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

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

doi:10.1152/ajpheart.00477.2012

Cited by 8 publications

(11 citation statements)

References 65 publications

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“…First, SMTC is a potent nNOS inhibitor which possesses a 17-fold selectivity for nNOS over eNOS in rat tissue in vivo (Furfine et al, 1994) and induced significant increases in MAP herein. Second, 0.56 mg/kg of SMTC (the identical dose utilized herein) does not attenuate the hypotensive response to rapid acetylcholine (ACh) infusion whereas it is blunted (smaller Δ MAP and faster recovery time) following non-selective NOS inhibition with L-NAME (Copp et al, 2010, 2011, 2012; Hirai et al, 2012). This is a crucial observation given that vasodilation in response to ACh is due, in large part, to eNOS-derived NO.…”

Section: Discussionmentioning

confidence: 96%

“…This is consistent with transient SMTC-induced MAP elevations reported previously (Komers et al, 2000; Wakefield et al, 2003). Importantly, in recent investigations from our laboratory MAP, HR, and skeletal muscle and kidney blood flow were measured ~4–5 minutes following SMTC administration (Copp et al, 2010, 2011, 2012; Hirai et al, 2012). Thus, the present data support that those measurements occurred when the cardiovascular effects of SMTC were peaking.…”

Section: Discussionmentioning

confidence: 99%

“…Between experimental conditions baseline values were determined as described above following a second ~5 minute stabilization period. SMTC is a highly selective inhibitor of nNOS versus eNOS both in vitro and in vivo (Furfine et al, 1994; Narayanan and Griffith, 1994; Wakefield et al, 2003) and this SMTC dose has been utilized recently in our laboratory to assess nNOS-mediated cardiovascular and skeletal muscle function in healthy (Copp et al, 2010, 2011), heart failure (Copp et al, 2012), and senescent (Hirai et al, 2012) rats (see Experimental considerations for further details regarding efficacy and selectivity of nNOS inhibition with SMTC). In one rat, a short bout of combined hypoxia and hypercapnia (i.e., shutting off the mechanical ventilator for ~20 seconds) was implemented as a positive control following saline and SMTC in which it was confirmed that a physiological increase in SND could be detected following completion of the experimental protocol (Figure 1 inset).…”

Section: Methodsmentioning

confidence: 99%

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Neuronal nitric oxide synthase inhibition and regional sympathetic nerve discharge: Implications for peripheral vascular control

Copp¹,

Hirai²,

Sims³

et al. 2013

Respiratory Physiology & Neurobiology

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Neuronal nitric oxide (NO) synthase (nNOS) inhibition with systemically-administered S-methyl-L-thiocitrulline (SMTC) elevates mean arterial pressure (MAP) and reduces rat hindlimb skeletal muscle and renal blood flow. We tested the hypothesis that those SMTC-induced cardiovascular effects resulted, in part, from increased sympathetic nerve discharge (SND). MAP, HR, and lumbar and renal SND (direct nerve recordings) were measured in 9 baroreceptor (sino-aortic)-denervated rats for 20 minutes each following both saline and SMTC (0.56 mg/kg i.v.). SMTC increased MAP (peak Δ MAP: 50±8 mmHg, p<0.01) compared to saline. Lumbar and renal SND were not different between saline and SMTC conditions at any time (p>0.05). The Δ SND between saline and SMTC conditions for the lumbar and renal nerves were not different from zero (peak Δ SND, lumbar: 2.0±6.8%; renal: 9.7±9.0%, p>0.05 versus zero for both). These data support that SMTC-induced reductions in skeletal muscle and renal blood flow reported previously reflect peripheral nNOS-derived NO vascular control as opposed to increased sympathetic vasoconstriction.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Neuronal nitric oxide synthase inhibition and regional sympathetic nerve discharge: Implications for peripheral vascular control

Copp¹,

Hirai²,

Sims³

et al. 2013

Respiratory Physiology & Neurobiology

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“…Beside endothelial eNOS activity or NO metabolism, limitations of NO-availability may possibly also arise neuronal NOS as another NO sources, that shows an age-related impact on microcirculation [61]. Furthermore, aging may lead to a NO-dependent redistribution of microvascular blood flow distribution from ‘red’ and ‘white’ muscle groups/ regions with consequences for endurance training effects [8, 62, 63].…”

Section: Discussionmentioning

confidence: 99%

Age-related differences in skeletal muscle microvascular response to exercise as detected by contrast-enhanced ultrasound (CEUS)

