Dietary nitrate supplementation: impact on skeletal muscle vascular control in exercising rats with chronic heart failure

Abstract

Chronic heart failure (CHF) results in central and peripheral derangements that ultimately reduce skeletal muscle O2 delivery and impair exercise tolerance. Dietary nitrate (NO3 (-)) supplementation improves skeletal muscle vascular function and tolerance to exercise. We tested the hypothesis that NO3 (-) supplementation would elevate exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats. Myocardial infarction (MI) was induced (coronary artery ligation) in young adult male rats. After 21 days of recovery, rats randomly received 5 days of NO3 (-)-rich beetroot juice (CHF + BR, n = 10) or a placebo (CHF, n = 10). Mean arterial pressure (carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) were measured during treadmill exercise (20 m/min, 5% grade). CHF-induced dysfunction, as determined by myocardial infarction size (29 ± 3% and 33 ± 4% in CHF and CHF + BR, respectively) and left ventricular end-diastolic pressure (18 ± 2 and 18 ± 2 mmHg in CHF and CHF + BR, respectively), and exercising mean arterial pressure (131 ± 3 and 128 ± 4 mmHg in CHF and CHF + BR, respectively) were not different (P > 0.05) between groups. Total exercising hindlimb skeletal muscle BF (95 ± 5 and 116 ± 9 ml·min(-1)·100 g(-1) in CHF and CHF + BR, respectively) and VC (0.75 ± 0.05 and 0.90 ± 0.05 ml·min(-1)·100 g(-1)·mmHg(-1) in CHF and CHF + BR, respectively) were 22% and 20% greater in BR-supplemented rats, respectively (P < 0.05). During exercise, BF in 9 and VC in 10 hindlimb muscles and muscle portions were significantly greater in the CHF + BR group. These results provide strong evidence that dietary NO3 (-) supplementation improves skeletal muscle vascular function during exercise in rats with CHF and, thus, support the use of BR as a novel therapeutic modality for the treatment of CHF.

The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

“…However, there is increasing evidence for a specific role of this particular characteristic of the anions in patients with HF (Coggan and Peterson, 2016). A recent study in rats that develop HF after induction of MI by coronary artery ligation (Ferguson et al, 2016) has demonstrated the benefits of dietary nitrate treatment. At 21 days after coronary artery occlusion, rats were randomized to 5 days of nitrate-rich (1 mmol/kg per day nitrate) versus nitrate-deplete beetroot juice and underwent investigations of skeletal muscle blood flow and vascular conductance.…”

Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction

“…12 Thus, circulating nitrate/nitrite may serve as an alternative pool for bioactive NO, which can sustain/enhance NO signaling when the traditional pathway for NO generation is less functional. 9, 13 Indeed, nitrate/nitrite supplementation has been shown to increase blood flow to exercising muscle in rats with 14, 15 and without 16, 17 heart failure. NO-induced vasodilation during exercise may facilitate the matching of perfusion to metabolic activity.…”

Effects of Dietary Inorganic Nitrate Supplementation on Exercise Performance in Patients With Heart Failure: Protocol for a Randomized, Placebo-Controlled, Cross-Over Trial

“…As this activation is known to lead to increases in maximal power output, particularly in type II fibers, it lends further support to nitrate’s efficacy in CHF (where patients are known to be more type II-fiber dominant). In further support of these findings, 2 separate CHF rat model studies, 1 using an acute dose (5 mg/kg sodium nitrite) and 1 using a chronic dose (1 mmol nitrate/kg/day for 5 days), demonstrated significant increases in blood flow and vascular conductance in skeletal muscle [ 38 , 39 ]. The acute sodium nitrite infusion also showed a preferential increase in blood flow, specifically in the muscles of the rats with a higher percentage of both type IIb + IId/x fast-twitch fibers [ 38 ].…”