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Hypertension is characterized by systemic microvascular endothelial dysfunction, in part due to a functional absence of hydrogen sulfide (H 2 S)-mediated endothelium-dependent dilation. Treatment with a sulfhydryl-donating ACE inhibitor (SH-ACE inhibitor) improves endothelial function in preclinical models of hypertension. To date, no studies have directly assessed the effects of SH-ACE-inhibitor treatment on H 2 S-dependent vasodilation in humans with hypertension. We hypothesized that SH-ACE-inhibitor treatment would improve H 2 S-mediated endothelium-dependent vasodilation. Ten adults with hypertension [1 woman and 9 men; 56 ± 9 yr; systolic blood pressure (SBP): 141 ± 8.5 mmHg; diastolic blood pressure (DBP): 90.3 ± 6 mmHg] were treated (16 wk) with the SH-ACE-inhibitor captopril. Red blood cell flux (laser-Doppler flowmetry) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh; 10 -10 to 10 -1 M) alone (control) and in combination with an inhibitor of enzymatic H 2 S production [10 -3 M aminooxyacetate (AOAA)] preintervention and postintervention. Cutaneous vascular conductance (CVC; flux/mmHg) was calculated and normalized to the site-specific maximal CVC (0.028 M sodium nitroprusside and local heat to 43°C). Area under the curve was calculated using the trapezoid method. The 16-wk SH-ACE-inhibitor treatment resulted in a reduction of blood pressure (systolic BP: 129 ± 10 mmHg; diastolic BP: 81 ± 9 mmHg, both P < 0.05). Preintervention, inhibition of H 2 S production had no effect on ACh-induced vasodilation (316 ± 40 control vs. 322 ± 35 AU AOAA; P = 0.82). Captopril treatment improved ACh-induced vasodilation (316 ± 40 pre vs. 399 ± 55 AU post; P = 0.04) and increased the H 2 S-dependent component of ACh-induced vasodilation (pre: -6.6 ± 65.1 vs. post: 90.2 ± 148.3 AU, P = 0.04). These data suggest that SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in adults with hypertension, in part via H 2 S-dependent mechanisms. NEW & NOTEWORTHY This is the first study to prospectively assess the effects of sulfhydryl antihypertensive treatment on microvascular endothelial function in adults with hypertension. Our data suggest that 16 wk of SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in middle-aged adults with hypertension, in part via H 2 S-dependent mechanisms.

Background: While excess dietary sodium impairs vascular function by increasing oxidative stress, the dietary incorporation of dairy foods improves vascular health. We demonstrated that single-meal cheese consumption ameliorates acute, sodium-induced endothelial dysfunction. However, controlled feeding studies examining the inclusion of cheese, a dairy product that contains both bioactive constituents and sodium, are lacking., Objectives: We tested the hypothesis that microcirculatory endothelium-dependent dilation (EDD) would be impaired by a high-sodium diet, but a sodium-matched diet high in dairy cheese would preserve EDD through oxidant stress mechanisms., Methods: We gave 11 adults without salt-sensitive blood pressure (<10 mmHg Δ mean arterial pressure; 64 ± 2 y) 4 separate 8-d controlled dietary interventions in a randomized, crossover design: a low-sodium, no-dairy intervention (LNa; 1500 mg/d sodium); a low-sodium, high-cheese intervention (LNaC; 1500 mg/d sodium, 170 g/d cheese); a high-sodium, no-dairy intervention (HNa; 5500 mg/d sodium); and a high-sodium, high-cheese intervention (HNaC; 5500 mg/d sodium, 170 g/d cheese). On Day 8 of each diet, EDD was assessed through a localized infusion (intradermal microdialysis) of acetylcholine (ACh), both alone and during coinfusion of NG-nitro-L-arginine methyl ester (NO synthase inhibitor), L-ascorbate (nonspecific antioxidant), apocynin [NAD(P)H oxidase inhibitor], or tempol (superoxide scavenger)., Results: Compared with LNa, microvascular responsiveness to ACh was attenuated during HNa (LNa: -4.82 ± 0.20 versus HNa: -3.21 ± 0.55 M logEC50; P = 0.03) but not LNaC (-5.44 ± 0.20 M logEC50) or HNaC (-4.46 ± 0.50 M logEC50). Further, ascorbate, apocynin, and tempol administration each increased ACh-induced vasodilation during HNa only (Ringer's: 38.9 ± 2.4; ascorbate: 48.0 ± 2.5; tempol: 45.3 ± 2.7; apocynin: 48.5 ± 2.6% maximum cutaneous vascular conductance; all P values < 0.01)., Conclusions: These results demonstrate that incorporating dairy cheese into a high-sodium diet preserves EDD by decreasing the concentration of superoxide radicals. Consuming sodium in cheese, rather than in nondairy sources of sodium, may be an effective strategy to reduce cardiovascular disease risk in salt-insensitive, older adults. This trial was registered at clinicaltrials.gov as NCT03376555., (Copyright © American Society for Nutrition 2019.)

