Endothelium-mediated modulation of ergoreflex and improvement in exercise ventilation by acute sildenafil in heart failure patients.
Reflex neural oversignaling sensitive to muscle by-products (ergoreflex) causes exercise hyperventilation in heart failure (HF). We probed whether an improved endothelial function with sildenafil intake may prevent this effect. In 16 chronic heart failure patients and 16 normal subjects, before and after sildenafil intake (50 mg) or placebo, we measured ergoreflex, flow-mediated brachial artery dilation (FMD, an index of endothelial function), and, during maximal exercise, the slope of ventilation to carbon dioxide production (VE/VCO2, an index of ventilatory efficiency), the ratio of changes in O2 uptake (VO2) versus work rate (WR) (deltaVO2/deltaWR, an index of aerobic efficiency). After sildenafil intake, patients, unlike controls, showed a significant decrease in ergoreflex and VE/VCO2 slope and an increase in FMD and deltaVO2/deltaWR. Ergoreflex changes with sildenafil intake correlated with those in FMD and VE/VCO2. Phosphodiesterase-5 inhibition, by improving endothelial activity and muscle perfusion, modulates signaling and improves ventilatory and aerobic efficiencies, potentially indicating a novel pathway in the HF therapeutic management.
Guazzi
M
M
Cardiopulmonary Unit, Cardiology Division, University of Milano, San Paolo Hospital, Milano, Italy. marco.guazzi@unimi.it
Casali
M
M
Berti
F
F
Rossoni
G
G
Colonna
V D'Gennaro
VD
Guazzi
M D
MD
D001916:Brachial Artery / Q000187:drug effects / Q000503:physiopathology; D002245:Carbon Dioxide / Q000378:metabolism; D016022:Case-Control Studies; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D015444:Exercise; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006985:Hyperventilation / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000294:innervation; D010101:Oxygen Consumption / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D012123:Pulmonary Ventilation / Q000187:drug effects*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D012018:Reflex / Q000187:drug effects*; D012129:Respiratory Function Tests; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D002245:Carbon Dioxide; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5