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

Abstract

Ϫ to NO may impact exercise-induced hyperemia, particularly in muscles with pathologically reduced O 2 delivery. We tested the hypothesis that NO 2 Ϫ 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 ϩ IId/x fibers. CHF (coronary artery ligation) was induced in adult male Sprague-Dawley rats. After a Ͼ21-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 NO 2 Ϫ infusion. The myocardial infarct size (35 Ϯ 3%) indicated moderate CHF. NO 2 Ϫ infusion increased total hindlimb skeletal muscle VC (CHF: 0.85 Ϯ 0.09 ml·min Ϫ1 ·100 g Ϫ1 ·mmHg Ϫ1 and CHF ϩ NO 2 Ϫ : 0.93 Ϯ 0.09 ml·min Ϫ1 ·100 g Ϫ1 ·mmHg Ϫ1 , P Ͻ 0.05) without changing MAP (CHF: 123 Ϯ 4 mmHg and CHF ϩ NO 2 Ϫ : 120 Ϯ 4 mmHg, P ϭ 0.17). Total hindlimb skeletal muscle BF was not significantly different (CHF: 102 Ϯ 7 and CHF ϩ NO 2 Ϫ : 109 Ϯ 7 ml·min Ϫ1 ·100 g Ϫ1 ml·min Ϫ1 ·100 g Ϫ1 , P Ͼ 0.05). BF increased in 6 (ϳ21%) and VC in 8 (ϳ29%) of the 28 individual muscles and muscle parts. Muscles and muscle portions exhibiting greater BF and VC after NO 2 Ϫ infusion comprised Ն63% type IIb ϩ IId/x muscle fibers. These data demonstrate that NO 2 Ϫ infusion can augment skeletal muscle vascular control during exercise in CHF rats. Given the targeted effects shown herein, a NO 2 Ϫ -based therapy may provide an attractive "needs-based" approach for treatment of the vascular dysfunction in CHF. CHRONIC HEART FAILURE (CHF) is characterized by a combination of central and peripheral circulatory dysfunction that ultimately impairs exercise tolerance and quality of life (30,47). About 23 million individuals worldwide suffer from this disease (37), and while central cardiac dysfunction is fundamental to the etiology of CHF, the peripheral vascular impairments induced by CHF are of paramount importance. CHFinduced vascular dysregulation is thought to be due, in part, to reduced nitric oxide (NO)-mediated function (Ref. 20; for a review, see Ref. 47). Although exercise rehabilitation represents an effective therapeutic modality for treating CHF (9), reduced NO bioavailability in CHF is associated with an impaired ability to perform exercise and/or even complete daily physical activities. Consequently, interventions that increase NO bioavailability may ameliorate the skeletal muscle vascular dysfunction evident in this disease (20,25) and thus have great potential to improve exercise tolerance and quality of life in this population.NO is synthesized endogenously via three isoforms of NO synthase (NOS) as well as by the nonenzymatic reduction of NO 3 Ϫ to NO 2 Ϫ and, finally, to NO (for a review, see Ref. 38). The contribution of the NO 3 Ϫ -NO 2 Ϫ -NO pathway can be upregulated when plasma NO 2 Ϫ concentration is increased either by dietary means (e.g., via beetroot juice) or direct venous or arterial NO 2 Ϫ...

Acute ingestion of dietary nitrate increases muscle blood flow via local vasodilation during handgrip exercise in young adults

“…Collectively, our findings indicate that acute NO À 3 supplementation increases muscle BF and VC, but does not reduce local tissue VO 2 , during rhythmic handgrip exercise in healthy humans. This increase in muscle perfusion and O 2 delivery could help explain improvements in exercise tolerance by improving metabolic control (Bailey et al 2009;Glean et al 2015;Kenjale et al 2011;Larsen et al 2010;Vanhatalo et al 2011).…”

“…Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. peripheral artery disease, chronic obstructive pulmonary disease, diabetes, and patients with angina (Boden et al 2012;Glean et al 2015;Kerley et al 2015;Shepherd et al 2015a,b;Zamani et al 2015). Specific to limb blood flow and BR ingestion, Casey et al observed improvements in hypoxic exercise vasodilation in older adults, thus eliminating the age-associated impairment that occurred prior to BR ingestion (Casey et al 2015).…”

INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction)

“…40-45 Inorganic nitrate and nitrite improve skeletal muscle microvascular conductance during exercise 46 and increase capillary O 2 tension facilitating O 2 diffusion into muscle cells. 47 Nitrite increases mitochondrial efficiency in skeletal muscle 48 and improves insulin sensitivity and glucose uptake.…”

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.…”