title: Role of endothelin-1 in mediating changes in cardiac sympathetic nerve activity in heart failure.
abstract: Heart failure (HF) is associated with increased sympathetic nerve activity to the heart (CSNA), which is directly linked to mortality in HF patients. Previous studies indicate that HF is associated with high levels of plasma endothelin-1 (ET-1), which correlates with the severity of the disease. We hypothesized that blockade of endothelin receptors would decrease CSNA. The effects of intravenous tezosentan (a nonselective ETA and ETB receptor antagonist) (8 mg·kg(-1)·h(-1)) on resting levels of CSNA, arterial pressure, and heart rate were determined in conscious normal sheep (n = 6) and sheep with pacing-induced HF (n = 7). HF was associated with a significant decrease in ejection fraction (from 74 ± 2% to 38 ± 1%, P < 0.001) and a significant increase in resting levels of CSNA burst incidence (from 56 ± 11 to 87 ± 2 bursts/100 heartbeats, P < 0.01). Infusion of tezosentan for 60 min significantly decreased resting mean aterial pressure (MAP) in both normal and HF sheep (-8 ± 4 mmHg and -4 ± 3 mmHg, respectively; P < 0.05). This was associated with a significant decrease in CSNA (by 25 ± 26% of control) in normal sheep, but there was no change in CSNA in HF sheep. Calculation of spontaneous baroreflex gain indicated significant impairment of the baroreflex control of HR after intravenous tezosentan infusion in normal animals but no change in HF animals. These data suggest that endogenous levels of ET-1 contribute to the baseline levels of CSNA in normal animals, but this effect is absent in HF.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville Victoria, Australia; and.
authors.forename: Yonis
authors.initials: Y
authors.lastname: Abukar
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville Victoria, Australia; and.
authors.forename: Clive N
authors.initials: CN
authors.lastname: May
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville Victoria, Australia; and Department of Physiology, The University of Auckland, Auckland, New Zealand r.ramchandra@auckland.ac.nz.
authors.forename: Rohit
authors.initials: R
authors.lastname: Ramchandra
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D017704:Baroreflex; D015415:Biomarkers / Q000097:blood; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage; D019332:Endothelin-1 / Q000097:blood*; D005260:Female; D006321:Heart / Q000294:innervation*; D006333:Heart Failure / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D011725:Pyridines / Q000008:administration & dosage; D012756:Sheep; D015398:Signal Transduction; D013318:Stroke Volume; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D013777:Tetrazoles / Q000008:administration & dosage; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D013777:Tetrazoles; C120582:tezosentan
keywords: cardiac sympathetic nerve; endothelin-1 receptor blockade; heart failure; tezosentan