Abstract
Nitric oxide (NO) derived from neuronal NO synthase (nNOS) modulates many physiological functions (e.g., vascular tone and mitochondrial respiration inhibition). Recent evidence indicates that NO from nNOS regulates resting, but not exercising, skeletal muscle blood flow (Q) in conscious healthy young rats (Copp et al., J Physiol 2010). Whether nNOS-derived NO modulates muscle microvascular O2 delivery-utilization (QO2/VO2) matching (i.e., microvascular PO2) and O2 flux at rest and/or during contractions in aged individuals is unknown. PURPOSE: To test the hypothesis that acute selective nNOS inhibition in aged rats would reduce Q, increase VO2 and result in lower microvascular PO2 at rest but not during muscle contractions. METHODS: 11 old Fischer 344 x Brown Norway rats (27-28 mo) had their spinotrapezius muscles exposed for measurement of Q (radiolabelled microspheres), microvascular PO2 (phosphorescence quenching) and VO2. Twitch contractions (1 Hz, ∼7 V, 3 min) were evoked pre and post infusion of the selective nNOS inhibitor S-methyl-L-thiocitrulline (SMTC; 2.1 μmol/kg i.a.). RESULTS: At rest, SMTC had no effects on Q (pre: 10 ± 2; post: 9 ± 1 mL/min/100g; P>0.05) but reduced VO2 by ∼23% (pre: 0.7 ± 0.1; post: 0.5 ± 0.1 mL/min/100g; P<0.05), elevating basal microvascular PO2 by ∼18% (pre: 37.7 ± 1.2; post: 44.2 ± 2.1 mmHg; P<0.05). During contractions, the overall microvascular PO2 kinetics (mean response time; pre: 19.7 ± 1.5; post: 20.0 ± 2.0 s), steady-state Q (pre: 115 ± 12; post: 104 ± 11 mL/min/100g), VO2 (pre: 12.0 ± 1.4; post: 10.4 ± 1.6 mL/min/100g) and microvascular PO2 (pre: 26.9 ± 1.3; post: 27.2 ± 2.4 mmHg) were not different (P>0.05) between control and SMTC conditions. CONCLUSIONS: Contrary to our hypothesis, SMTC had no effects on resting Q but reduced muscle VO2 and increased microvascular PO2 (the driving force for blood-myocyte O2 flux) in aged rats. This indicates that the locus of nNOS-derived NO control in skeletal muscle depends on age and metabolic rate (i.e., rest vs. contractions). Given the oxidative stress that develops with aging, these findings suggest that increased generation of reactive O2 species and decreased NO bioavailability (via uncoupled nNOS) attenuate NO-induced mitochondrial respiration inhibition in resting aged skeletal muscle. Support: KSU SMILE, AHA Midwest Affiliate
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