Essential Hypertension and Human Skin Blood Flow

原发性高血压与人体皮肤血流量

基本信息

批准号：
9277229
负责人：
Lacy M. ALEXANDER
金额：
$ 61.74万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277229
关键词：
3-Mercaptopyruvate sulfurtransferase Acetylcholine Adrenergic Agents Adult Age Angiotensin-Converting Enzyme Inhibitors Animal Model Antihypertensive Agents Attenuated Blood Circulation Blood Vessels Blood flow Cardiovascular Diseases Clinical Clinical Treatment Complex Cutaneous Cystathionine Data Disease Diuretics Dose Double-Blind Method Endothelium Enzymes Essential Hypertension Grant Guidelines Human Hydrogen Sulfide Hypertension In Vitro Inflammation Intervention Joints Lyase Mediating Microcirculation Microvascular Dysfunction Nerve Nitric Oxide Synthase Organ Outcome Oxidation-Reduction Pathology Pathway interactions Peripheral Pharmacology Pharmacotherapy Physiological Production Prostaglandin-Endoperoxide Synthase Randomized Research Retina Role Signal Pathway Signal Transduction Signaling Molecule Skin Stimulus Sulfhydryl Compounds Therapeutic Vascular Diseases Vasoconstrictor Agents Vasodilation Vasodilator Agents Work animal data base improved in vivo in vivo Model indexing inhibitor/antagonist lipophilicity mortality normotensive novel prevent public health relevance response skeletal therapeutic target thiazide vasodilator-stimulated phosphoprotein

项目摘要

DESCRIPTION (provided by applicant): Clinical outcomes data informing the Eighth Joint National Committee (JNC8) guidelines strongly support angiotensin converting enzyme inhibitors (ACEi) for the treatment of essential hypertension. Reduced mortality in hypertension-associated disease attributable to ACEi is strongly related to their secondary peripheral vascular effects. Emerging data indicate that ACEi containing a sulfhydryl group (SH-ACEi) exert beneficial peripheral vascular effects via lipophilic targeting to the endothelium where they act through hydrogen sulfide (H2S)-dependent mechanisms. H2S (1) prevents redox-induced damage in the vasculature by preserving NOS function, (2) attenuates eutrophic vessel remodeling29, and (3) is purported to be the mechanism by which SH-ACEi improves vascular function20. Therefore, examining H2S- mediated pathways is critical to elucidating (1) the mechanisms of vascular dysfunction in hypertension, and (2) its viability as a therapeutic target for SH-ACEi therapy. In the previous grant cycle, we developed and validated the human cutaneous microcirculation as a model for the in vivo examination of novel signaling mechanisms mediating microvascular dysfunction in hypertensive (HT) adults naïve to pharmacotherapy. The emerging importance of H2S as an endothelial signaling modulator and inhibitor of eutrophic vessel remodeling in hypertension highlights the need to explore target-based intervention strategies related to these mechanisms. SH-ACEi has been extensively prescribed for the secondary treatment of cardiovascular disease with highly effective clinical outcomes; however, the precise mechanisms that underlie the therapeutic benefit of SH-ACEi in the human vasculature are unclear. As a logical extension, we propose to elucidate the role of H2S-specific mechanisms in HT humans by completed two separate aims. In Specific Aim 1 we propose to examine the mechanisms underlying H2S- mediated vasodilation in the cutaneous microcirculation of adults with essential hypertension utilizing a cross-sectional approach. In Specific Aim 2 we propose to determine the peripheral vascular effects of sulfhydryl-containing antihypertensive pharmacotherapy on in vivo and in vitro indices of microvascular function and eutrophic vessel remodeling. We will utilize a 16- week randomized double-blind approach comparing and contrasting the effects of (1) a SH- ACEi, (2) a non-SH containing ACEi, and (3) a thiazide-type diuretic (nonvascular therapeutic control). The proposed work has the potential to uncover novel vascular signaling mechanisms related to the gasotransmitter H2S in hypertensive humans and better inform the clinical treatment of essential hypertension.

描述（由申请人提供）：临床结果数据，将第八个国民委员会（JNC8）转换为ACEI的NSIN转换为ACEI密切相关。）通过亲脂性靶向整个氢氢（H2S）依赖性机制的vascu效应。因此，检查H2S介导的途径对于阐明（1）血管功能障碍段E的机制E，我们开发并验证了人类皮肤微循环，作为在高血压（HT）成人中进行新型信号机制微血管功能障碍的体内检查的模型幼稚的药物疗法。人类Vascularture中的Sh-acei尚不清楚。在体内和狂血管功能和富营营养的血管中，我们将使用16周的随机双盲方法比较（1）A SH-ACEI，（2）非sh-acei，（2） ACEI和（3）噻嗪类型利尿剂（非血管治疗对照）。