Impaired Hydrogen Sulfide–Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults

Abstract

Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (Na2S) would be attenuated in HTN compared to normotensive (NTN) adults. Fifteen NTN [51±2 yrs; blood pressure (BP) 116±3/76±3 mmHg] and 14 HTN adults (57±2 yrs; BP 140±3/89±2 mmHg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10−6 –10−1 mol∙L−1) and Na2S (10−5–101 mol∙L−1) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (AOAA; 0.5 mmol∙L−1). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (all p<0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN compared to NTN adults (p=0.012). AOAA attenuated ACh-induced vasodilation in NTN adults (ACh: 1.31±0.13 vs. ACh+AOAA: 1.07±0.09 flux∙mmHg−1; P=0.025) but had no effect on vasodilation in HTN adults (ACh: 1.16±0.10 v. ACh+AOAA: 1.37±0.11 flux∙mmHg−1; p=0.47). Na2S-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension.

Honokiol ameliorates angiotensin II‐induced hypertension and endothelial dysfunction by inhibiting HDAC6‐mediated cystathionine γ‐lyase degradation

“…for the blood pressure measurements. Consistent with the ability of ACh to induce vascular relaxation by stimulating endothelial nitric oxide (NO) production, 12,17 ACh (0.1 nmol/L-10 μmol/L) dose-dependently induced the relaxation of aortic rings pre-constricted with 1 μmol/L phenylephrine in the control group whereas AngII significantly decreased the ACh-induced relaxation ( Figure 1D).…”

“…7,9,10 Alternatively, numerous studies have demonstrated that CSE-mediated H 2 S generation induces endothelium-dependent vasodilation and improves cardiovascular function and integrity. 11,12 Histone deacetylase 6 (HDAC6) is implicated in the pathophysiology of hypertension-related vascular diseases. 13,14 HDAC6 plays a significant role in the cardiac dysfunction mediated by angiotensin II (AngII), an inducer of hypertension.…”

Increases in placental nitric oxide, but not nitric oxide‐mediated relaxation, underlie the improvement in placental efficiency and antihypertensive effects of hydrogen sulphide donor in hypertensive pregnancy

“…As expected, treatment with NaHS increased H 2 S plasmatic levels in the Preg+NaHS group. Decreased levels of H 2 S are related to hypertension; however, we surprisingly found increased H 2 S plasmatic levels in HTN‐Preg. We suggest that desoxycorticosterone acetate (DOCA)‐induced hypertension may trigger mechanisms that increase H 2 S production, as a compensatory response, since it has been shown that H 2 S may exert protective effects during cardiovascular disorders .…”

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors

“…"H 2 S-Rich" and "H 2 S-Poor" Pathophysiological Conditions H 2 S has been implicated in the pathogenesis of multiple diseases, as overviewed in review articles. These range from cardiovascular diseases (e.g., myocardial reperfusion injury, cardiac hypertrophy, heart failure, atherosclerosis, hypertension) (Predmore et al, 2012b;Polhemus and Lefer, 2014;Ahmad et al, 2015;Meng et al, 2015aMeng et al, , 2016Shen et al, 2015;Wang et al, 2015a;Cao and Bian, 2016;Kanagy et al, 2017;Greaney et al, 2017) to various neurologic diseases (e.g., stroke, neuroinflammation) (Wang et al, 2014a;Bhatia, 2015;Kida and Ichinose, 2015;Wallace et al, 2015;Sen, 2017) and metabolic diseases (e.g., diabetes mellitus) (Desai et al, 2011;Szabo, 2012;Okamoto et al, 2015;Carter and Morton, 2016) to various forms of local and systemic inflammation (e.g., hemorrhagic shock, septic H 2 S Donors and H 2 S Biosynthesis Inhibitors shock, burn injury) (Wagner et al, 2009;Coletta and Szabo, 2013;McCook et al, 2014;Akter, 2016).…”

“…Despite its low potency that requires millimolar concentrations in cell-based assays, aminooxyacetic acid (AOAA), also known as (carboxymethoxy)amine hemihydrochloride (CHH) or hydroxylamine-O-acetic acid hemihydrochloride (Table 2), was extensively used for years to inhibit CBS not only in vitro but also in vivo (e.g., Mudd et al, 2011;Szabo et al, 2013). Interestingly, a recent human study using local acetylcholine perfusion and measurement of blood flow by laser Doppler flowmetry found that AOAA reduces acetylcholine-induced vascular relaxations, implicating H 2 S as a contributor to the regulation of vascular tone (Greaney et al, 2017).…”