Role of Neuronal Nitric Oxide Synthase in Modulating Microvascular and Contractile Function in Rat Skeletal Muscle

Copp, Steven W.; Hirai, Daniel M.; Ferguson, Scott K.; Musch, Timothy I.; Poole, David C.

doi:10.1111/j.1549-8719.2011.00111.x

Cited by 21 publications

(54 citation statements)

References 55 publications

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“…The hypothesis was tested that, contrary to what was observed previously in young rats (12), selective nNOS inhibition in old rats would result in attenuated or absent alterations in resting and contracting muscle blood flow, V O 2 , PO 2mv , and submaximal force production, thus indicating impaired nNOS-mediated microvascular and contractile control with aging.…”

mentioning

confidence: 62%

“…The rationale for this procedure is based on the Institutional Animal Care and Use Com-mittee stipulation that additional animals not be euthanized for replication of data. In addition, direct comparison between old and young (12) animals is facilitated by the fact that both experimental groups underwent the exact same protocols and old and young animal experiments were temporally interdigitated.…”

Section: Methodsmentioning

confidence: 99%

“…Comparison with young rats is facilitated using data from Copp et al (12). The rationale for this procedure is based on the Institutional Animal Care and Use Com-mittee stipulation that additional animals not be euthanized for replication of data.…”

Section: Methodsmentioning

confidence: 99%

“…Two separate contraction bouts were performed under control (1.2 ml heparinized saline) and selective nNOS inhibition (2.1 mol/kg SMTC dissolved in 1.2 ml heparinized saline) conditions. This dose of SMTC was selected based on previous studies designed to inhibit selectively nNOS in both humans and rodents (18,30,53,64) and our analysis of the highest possible SMTC dose that could be administered without affecting the hypotensive response to ACh, indicative of nonspecific eNOS inhibition (12,13). Each solution was infused at a rate of 0.2 ml/min into the tail artery catheter for a total time of 6 min, after which a ϳ2-min period was allowed for resting muscle PO2mv to stabilize.…”

Section: Methodsmentioning

confidence: 99%

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Effects of neuronal nitric oxide synthase inhibition on microvascular and contractile function in skeletal muscle of aged rats

Hirai

Copp

Holdsworth

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Hirai DM, Copp SW, Holdsworth CT, Ferguson SK, Musch TI, Poole DC. Effects of neuronal nitric oxide synthase inhibition on microvascular and contractile function in skeletal muscle of aged rats. Am J Physiol Heart Circ Physiol 303: H1076 -H1084, 2012. First published August 24, 2012; doi:10.1152 doi:10. /ajpheart.00477.2012 age is associated with derangements in skeletal muscle microvascular function during the transition from rest to contractions. We tested the hypothesis that, contrary to what was reported previously in young rats, selective neuronal nitric oxide (NO) synthase (nNOS) inhibition would result in attenuated or absent alterations in skeletal muscle microvascular oxygenation (PO 2mv), which reflects the matching between muscle O 2 delivery and utilization, following the onset of contractions in old rats. Spinotrapezius muscle blood flow (radiolabeled microspheres), PO 2mv (phosphorescence quenching), O2 utilization (V O2; Fick calculation), and submaximal force production were measured at rest and following the onset of contractions in anesthetized old male Fischer 344 ϫ Brown Norway rats (27 to 28 mo) pre-and postselective nNOS inhibition (2.1 mol/kg S-methyl-L-thiocitrulline; SMTC). At rest, SMTC had no effects on muscle blood flow (P Ͼ 0.05) but reduced V O2 by ϳ23% (P Ͻ 0.05), which elevated basal PO 2mv by ϳ18% (P Ͻ 0.05). During contractions, steady-state muscle blood flow, V O2, PO2mv, and force production were not altered after SMTC (P Ͼ 0.05 for all). The overall PO 2mv dynamics following onset of contractions was also unaffected by SMTC (mean response time: pre, 19.7 Ϯ 1.5; and post, 20.0 Ϯ 2.0 s; P Ͼ 0.05). These results indicate that the locus of nNOS-derived NO control in skeletal muscle depends on age and metabolic rate (i.e., rest vs. contractions). Alterations in nNOS-mediated regulation of contracting skeletal muscle microvascular function with aging may contribute to poor exercise capacity in this population.aging; blood flow; force; oxygen uptake; S-methyl-L-thiocitrulline NITRIC OXIDE (NO) is a ubiquitous signaling messenger synthesized primarily through the conversion of L-arginine to L-citrulline by the enzyme NO synthase (NOS). Within skeletal muscle, NO plays a critical role in the modulation of several physiological processes including vascular relaxation, oxidative metabolism, and excitation-contraction coupling (56). All three major NOS isoforms are expressed in mammalian skeletal muscle, namely, neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS) (56). Several lines of evidence indicate that NO derived from nNOS participates significantly in the matching of muscle O 2 delivery and utilization (Q O 2 /V O 2 ) at rest and during contractions as well as submaximal force production in healthy young individuals (12; see also Refs. 13,15,19,28,33,36,39,45,52,53,60).Advancing age is associated with impairments in the O 2 transport pathway and exercise capacity (47). Derangements in NO-mediated function likely represent one of the main mechanisms underlying tem...

