脉高压治疗无效 由于对调节的基本机制的理解不足， 肺血管张力。这项建议的科学重点是 了解血管收缩剂和血管舒张剂介导的信号转导， 肺血管组织 调查员的研究小组正在前往 犹他州大学利用与专家的协作， 细胞生物学（Dr. John R. Hoidal）、细胞内Ca++（William H. 巴里）和信号转导（Stephen M. Prescott和Guy A. 齐默尔曼）。建议的实验联合收割机生物化学和生理学 测量.第一个具体目标将确定肺的影响， 血管收缩剂对肺血管内~（45）Ca ~（++）内流的影响及 肺动脉内皮细胞和平滑肌细胞内Ca ~（++）。 第二个具体目标是检验血管收缩剂 激活磷脂酰肌醇循环，这些产品有助于 通过增加细胞内Ca +4和激活 蛋白激酶C这一特定目标将决定血管收缩剂 刺激1，2二酰基甘油的产生和1，2二酰基甘油的水解 肺动脉内皮细胞和平滑肌细胞中的磷酸肌醇。 这些产品的重要性将通过研究 磷脂酶C和蛋白激酶C对激动剂诱导的 肺血管收缩第三个特定的alm将决定 环AMP或环GMP阻止激动剂诱导的 血管收缩这一具体目标也将决定 cAMP和cGMP对激动剂诱导的Ca ~（++）内流、细胞内Ca ~（++） 4+释放，并形成1，2二酰基甘油或水解 磷酸肌醇。第四个具体的alm将探讨的机制 肺血管收缩剂通过其抑制血管扩张剂的作用。 将研究这种功能性拮抗作用的可能机制 包括蛋白激酶C的激活抑制了 异丙肾上腺素刺激百日咳引起环腺苷酸增加 毒素敏感性鸟嘌呤核苷酸调节蛋白（Gi或Go）。的 拟议的研究将导致更好地了解机制， 血管收缩剂和血管扩张剂单独或协同作用， 肺血管张力

The candidate's long-term career objective is to understand the mechanisms that regulate pulmonary vascular tone in the expectation that this will eventually improve therapy for patients with pulmonary hypertension. His research has evolved from studies in patients and awake animals to the study of isolated vessels and cells. This change has been driven by the conviction that Current therapy for pulmonary hypertension is ineffective because of inadequate understanding of the basic mechanisms that regulate Pulmonary vascular tone. The scientific focus of this proposal is to understand vasoconstrictor and vasodilator mediated signal transduction in pulmonary vascular tissue. The investigator's research group is moving to the University of Utah to take advantage of colla ration with experts in cell biology (Dr. John R. Hoidal), intracellular Ca++ (Dr. William H. Barry), and signal transduction (Dr. Stephen M. Prescott and Dr. Guy A. Zimmerman). The proposed experiments combine biochemical and physiological measurements. The first specific aim will define the effects of pulmonary vasoconstrictors on 45 Ca++ entry in pulmonary vessels and the release of intracellular Ca++ in pulmonary artery endothelial and smooth muscle cells. The second specific aim will test the hypothesis that vasoconstrictors activate the phosphatidylinositol cycle and that these products contribute to vasoconstriction by increasing intracellular Ca +4 and activating protein kinase C. This specific aim will determine whether vasoconstrictors stimulate the production of 1,2 diacylglycerols and hydrolysis of phosphoinositides in pulmonary artery endothelial and smooth muscle cells. The importance of these products will be tested by studying the effect of inhibitors of phospholipase C and protein kinase C on agonist-induced pulmonary vasoconstriction. The third specific alm will determine the ability of cyclic AMP or cyclic GMP to prevent agonist-induced vasoconstriction. This specific aim will also determine the effects of cyclic AMP and cyclic GMP on agonist-induced Ca++ entry, intracellular Ca 4+ release, and the formation of 1,2 diacylglycerols or the hydrolysis of phosphoinositides. The fourth specific alm will investigate the mechanisms by which pulmonary vasoconstrictors inhibit the action of vasodilators. Possible mechanisms for this functional antagonism will be studied including the hypothesis that activation of protein kinase C inhibits the increase in cyclic AMP caused by isoproterenol by stimulating a pertussis toxin sensitive guanine nucleotide regulatory protein (Gi or Go). The proposed research will lead to a better understanding of the mechanisms by which vasoconstrictors and vasodilators act alone and in concert to control pulmonary vascular tone.