Hydrogen Sulfide‐dependent Cutaneous Vasodilation is Improved Following Chronic Sulfhydryl‐donating Antihypertensive Pharmacotherapy in Hypertensive Adults

Abstract

Hypertension is characterized by systemic microvascular endothelial dysfunction, mediated in part by a functional absence in the hydrogen sulfide (H2S)‐mediated component of endothelial‐dependent dilation. Long‐term systemic treatment with an H2S donor improves endothelial function in rodent models of hypertension. Although cross‐sectional studies demonstrate improvements in endothelium‐dependent dilation in hypertensive adults treated with angiotensin converting enzyme inhibitors (ACEi), to date, no studies have directly assessed the effects of pharmacological antihypertensive treatment on H2S‐dependent dilation in hypertensive humans. The purpose of this randomized double‐blind clinical trial was to examine the effect of chronic sulfhydryl‐donating (SH) ACEi on H2S‐dependent dilation in hypertensive adults. We hypothesized that SH‐ACEi would result in greater improvements in the H2S‐mediated component of endothelium‐dependent dilation compared to non‐SH antihypertensive pharmacological treatment. Eighteen hypertensive adults (55±2 yrs, 141±3/91±2mmHg, 29±1 kg/m2) were randomized to either a non‐SH (n=9; hydrochlorothiazide or enalapril) or a SH‐ACEi (n=9; captopril) antihypertensive medication. Red blood cell flux (laser Doppler flowmetry) was measured continuously during graded intradermal microdialysis perfusion of the endothelium‐dependent agonist acetylcholine (ACh; 10−10‐10−1 M) alone and in combination with an inhibitor of enzymatic H2S production (1 mM aminooxyacetate; AOAA) pre‐ and post‐treatment (16‐weeks). Cutaneous vascular conductance (CVC; flux/mmHg) was calculated and normalized as a percentage of the site‐specific maximum CVC (28 mM sodium nitroprusside and local heat of 43°C). Area under the dose‐response curve was calculated using the trapezoid method. The H2S‐mediated component of ACh‐induced dilation was calculated as the difference between ACh perfusion alone and AOAA perfusion (arbitrary units; AU). There were no differences in the magnitude of reduction in mean arterial pressure between non‐SH and SH‐ACEi therapy (non‐SH: Δ7±4 mmHg vs. SH‐ACEi: Δ10±4 mmHg, p=0.54). Before antihypertensive treatment, inhibition of H2S had no effect on ACh‐induced dilation (non‐SH: 299±32 ACh vs. 362±52 AU AOAA, p=0.21; SH: 316±40 ACh vs. 322±35 AU AOAA; p=0.82). Both non‐SH and SH‐ACEi antihypertensive treatment improved ACh‐induced dilation (non‐SH: 299±32 pre vs. 369±40 AU post, p=0.03; SH: 316±40 pre vs. 399±55 AU post; p=0.04). Non‐SH therapy had no effect on H2S‐mediated dilation (−62±46 pre vs. 9±43 AU post, p=0.32). However, SH‐ACEi improved the H2S‐dependent component of ACh‐induced dilation (−5±22 pre vs. 101±51 AU post, p=0.049). Collectively, these preliminary data suggest that chronic SH‐ACEi antihypertensive treatment improves cutaneous microvascular endothelium‐dependent dilation in middle‐aged hypertensive adults, in part via H2S‐dependent mechanisms.Support or Funding InformationNIH HL093238