Sodium Nitrate Supplementation Improves Blood Pressure Reactivity in Patients with Peripheral Artery Disease

Mechanical and metabolic signals arising during skeletal muscle contraction reflexly increase sympathetic nerve activity and blood pressure (i.e., the exercise pressor reflex). In a rat model of simulated peripheral artery disease in which a femoral artery is chronically (~72 h) ligated, the mechanically sensitive component of the exercise pressor reflex during 1-Hz dynamic contraction is exaggerated compared with that found in normal rats. Whether this is due to an enhanced acute sensitization of mechanoreceptors by metabolites produced during contraction or involves a chronic sensitization of mechanoreceptors is unknown. To investigate this issue, in decerebrate, unanesthetized rats, we tested the hypothesis that the increases in mean arterial blood pressure and renal sympathetic nerve activity during 1-Hz dynamic stretch are larger when evoked from a previously “ligated” hindlimb compared with those evoked from the contralateral “freely perfused” hindlimb. Dynamic stretch provided a mechanical stimulus in the absence of contraction-induced metabolite production that closely replicated the pattern of the mechanical stimulus present during dynamic contraction. We found that the increases in mean arterial blood pressure (freely perfused: 14 ± 1 and ligated: 23 ± 3 mmHg, P = 0.02) and renal sympathetic nerve activity were significantly greater during dynamic stretch of the ligated hindlimb compared with the increases during dynamic stretch of the freely perfused hindlimb. These findings suggest that the exaggerated mechanically sensitive component of the exercise pressor reflex found during dynamic muscle contraction in this rat model of simulated peripheral artery disease involves a chronic sensitizing effect of ligation on muscle mechanoreceptors and cannot be attributed solely to acute contraction-induced metabolite sensitization. NEW & NOTEWORTHY We found that the pressor and sympathetic nerve responses during dynamic stretch were exaggerated in rats with a ligated femoral artery (a model of peripheral artery disease). Our findings provide mechanistic insights into the exaggerated exercise pressor reflex in this model and may have important implications for peripheral artery disease patients.

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Genetic Variation in Blood Pressure and Lifetime Risk of Peripheral Artery Disease: A Mendelian Randomization Study

10.1101/2020.08.23.20180240 ◽

2020 ◽

Author(s):

Michael G Levin ◽

Derek Klarin ◽

Venexia M Walker ◽

Dipender Gill ◽

Julie Lynch ◽

...

Keyword(s):

Blood Pressure ◽

Calcium Channel ◽

Peripheral Artery Disease ◽

Genetic Correlations ◽

Channel Blockers ◽

Peripheral Artery ◽

Antihypertensive Medications ◽

Increased Risk ◽

Genes Encoding ◽

Artery Disease

Aims: We aimed to estimate the effect of blood pressure and blood pressure lowering medications (via genetic proxies) on peripheral artery disease. Methods and Results: GWAS summary statistics were obtained for BP (International Consortium for Blood Pressure + UK Biobank GWAS; N = up to 757,601 individuals), peripheral artery disease (PAD; VA Million Veteran Program; N = 24,009 cases, 150,983 controls), and coronary artery disease (CAD; CARDIoGRAMplusC4D 1000 Genomes; N = 60,801 cases, 123,504 controls). Genetic correlations between systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP) and CAD and PAD were estimated using LD score regression. The strongest correlation was between SBP and CAD (rg = 0.36; p = 3.9 x 10-18). Causal effects were estimated by two-sample MR using a range of pleiotropy-robust methods. Increased SBP, DBP, and PP increased risk of both PAD (SBP OR 1.25 [1.19-1.31] per 10mmHg increase, p = 3 x 10-18; DBP OR 1.27 [1.17-1.39], p = 4 x 10-8; PP OR 1.51 [1.38-1.64], p = 1 x 10-20) and CAD (SBP OR 1.37 [1.29-1.45], p = 2 x 10-24; DBP OR 1.6 [1.45-1.76], p = 7 x 10-22; PP OR 1.56 [1.4-1.75], p = 1 x 10-15). The effects of SBP and DBP were greater for CAD than PAD (pdiff = 0.024 for SBP, pdiff = 4.9 x 10-4 for DBP). Increased liability to PAD increased PP (beta = 1.04 [0.62-1.45] mmHg per 1 unit increase in log-odds in liability to PAD, p = 1 x 10-6). MR was also used to estimate the effect of BP lowering through different classes of antihypertensive medications using genetic instruments containing BP-trait associated variants located within genes encoding protein targets of each medication. SBP lowering via calcium channel blocker-associated variants was protective of CAD (OR 0.38 per 10mmHg decrease in SBP; 95% CI 0.19-0.77; p = 0.007). Conclusions: Higher BP is likely to cause both PAD and CAD but may have a larger effect on CAD risk. BP-lowering through calcium-channel blockers (as proxied by genetic variants) decreased risk of CAD.

