Sildenafil improves microvascular O2 delivery-to-utilization matching and accelerates exercise O2 uptake kinetics in chronic heart failure

• Published in: American journal of physiology. Heart and circulatory physiology 2012-12, Vol.303 (12), p.H1474-H1480
• Main Authors: Sperandio, Priscila A, Oliveira, Mayron F, Rodrigues, Miguel K, Berton, Danilo C, Treptow, Erika, Nery, Luiz E, Almeida, Dirceu R, Neder, J Alberto
• Format: Article
• Language: English
• Subjects: Aged; Cardiac Output - drug effects; Cardiac Output - physiology; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Exercise - physiology; Exercise Tolerance - drug effects; Exercise Tolerance - physiology; Heart Failure - metabolism; Heart Failure - physiopathology; Humans; Male; Microcirculation - drug effects; Microcirculation - physiology; Middle Aged; Muscle, Skeletal - blood supply; Muscle, Skeletal - metabolism; Nitric Oxide - metabolism; Oxygen - metabolism; Oxygen Consumption - drug effects; Oxygen Consumption - physiology; Piperazines - pharmacology; Prospective Studies; Purines - pharmacology; Regional Blood Flow - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Sildenafil Citrate; Sulfones - pharmacology; Vasodilator Agents - pharmacology
• ISSN: 1522-1539
• DOI: 10.1152/ajpheart.00435.2012

Nitric oxide (NO) can temporally and spatially match microvascular oxygen (O(2)) delivery (Qo(2mv)) to O(2) uptake (Vo(2)) in the skeletal muscle, a crucial adjustment-to-exercise tolerance that is impaired in chronic heart failure (CHF). To investigate the effects of NO bioavailability induced by sildenafil intake on muscle Qo(2mv)-to-O(2) utilization matching and Vo(2) kinetics, 10 males with CHF (ejection fraction = 27 ± 6%) undertook constant work-rate exercise (70-80% peak). Breath-by-breath Vo(2), fractional O(2)extraction in the vastus lateralis {∼deoxygenated hemoglobin + myoglobin ([deoxy-Hb + Mb]) by near-infrared spectroscopy}, and cardiac output (CO) were evaluated after sildenafil (50 mg) or placebo. Sildenafil increased exercise tolerance compared with placebo by ∼20%, an effect that was related to faster on- and off-exercise Vo(2) kinetics (P < 0.05). Active treatment, however, failed to accelerate CO dynamics (P > 0.05). On-exercise [deoxy-Hb + Mb] kinetics were slowed by sildenafil (∼25%), and a subsequent response "overshoot" (n = 8) was significantly lessened or even abolished. In contrast, [deoxy-Hb + Mb] recovery was faster with sildenafil (∼15%). Improvements in muscle oxygenation with sildenafil were related to faster on-exercise Vo(2) kinetics, blunted oscillations in ventilation (n = 9), and greater exercise capacity (P < 0.05). Sildenafil intake enhanced intramuscular Qo(2mv)-to-Vo(2) matching with beneficial effects on Vo(2) kinetics and exercise tolerance in CHF. The lack of effect on CO suggests that improvement in blood flow to and within skeletal muscles underlies these effects.