Skeletal Muscle Vascular Control During Exercise: Impact of Nitrite Infusion During Nitric Oxide Synthase Inhibition in Healthy Rats.

The nitric oxide synthase (NOS)-independent pathway of nitric oxide (NO) production in which nitrite (NO2 (-)) is reduced to NO may have therapeutic applications for those with cardiovascular diseases in which the NOS pathway is downregulated. We tested the hypothesis that NO2 (-) infusion would reduce mean arterial pressure (MAP) and increase skeletal muscle blood flow (BF) and vascular conductance (VC) during exercise in the face of NOS blockade via L-NAME. Following infusion of L-NAME (10 mg kg(-1), L-NAME), male Sprague-Dawley rats (3-6 months, n = 8) exercised without N(G)-nitro-L arginine methyl ester (L-NAME) and after infusion of sodium NO2 (-) (7 mg kg(-1); L-NAME + NO2 (-)). MAP and hindlimb skeletal muscle BF (radiolabeled microsphere infusions) were measured during submaximal treadmill running (20 m min(-1), 5% grade). Across group comparisons were made with a published control data set (n = 11). Relative to L-NAME, NO2 (-) infusion significantly reduced MAP (P < 0.03). The lower MAP in L-NAME+NO2 (-) was not different from healthy control animals (control: 137 ± 3 L-NAME: 157 ± 7, L-NAME + NO2 (-): 136 ± 5 mm Hg). Also, NO2 (-) infusion significantly increased VC when compared to L-NAME (P < 0.03), ultimately negating any significant differences from control animals (control: 0.78 ± 0.05, L-NAME: 0.57 ± 0.03, L-NAME + NO2 (-); 0.69 ± 0.04 mL min(-1) 100 g(-1) mm Hg(-1)) with no apparent fiber-type preferential effect. Overall, hindlimb BF was decreased significantly by L-NAME; however, in L-NAME + NO2 (-), BF improved to a level not significantly different from healthy controls (control: 108 ± 8, L-NAME: 88 ± 3, L-NAME + NO2 (-): 94 ± 6 mL min(-1) 100 g(-1), P = 0.38 L-NAME vs L-NAME + NO2 (-)). Individuals with diseases that impair NOS activity, and thus vascular function, may benefit from a NO2 (-)-based therapy in which NO bioavailability is elevated in an NOS-independent manner.

Effects of nitrite infusion on skeletal muscle vascular control during exercise in rats with chronic heart failure.

Chronic heart failure (CHF) reduces nitric oxide (NO) bioavailability and impairs skeletal muscle vascular control during exercise. Reduction of NO2 (-) to NO may impact exercise-induced hyperemia, particularly in muscles with pathologically reduced O2 delivery. We tested the hypothesis that NO2 (-) infusion would increase exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats with a preferential effect in muscles composed primarily of type IIb + IId/x fibers. CHF (coronary artery ligation) was induced in adult male Sprague-Dawley rats. After a >21-day recovery, mean arterial pressure (MAP; carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) were measured during treadmill exercise (20 m/min, 5% incline) with and without NO2 (-) infusion. The myocardial infarct size (35 ± 3%) indicated moderate CHF. NO2 (-) infusion increased total hindlimb skeletal muscle VC (CHF: 0.85 ± 0.09 ml·min(-1)·100 g(-1)·mmHg(-1) and CHF + NO2 (-): 0.93 ± 0.09 ml·min(-1)·100 g(-1)·mmHg(-1), P < 0.05) without changing MAP (CHF: 123 ± 4 mmHg and CHF + NO2 (-): 120 ± 4 mmHg, P = 0.17). Total hindlimb skeletal muscle BF was not significantly different (CHF: 102 ± 7 and CHF + NO2 (-): 109 ± 7 ml·min(-1)·100 g(-1) ml·min(-1)·100 g(-1), P > 0.05). BF increased in 6 (∼21%) and VC in 8 (∼29%) of the 28 individual muscles and muscle parts. Muscles and muscle portions exhibiting greater BF and VC after NO2 (-) infusion comprised ≥63% type IIb + IId/x muscle fibers. These data demonstrate that NO2 (-) infusion can augment skeletal muscle vascular control during exercise in CHF rats. Given the targeted effects shown herein, a NO2 (-)-based therapy may provide an attractive "needs-based" approach for treatment of the vascular dysfunction in CHF.

Microvascular oxygen pressures in muscles comprised of different fiber types: Impact of dietary nitrate supplementation.

Nitrate (NO3(-)) supplementation via beetroot juice (BR) preferentially improves vascular conductance and O2 delivery to contracting skeletal muscles comprised predominantly of type IIb + d/x (i.e. highly glycolytic) fibers following its reduction to nitrite and nitric oxide (NO). To address the mechanistic basis for NO3(-) to improve metabolic control we tested the hypothesis that BR supplementation would elevate microvascular PO2 (PO2mv) in fast twitch but not slow twitch muscle. Twelve young adult male Sprague-Dawley rats were administered BR ([NO3(-)] 1 mmol/kg/day, n = 6) or water (control, n = 6) for 5 days. PO2mv (phosphorescence quenching) was measured at rest and during 180 s of electrically-induced 1-Hz twitch contractions (6-8 V) of the soleus (9% type IIb +d/x) and mixed portion of the gastrocnemius (MG, 91% type IIb + d/x) muscles. In the MG, but not the soleus, BR elevated contracting steady state PO2mv by ~43% (control: 14 ± 1, BR: 19 ± 2 mmHg (P < 0.05)). This higher PO2mv represents a greater blood-myocyte O2 driving force during muscle contractions thus providing a potential mechanism by which NO3(-) supplementation via BR improves metabolic control in fast twitch muscle. Recruitment of higher order type II muscle fibers is thought to play a role in the development of the VO2 slow component which is inextricably linked to the fatigue process. These data therefore provide a putative mechanism for the BR-induced improvements in high-intensity exercise performance seen in humans.