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Eight weeks of nitrate supplementation improves blood flow and reduces the exaggerated pressor response during forearm exercise in peripheral artery disease

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00015.2018 ◽

2018 ◽

Vol 315 (1) ◽

pp. H101-H108 ◽

Cited By ~ 9

Author(s):

Nicholas T. Kruse ◽

Kenichi Ueda ◽

William E. Hughes ◽

Darren P. Casey

Keyword(s):

Blood Flow ◽

Peripheral Artery Disease ◽

Pressor Response ◽

Treated Group ◽

Moderate Intensity ◽

Peripheral Artery ◽

Pressor Responses ◽

Nitrate Supplementation ◽

Artery Disease ◽

Forearm Exercise

Peripheral artery disease (PAD) is characterized by a reduced blood flow (BF) and an elevated blood pressure (pressor) response during lower extremity exercise. Although PAD is evident in the upper extremities, no studies have determined BF and pressor responses during upper extremity exercise in PAD. Emerging evidence suggests that inorganic nitrate supplementation may serve as an alternative dietary strategy to boost nitric oxide bioavailability, improving exercising BF and pressor responses during exercise. The present study investigated 1) BF and pressor responses to forearm exercise in patients with PAD ( n = 21) relative to healthy age-matched control subjects ( n = 16) and 2) whether 8 wk of NaNO3 supplementation influenced BF and pressor responses to forearm exercise in patients with PAD. Patients with moderate to severe PAD were randomly assigned to a NaNO3 (1 g/day, n = 13)-treated group or a placebo (microcrystalline cellulose, n = 8)-treated group. Brachial artery forearm BF (FBF; via Doppler) and blood pressure (via finger plethysmography) were measured during mild-intensity (~3.5-kg) and moderate-intensity (~7-kg) handgrip exercise. The absolute change (from baseline) in FBF was reduced (except in the 3.5-kg condition) and BP responses were increased in patients with PAD compared with healthy control subjects in 3.5- and 7-kg conditions (all P < 0.05). Plasma nitrate and nitrite were elevated, exercising (7-kg) ΔFBF was improved (from 141 ± 17 to 172 ± 20 ml/min), and mean arterial pressure response was reduced (from 13 ± 1 to 9 ± 1 mmHg, P < 0.05) in patients with PAD that received NaNO3 supplementation for 8 wk relative to those that received placebo. These results suggest that the BF limitation and exaggerated pressor response to moderate-intensity forearm exercise in patients with PAD are improved with 8 wk of NaNO3 supplementation. NEW & NOTEWORTHY Peripheral artery disease (PAD) results in an exaggerated pressor response and reduced blood flow during lower limb exercise; however, the effect of PAD in the upper limbs has remained unknown. These results suggest that 8 wk of inorganic nitrate supplementation improves the blood flow limitation and exaggerated pressor response to moderate-intensity forearm exercise in PAD.

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Systemic and regional hemodynamic response to activation of the exercise pressor reflex in patients with peripheral artery disease

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00493.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. H916-H924 ◽

Cited By ~ 1

Author(s):

Danielle Jin-Kwang Kim ◽

Marcos Kuroki ◽

Jian Cui ◽

Zhaohui Gao ◽

J. Carter Luck ◽

...

