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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093238-09
Application #
9503047
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Reid, Diane M
Project Start
2009-07-01
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Miscellaneous
Type
Sch Allied Health Professions
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Craighead, Daniel H; Wang, Huilei; Santhanam, Lakshmi et al. (2018) Acute lysyl oxidase inhibition alters microvascular function in normotensive but not hypertensive men and women. Am J Physiol Heart Circ Physiol 314:H424-H433
Alba, Billie K; Greaney, Jody L; Ferguson, Sara B et al. (2018) Endothelial function is impaired in the cutaneous microcirculation of adults with psoriasis through reductions in nitric oxide-dependent vasodilation. Am J Physiol Heart Circ Physiol 314:H343-H349
Craighead, Daniel H; Smith, Caroline J; Alexander, Lacy M (2017) Blood pressure normalization via pharmacotherapy improves cutaneous microvascular function through NO-dependent and NO-independent mechanisms. Microcirculation 24:
Greaney, Jody L; Kenney, W Larry; Alexander, Lacy M (2017) Neurovascular mechanisms underlying augmented cold-induced reflex cutaneous vasoconstriction in human hypertension. J Physiol 595:1687-1698
Stanhewicz, Anna E; Jandu, Sandeep; Santhanam, Lakshmi et al. (2017) Increased Angiotensin II Sensitivity Contributes to Microvascular Dysfunction in Women Who Have Had Preeclampsia. Hypertension 70:382-389
Craighead, Daniel H; McCartney, Nathaniel B; Tumlinson, James H et al. (2017) Mechanisms and time course of menthol-induced cutaneous vasodilation. Microvasc Res 110:43-47
Smith, Caroline J; Craighead, Daniel H; Alexander, Lacy M (2017) Effects of vehicle microdialysis solutions on cutaneous vascular responses to local heating. J Appl Physiol (1985) 123:1461-1467
Greaney, Jody L; Kutz, Jessica L; Shank, Sean W et al. (2017) Impaired Hydrogen Sulfide-Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults. Hypertension 69:902-909
Craighead, Daniel H; Alexander, Lacy M (2017) Menthol-Induced Cutaneous Vasodilation Is Preserved in Essential Hypertensive Men and Women. Am J Hypertens 30:1156-1162
Stanhewicz, Anna E; Jandu, Sandeep; Santhanam, Lakshmi et al. (2017) Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia. Clin Sci (Lond) 131:2777-2789

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