In epidemiological studies, chronic dairy milk consumption is associated with improved vascular health and reduced age-related increases in blood pressure. Although milk protein supplementation augments conduit artery flow-mediated dilation, whether or not acute dairy milk intake may improve microvascular function remains unclear. We hypothesised that dairy milk would increase direct measurement of endothelial nitric oxide (NO)-dependent cutaneous vasodilation in response to local skin heating. Eleven men and women (61 (sem 2) years) ingested two or four servings (473 and 946 ml) of 1 % dairy milk or a rice beverage on each of 4 separate study days. In a subset of five subjects, an additional protocol was completed after 473 ml of water ingestion. Once a stable blood flow occurred, 15 mm-N G -nitro-l-arginine methyl ester was perfused (intradermal microdialysis) to quantify NO-dependent vasodilation. Red-blood-cell flux (RBF) was measured by laser-Doppler flowmetry, and cutaneous vascular conductance (CVC=RBF/mean arterial pressure) was calculated and normalised to maximum (%CVCmax; 28 mm-sodium nitroprusside). Full expression of cutaneous vasodilation was not different among dairy milk, rice beverage and water, and there was no effect of serving size on the total vasodilatory response. Contrary to our hypothesis, NO-dependent vasodilation was lower for dairy milk than rice beverage (D: 49 (sem 5), R: 55 (sem 5) %CVCmax; P<0·01). Acute dairy milk ingestion does not augment NO-dependent vasodilation in the cutaneous microcirculation compared with a rice beverage control.

Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22 ± 1 years) and 11 older (O: 71 ± 3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringer's solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVCmax) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O = 82 ± 3 vs Y = 96 ± 1, P = 0.002) and NO-dependent vasodilatation (%CVCmax: O = 26 ± 6% vs Y = 49 ± 5, P = 0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVCmax = 91 ± 2, P = 0.03) and NO-dependent (%CVCmax = 43 ± 9%, P = 0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1°C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVCmax: O = 31 ± 8 vs Y = 44 ± 5, P = 0.001) and NO-dependent (%CVCmax: O = 9 ± 2 vs Y = 21 ± 2, P = 0.003) vasodilatation. Folic acid increased CVC (%CVCmax = 47 ± 5%, P = 0.001) and NO-dependent vasodilatation (20 ± 3%, P = 0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms.

The cutaneous circulation is used to examine vascular adrenergic function in clinical populations; however, limited studies have examined whether there are regional limb and sex differences in microvascular adrenergic responsiveness. We hypothesized that cutaneous adrenergic responsiveness would be greater in the leg compared with the arm and that these regional limb differences would be blunted in young women (protocol 1). We further hypothesized that cutaneous vasoconstriction to exogenous norepinephrine (NE) during β-adrenergic receptor antagonism would be augmented in young women (protocol 2). In protocol 1, one microdialysis fiber was placed in the skin of the calf and the ventral forearm in 20 healthy young adults (11 men and 9 women). Laser-Doppler flowmetry was used to measure red blood cell flux in response to graded intradermal microdialysis infusions of NE (10(-12) to 10(-2) M). In protocol 2, three microdialysis fibers were placed in the forearm (6 men and 8 women) for the local perfusion of lactated Ringer (control), 5 mM yohimbine (α-adrenergic receptor antagonist), or 2 mM propranolol (β-adrenergic receptor antagonist) during concurrent infusions of NE (10(-12) to 10(-2) M). There were no limb or sex differences in cutaneous adrenergic responsiveness (logEC50) to exogenous NE. During α-adrenergic receptor blockade, women had greater exogenous NE-induced cutaneous vasodilation at the lowest doses of NE (10(-12) to 10(-10) M). Collectively, these data indicate that there are no limb or sex differences in cutaneous adrenergic responsiveness to exogenous NE; however, young women have a greater β-adrenergic receptor-mediated component of the vascular responsiveness to exogenous NE., (Copyright © 2014 the American Physiological Society.)