Effect of sodium nitrite on local control of contracting skeletal muscle microvascular oxygen pressure in healthy rats

Exercise intolerance characteristic of diseases such as chronic heart failure (CHF) and diabetes is associated with reduced nitric oxide (NO) bioavailability from nitric oxide synthase (NOS), resulting in an impaired microvascular O2 driving pressure (Po2 mv; O2 delivery/O2 utilization) and metabolic control. Infusions of the potent NO donor sodium nitroprusside augment NO bioavailability yet decrease mean arterial pressure (MAP) thereby reducing its potential efficacy for patient populations. To eliminate or reduce hypotensive sequelae, [Formula: see text] was superfused onto the spinotrapezius muscle. It was hypothesized that local [Formula: see text] administration would elevate resting Po2 mv and slow Po2 mv kinetics [increased time constant (τ) and mean response time (MRT)] following the onset of muscle contractions without decreasing MAP. In 12 anesthetized male Sprague-Dawley rats, Po2 mv of the circulation-intact spinotrapezius muscle was measured by phosphorescence quenching during 180 s of electrically induced twitch contractions (1 Hz) before and after superfusion of sodium nitrite (NaNO2 30 mM). [Formula: see text] superfusion elevated resting Po2 mv (control: 28.4 ± 1.1 vs. [Formula: see text]: 31.6 ± 1.2 mmHg; P ≤ 0.05), τ (control: 12.3 ± 1.2 vs. [Formula: see text]: 19.7 ± 2.2 s; P ≤ 0.05), and MRT (control: 19.3 ± 1.9 vs. [Formula: see text]: 25.6 ± 3.3 s; P ≤ 0.05). Importantly, these effects occurred in the absence of any reduction in MAP (103 ± 4 vs. 105 ± 4 mmHg, pre- and postsuperfusion respectively; P > 0.05). These results indicate that [Formula: see text] supplementation delivered to the muscle directly through [Formula: see text] superfusion enhances the blood-myocyte oxygen driving pressure without compromising MAP at rest and following the onset of muscle contraction. This strategy has substantial clinical utility for a range of ischemic conditions. NEW & NOTEWORTHY Ischemic conditions as diverse as chronic heart failure (CHF) and frostbite inflict tissue damage via inadequate O2 delivery. Herein we demonstrate that direct application of sodium nitrite enhances the O2 supply-O2 demand relationship, raising microvascular O2 pressure in healthy skeletal muscle. This therapeutic action of nitrite-derived nitric oxide occurred without inducing systemic hypotension and has the potential to relieve focal ischemia and preserve tissue vitality by enhancing O2 delivery.

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Exercise intolerance in patients with chronic heart failure and increased expression of inducible nitric oxide synthase in the skeletal muscle

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(98)00531-2 ◽

1999 ◽

Vol 33 (1) ◽

pp. 174-179 ◽

Cited By ~ 91

Author(s):

Rainer Hambrecht ◽

Volker Adams ◽

Stephan Gielen ◽

Axel Linke ◽

Sven Möbius-Winkler ◽

...

Keyword(s):

Nitric Oxide ◽

Heart Failure ◽

Skeletal Muscle ◽

Chronic Heart Failure ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Exercise Intolerance ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Sex and nitric oxide bioavailability interact to modulate interstitial Po2 in healthy rat skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.01022.2017 ◽

2018 ◽

Vol 124 (6) ◽

pp. 1558-1566 ◽

Cited By ~ 7

Author(s):

Jesse C. Craig ◽

Trenton D. Colburn ◽

Daniel M. Hirai ◽

Michael J. Schettler ◽

Timothy I. Musch ◽

...

Keyword(s):