et al. 2017

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BackgroundAging involves reductions in exercise total limb blood flow and exercise capacity. We hypothesized that this may involve early age-related impairments of skeletal muscle microvascular responsiveness as previously reported for insulin but not for exercise stimuli in humans.MethodsUsing an isometric exercise model, we studied the effect of age on contrast-enhanced ultrasound (CEUS) parameters, i.e. microvascular blood volume (MBV), flow velocity (MFV) and blood flow (MBF) calculated from replenishment of Sonovue contrast-agent microbubbles after their destruction. CEUS was applied to the vastus lateralis (VLat) and intermedius (VInt) muscle in 15 middle-aged (MA, 43.6±1.5 years) and 11 young (YG, 24.1±0.6 years) healthy males before, during, and after 2 min of isometric knee extension at 15% of peak torque (PT). In addition, total leg blood flow as recorded by femoral artery Doppler-flow. Moreover, fiber-type-specific and overall capillarisation as well as fiber composition were additionally assessed in Vlat biopsies obtained from CEUS site. MA and YG had similar quadriceps muscle MRT-volume or PT and maximal oxygen uptake as well as a normal cardiovascular risk factors and intima-media-thickness.ResultsDuring isometric exercise MA compared to YG reached significantly lower levels in MFV (0.123±0.016 vs. 0.208±0.036 a.u.) and MBF (0.007±0.001 vs. 0.012±0.002 a.u.). In the VInt the (post-occlusive hyperemia) post-exercise peaks in MBV and MBF were significantly lower in MA vs. YG. Capillary density, capillary fiber contacts and femoral artery Doppler were similar between MA and YG.ConclusionsIn the absence of significant age-related reductions in capillarisation, total leg blood flow or muscle mass, healthy middle-aged males reveal impaired skeletal muscle microcirculatory responses to isometric exercise. Whether this limits isometric muscle performance remains to be assessed.

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“…2001; Copp et al . 2012) and aged (Hirai et al . 2012) populations which have been associated with impaired nNOS‐mediated function.…”

Section: Introductionmentioning

confidence: 99%

Muscle fibre‐type dependence of neuronal nitric oxide synthase‐mediated vascular control in the rat during high speed treadmill running

Copp

Holdsworth

Ferguson

et al. 2013

The Journal of Physiology

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Key points• Neuronal nitric oxide (NO) synthase (nNOS) inhibition does not impact skeletal muscle blood flow or vascular conductance (VC) during low-speed (20 m min −1 ) treadmill running.• This may be due to the fact that low exercise intensities recruit primarily oxidative muscle and that nNOS-derived NO contributes to vascular control primarily within glycolytic muscle.• Rats ran in the severe-intensity domain at 15% above critical speed (an important glycolytic fast-twitch fibre recruitment boundary in the rat) before and after selective nNOS inhibition with S-methyl-L-thiocitrulline (SMTC).• SMTC reduced blood flow and VC during supra-critical speed treadmill running (52.5 ± 1.3 m min −1 ) with the greatest proportional reductions observed in glycolytic fast-twitch compared to oxidative slow-and fast-twitch muscle. There were no effects of SMTC on muscle blood flow or VC during low-speed running (20 m min −1 ).• The present data reveal important fibre-type-and exercise intensity-dependent peripheral vascular effects of nNOS-derived NO during whole-body exercise.Abstract We have recently shown that nitric oxide (NO) derived from neuronal NO synthase (nNOS) does not contribute to the hyperaemic response within rat hindlimb skeletal muscle during low-speed treadmill running. This may be attributed to low exercise intensities recruiting primarily oxidative muscle and that vascular effects of nNOS-derived NO are manifest principally within glycolytic muscle. We tested the hypothesis that selective nNOS inhibition via S-methyl-L-thiocitrulline (SMTC) would reduce rat hindlimb skeletal muscle blood flow and vascular conductance (VC) during high-speed treadmill running above critical speed (asymptote of the hyperbolic speed versus time-to-exhaustion relationship for high-speed running and an important glycolytic fast-twitch fibre recruitment boundary in the rat) principally within glycolytic fast-twitch muscle. Six rats performed three high-speed treadmill runs to exhaustion to determine critical speed. Subsequently, hindlimb skeletal muscle blood flow (radiolabelled microspheres) and VC (blood flow/mean arterial pressure) were determined during supra-critical speed treadmill running (critical speed + 15%, 52.5 ± 1.3 m min −1 ) before (control) and after selective nNOS inhibition with 0.56 mg kg −1 SMTC. SMTC reduced total hindlimb skeletal muscle blood flow (control: 241 ± 23, SMTC: 204 ± 13 ml min −1 (100 g) −1 , P < 0.05) and VC (control: 1.88 ± 0.20, SMTC: 1.48 ± 0.13 ml min −1 (100 g) −1 mmHg −1 , P < 0.05) during high-speed running. The relative reductions in blood flow and VC were greater in the highly glycolytic muscles and muscle parts consisting of 100% type IIb+d/x fibres compared to the highly oxidative muscles and muscle parts consisting of ≤35% type IIb+d/x muscle fibres (P < 0.05). These results C

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

Cited by 8 publications

References 65 publications

Neuronal nitric oxide synthase inhibition and regional sympathetic nerve discharge: Implications for peripheral vascular control

Neuronal nitric oxide synthase inhibition and regional sympathetic nerve discharge: Implications for peripheral vascular control

Age-related differences in skeletal muscle microvascular response to exercise as detected by contrast-enhanced ultrasound (CEUS)

Muscle fibre‐type dependence of neuronal nitric oxide synthase‐mediated vascular control in the rat during high speed treadmill running

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