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 nave 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.
Essential hypertension is a complex pathology and clinical guidelines (JNC8) strongly support angiotensin converting enzyme inhibitors (ACEi) for the treatment of essential hypertension. It is increasingly recognized that secondary peripheral vascular effects of systemic ACEi significantly contribute to reduced mortality in hypertension-associated disease. A specific class of ACEi containing a sulfhydryl group purported exerts a beneficial peripheral effect through their highly lipophilic targeting to the endothelium where the act through hydrogen sulfide (H2S)-dependent mechanisms. With the emergence of the importance of H2S as a modulator in hypertension, there is an immediate need to explore the therapeutic potential related to these signaling mechanisms in humans. The proposed work has the potential to uncover novel vascular signaling mechanisms related to the gasotransmitter H2S in humans and better inform the clinical treatment of essential hypertension.
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