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Peripheral Artery Disease ◽

Plantar Flexion ◽

Peripheral Artery ◽

Exercise Pressor Reflex ◽

Femoral Blood Flow ◽

Femoral Blood ◽

Pressor Reflex ◽

Artery Disease

Patients with peripheral artery disease (PAD) have an accentuated exercise pressor reflex (EPR) during exercise of the affected limb. The underlying hemodynamic changes responsible for this, and its effect on blood flow to the exercising extremity, are unclear. We tested the hypothesis that the exaggerated EPR in PAD is mediated by an increase in total peripheral resistance (TPR), which augments redistribution of blood flow to the exercising limb. Twelve patients with PAD and 12 age- and sex-matched subjects without PAD performed dynamic plantar flexion (PF) using the most symptomatic leg at progressive workloads of 2–12 kg (increased by 1 kg/min until onset of fatigue). We measured heart rate, beat-by-beat blood pressure, femoral blood flow velocity (FBV), and muscle oxygen saturation ([Formula: see text]) continuously during the exercise. Femoral blood flow (FBF) was calculated from FBV and baseline femoral artery diameter. Stroke volume (SV), cardiac output (CO), and TPR were derived from the blood pressure tracings. Mean arterial blood pressure and TPR were significantly augmented in PAD compared with control during PF. FBF increased during exercise to an equal extent in both groups. However, [Formula: see text] of the exercising limb remained significantly lower in PAD compared with control. We conclude that the exaggerated pressor response in PAD is mediated by an abnormal TPR response, which augments redistribution of blood flow to the exercising extremity, leading to an equal rise in FBF compared with controls. However, this increase in FBF is not sufficient to normalize the SmO2 response during exercise in patients with PAD. NEW & NOTEWORTHY In this study, peripheral artery disease (PAD) patients and healthy control subjects performed graded, dynamic plantar flexion exercise. Data from this study suggest that previously reported exaggerated exercise pressor reflex in patients with PAD is driven by greater vasoconstriction in nonexercising vascular territories which also results in a redistribution of blood flow to the exercising extremity. However, this rise in femoral blood flow does not fully correct the oxygen deficit due to changes in other mechanisms that require further investigation.

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Vascular Inflammation, Calf Muscle Oxygen Saturation, and Blood Glucose are Associated With Exercise Pressor Response in Symptomatic Peripheral Artery Disease

Angiology ◽

10.1177/0003319719838399 ◽

2019 ◽

Vol 70 (8) ◽

pp. 747-755 ◽

Cited By ~ 2

Author(s):

Andrew W. Gardner ◽

Polly S. Montgomery ◽

Ming Wang ◽

Chixiang Chen ◽

Marcos Kuroki ◽

...

Keyword(s):

Blood Pressure ◽

Blood Glucose ◽

Oxygen Saturation ◽

Peripheral Artery Disease ◽

Pressor Response ◽

Calf Muscle ◽

Peripheral Artery ◽

Muscle Oxygen ◽

Artery Disease ◽

Vascular Biomarkers

We determined whether calf muscle oxygen saturation (StO2) and vascular biomarkers of inflammation and oxidative stress were associated with an exercise pressor response during treadmill walking in 179 patients with symptomatic peripheral artery disease (PAD). The exercise pressor response was measured as the change in blood pressure from rest to the end of the first 2-minute treadmill stage (2 mph, 0% grade). There was a wide range in the change in systolic blood pressure (−46 to 50 mm Hg) and in diastolic blood pressure (−23 to 38 mm Hg), with mean increases of 4.3 and 1.4 mm Hg, respectively. In multiple regression analyses, significant predictors of systolic pressure included glucose ( P < .001) and insulin ( P = .039). Significant predictors of diastolic pressure included cultured endothelial cell apoptosis ( P = .019), the percentage drop in exercise calf muscle (StO2; P = .023), high-sensitivity C-reactive protein ( P = .032), and glucose ( P = .033). Higher levels in pro-inflammatory vascular biomarkers, impaired calf muscle StO2 during exercise, and elevated blood glucose were independently associated with greater exercise pressor response in patients with symptomatic PAD. The clinical implication is that exercise and nutritional interventions designed to improve inflammation, microcirculation, and glucose metabolism may also lower blood pressure during exercise in patients with symptomatic PAD.

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