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confidence: 62%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Effects of neuronal nitric oxide synthase inhibition on microvascular and contractile function in skeletal muscle of aged rats

Hirai

Copp

Holdsworth

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

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“…However, the relevance of these findings to humans is unclear because, unlike rodents that have highly compartmentalized skeletal muscle containing predominantly fast, slow, or intermediate fiber types, human skeletal muscle is mixed (14,15,278). However, an important finding from these studies is that blockade of neuronal NOS can influence the blood flow response to exercise, indicating that in addition to the vascular endothelium, NO might also be released by the contracting skeletal muscles (97,99,102).…”

Section: N Substances Released From the Endotheliummentioning

confidence: 90%

Regulation of Increased Blood Flow (Hyperemia) to Muscles During Exercise: A Hierarchy of Competing Physiological Needs

Joyner

Casey

2015

Physiological Reviews

534

513

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LJoyner MJ, Casey DP. Regulation of Increased Blood Flow (Hyperemia) to Muscles During Exercise: A Hierarchy of Competing Physiological Needs. Physiol Rev 95: 549 -601, 2015; doi:10.1152/physrev.00035.2013.-This review focuses on how blood flow to contracting skeletal muscles is regulated during exercise in humans. The idea is that blood flow to the contracting muscles links oxygen in the atmosphere with the contracting muscles where it is consumed. In this context, we take a top down approach and review the basics of oxygen consumption at rest and during exercise in humans, how these values change with training, and the systemic hemodynamic adaptations that support them. We highlight the very high muscle blood flow responses to exercise discovered in the 1980s. We also discuss the vasodilating factors in the contracting muscles responsible for these very high flows. Finally, the competition between demand for blood flow by contracting muscles and maximum systemic cardiac output is discussed as a potential challenge to blood pressure regulation during heavy large muscle mass or whole body exercise in humans. At this time, no one dominant dilator mechanism accounts for exercise hyperemia. Additionally, complex interactions between the sympathetic nervous system and the microcirculation facilitate high levels of systemic oxygen extraction and permit just enough sympathetic control of blood flow to contracting muscles to regulate blood pressure during large muscle mass exercise in humans.

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Exercise Training and Peripheral Arterial Disease

Haas

Lloyd

Yang

et al. 2012

Comprehensive Physiology

117

108

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Peripheral arterial disease (PAD) is a common vascular disease that reduces blood flow capacity to the legs of patients. PAD leads to exercise intolerance that can progress in severity to greatly limit mobility, and in advanced cases leads to frank ischemia with pain at rest. It is estimated that 12–15 million people in the United States are diagnosed with PAD, with a much larger population that is undiagnosed. The presence of PAD predicts a 50–1500% increase in morbidity and mortality, depending on severity. Treatment of patients with PAD is limited to modification of cardiovascular disease risk factors, pharmacological intervention, surgery, and exercise therapy. Extended exercise programs that involve walking ~5 times/wk, at a significant intensity that requires frequent rest periods, are most significant. Pre-clinical studies and virtually all clinical trials demonstrate the benefits of exercise therapy, including: improved walking tolerance, modified inflammatory/hemostatic markers, enhanced vasoresponsiveness, adaptations within the limb (angiogenesis, arteriogenesis, mitochondrial synthesis) that enhance oxygen delivery and metabolic responses, potentially delayed progression of the disease, enhanced quality of life indices, and extended longevity. A synthesis is provided as to how these adaptations can develop in the context of our current state of knowledge and events known to be orchestrated by exercise. The benefits are so compelling that exercise prescription should be an essential option presented to patients with PAD in the absence of contraindications. Obviously, selecting for a life style pattern, that includes enhanced physical activity prior to the advance of PAD limitations, is the most desirable and beneficial.

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Role of Neuronal Nitric Oxide Synthase in Modulating Microvascular and Contractile Function in Rat Skeletal Muscle

Abstract: These data demonstrate important physiological roles for nNOS-derived NO during contractions in healthy rat skeletal muscle and implicate maladaptations in nNOS function in pathological conditions associated with reduced NO bioavailability.

Cited by 21 publications

References 55 publications

Effects of neuronal nitric oxide synthase inhibition on microvascular and contractile function in skeletal muscle of aged rats

Effects of neuronal nitric oxide synthase inhibition on microvascular and contractile function in skeletal muscle of aged rats

Regulation of Increased Blood Flow (Hyperemia) to Muscles During Exercise: A Hierarchy of Competing Physiological Needs

Exercise Training and Peripheral Arterial Disease

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