Nitric Oxide ◽

Skeletal Muscle ◽

Sex Differences ◽

Male Rats ◽

Female Rat ◽

Sprague Dawley ◽

Rat Skeletal Muscle ◽

Kinetics Parameters ◽

No Donor ◽

No Bioavailability

Premenopausal women express reduced blood pressure and risk of cardiovascular disease relative to age-matched men. This purportedly relates to elevated estrogen levels increasing nitric oxide synthase (NOS) activity and NO-mediated vasorelaxation. We tested the hypotheses that female rat skeletal muscle would: 1) evince a higher O2 delivery-to-utilization ratio (Q̇o2/V̇o2) during contractions; and 2) express greater modulation of Q̇o2/V̇o2 with changes to NO bioavailability compared with male rats. The spinotrapezius muscle of Sprague-Dawley rats (females = 8, males = 8) was surgically exposed and electrically-stimulated (180 s, 1 Hz, 6 V). OxyphorG4 was injected into the muscle and phosphorescence quenching employed to determine the temporal profile of interstitial Po2 (Po2is, determined by Q̇o2/V̇o2). This was performed under three conditions: control (CON), 300 µM sodium nitroprusside (SNP; NO donor), and 1.5 mM Nω-nitro-l-arginine methyl ester (l-NAME; NOS blockade) superfusion. No sex differences were found for the Po2is kinetics parameters in CON or l-NAME ( P > 0.05), but females elicited a lower baseline following SNP (males 42 ± 3 vs. females 36 ± 2 mmHg, P < 0.05). Females had a lower ΔPo2is during contractions following SNP (males 22 ± 3 vs. females 17 ± 2 mmHg, P < 0.05), but there were no sex differences for the temporal response to contractions ( P > 0.05). The total NO effect (SNP minus l-NAME) on Po2is was not different between sexes. However, the spread across both conditions was shifted to a lower absolute range for females (reduced SNP baseline and greater reduction following l-NAME). These data support that females have a greater reliance on basal NO bioavailability and males have a greater responsiveness to exogenous NO and less responsiveness to reduced endogenous NO. NEW & NOTEWORTHY Interstitial Po2 (Po2is; determined by O2 delivery-to-utilization matching) plays an important role for O2 flux into skeletal muscle. We show that both sexes regulate Po2is at similar levels at rest and during skeletal muscle contractions. However, modulating NO bioavailability exposes sex differences in this regulation with females potentially having a greater reliance on basal NO bioavailability and males having a greater responsiveness to exogenous NO and less responsiveness to reduced endogenous NO.

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Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle.

Circulation ◽

10.1161/01.cir.69.6.1079 ◽

1984 ◽

Vol 69 (6) ◽

pp. 1079-1087 ◽

Cited By ~ 293

Author(s):

J R Wilson ◽

J L Martin ◽

D Schwartz ◽

N Ferraro

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Chronic Heart Failure ◽

Exercise Intolerance

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981-50 Contribution of Skeletal Muscle Fatigue versus Dyspnea to Exercise Intolerance in Chronic Heart Failure

Journal of the American College of Cardiology ◽

10.1016/0735-1097(95)92562-j ◽

1995 ◽

Vol 25 (2) ◽

pp. 265A-266A

Author(s):

Shinobu Matsui ◽

Nobuki Tamura ◽

Saeko Kobayashi ◽

Noboru Takekoshi ◽

Eiji Murakami

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Chronic Heart Failure ◽

Muscle Fatigue ◽

Exercise Intolerance ◽

Skeletal Muscle Fatigue

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Exercise training in chronic heart failure: improving skeletal muscle O2transport and utilization

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00469.2015 ◽

2015 ◽

Vol 309 (9) ◽

pp. H1419-H1439 ◽

Cited By ~ 81

Author(s):

Daniel M. Hirai ◽

Timothy I. Musch ◽

David C. Poole

Keyword(s):

Quality Of Life ◽

Heart Failure ◽

Skeletal Muscle ◽

Chronic Heart Failure ◽

Exercise Training ◽

Physical Capacity ◽

Exercise Intolerance ◽

Whole Body ◽

Functional Components

Chronic heart failure (CHF) impairs critical structural and functional components of the O2transport pathway resulting in exercise intolerance and, consequently, reduced quality of life. In contrast, exercise training is capable of combating many of the CHF-induced impairments and enhancing the matching between skeletal muscle O2delivery and utilization ( Q̇mO2and V̇mO2, respectively). The Q̇mO2/ V̇mO2ratio determines the microvascular O2partial pressure (PmvO2), which represents the ultimate force driving blood-myocyte O2flux (see Fig. 1). Improvements in perfusive and diffusive O2conductances are essential to support faster rates of oxidative phosphorylation (reflected as faster V̇mO2kinetics during transitions in metabolic demand) and reduce the reliance on anaerobic glycolysis and utilization of finite energy sources (thus lowering the magnitude of the O2deficit) in trained CHF muscle. These adaptations contribute to attenuated muscle metabolic perturbations (e.g., changes in [PCr], [Cr], [ADP], and pH) and improved physical capacity (i.e., elevated critical power and maximal V̇mO2). Preservation of such plasticity in response to exercise training is crucial considering the dominant role of skeletal muscle dysfunction in the pathophysiology and increased morbidity/mortality of the CHF patient. This brief review focuses on the mechanistic bases for improved Q̇mO2/ V̇mO2matching (and enhanced PmvO2) with exercise training in CHF with both preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). Specifically, O2convection within the skeletal muscle microcirculation, O2diffusion from the red blood cell to the mitochondria, and muscle metabolic control are particularly susceptive to exercise training adaptations in CHF. Alternatives to traditional whole body endurance exercise training programs such as small muscle mass and inspiratory muscle training, pharmacological treatment (e.g., sildenafil and pentoxifylline), and dietary nitrate supplementation are also presented in light of their therapeutic potential. Adaptations within the skeletal muscle O2transport and utilization system underlie improvements in physical capacity and quality of life in CHF and thus take center stage in the therapeutic management of these patients.

