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...

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.

No abstract