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Complete Coding Sequence of Inducible Nitric Oxide Synthase from Human Heart and Skeletal Muscle of Patients with Chronic Heart Failure

Nitric Oxide ◽

10.1006/niox.1998.0184 ◽

1998 ◽

Vol 2 (4) ◽

pp. 242-249 ◽

Cited By ~ 8

Author(s):

Volker Adams ◽

Silke Krabbes ◽

Hong Jiang ◽

Jiangtao Yu ◽

Axel Rahmel ◽

...

Keyword(s):

Nitric Oxide ◽

Heart Failure ◽

Skeletal Muscle ◽

Chronic Heart Failure ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Human Heart ◽

Coding Sequence ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Skeletal muscle microvascular oxygenation dynamics in heart failure: exercise training and nitric oxide-mediated function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00901.2013 ◽

2014 ◽

Vol 306 (5) ◽

pp. H690-H698 ◽

Cited By ~ 22

Author(s):

Daniel M. Hirai ◽

Steven W. Copp ◽

Clark T. Holdsworth ◽

Scott K. Ferguson ◽

Danielle J. McCullough ◽

...

Keyword(s):

Nitric Oxide ◽

Heart Failure ◽

Skeletal Muscle ◽

Exercise Training ◽

Citrate Synthase ◽

Diastolic Pressure ◽

Left Ventricular ◽

Metabolic Demand ◽

No Donor ◽

Microvascular Oxygenation

Chronic heart failure (CHF) impairs nitric oxide (NO)-mediated regulation of skeletal muscle O2 delivery-utilization matching such that microvascular oxygenation falls faster (i.e., speeds PO2 mv kinetics) during increases in metabolic demand. Conversely, exercise training improves (slows) muscle PO2 mv kinetics following contractions onset in healthy young individuals via NO-dependent mechanisms. We tested the hypothesis that exercise training would improve contracting muscle microvascular oxygenation in CHF rats partly via improved NO-mediated function. CHF rats (left ventricular end-diastolic pressure = 17 ± 2 mmHg) were assigned to sedentary (n = 11) or progressive treadmill exercise training (n = 11; 5 days/wk, 6–8 wk, final workload of 60 min/day at 35 m/min; −14% grade downhill running) groups. PO2 mv was measured via phosphorescence quenching in the spinotrapezius muscle at rest and during 1-Hz twitch contractions under control (Krebs-Henseleit solution), sodium nitroprusside (SNP; NO donor; 300 μM), and NG-nitro-l-arginine methyl ester (L-NAME, nonspecific NO synthase blockade; 1.5 mM) superfusion conditions. Exercise-trained CHF rats had greater peak oxygen uptake and spinotrapezius muscle citrate synthase activity than their sedentary counterparts ( p < 0.05 for both). The overall speed of the PO2 mv fall during contractions (mean response time; MRT) was slowed markedly in trained compared with sedentary CHF rats (sedentary: 20.8 ± 1.4, trained: 32.3 ± 3.0 s; p < 0.05), and the effect was not abolished by L-NAME (sedentary: 16.8 ± 1.5, trained: 31.0 ± 3.4 s; p > 0.05). Relative to control, SNP increased MRT in both groups such that trained CHF rats had slower kinetics (sedentary: 43.0 ± 6.8, trained: 55.5 ± 7.8 s; p < 0.05). Improved NO-mediated function is not obligatory for training-induced improvements in skeletal muscle microvascular oxygenation (slowed PO2 mv kinetics) following contractions onset in rats with CHF.

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