title: Chronic endothelin-1 blockade reduces sympathetic nerve activity in rabbits with heart failure.
abstract: Endothelin-1 (ET-1) is elevated in chronic heart failure (CHF). In this study, we determined the effects of chronic ET-1 blockade on renal sympathetic nerve activity (RSNA) in conscious rabbits with pacing-induced CHF. Rabbits were chronically paced at 320--340 beats/min for 3--4 wk until clinical and hemodynamic signs of CHF were present. Resting RSNA and arterial baroreflex control of RSNA were determined. Responses were determined before and after the ET-1 antagonist L-754,142 (a combined ET(A) and ET(B) receptor antagonist, n = 5) was administered by osmotic minipump infusion (0.5 mg. kg(-1) x h(-1) for 48 h). In addition, five rabbits with CHF were treated with the specific ET(A) receptor antagonist BQ-123. Baseline RSNA (expressed as a percentage of the maximum nerve activity during sodium nitroprusside infusion) was significantly higher (58.3 +/- 4.9 vs. 27.0 +/- 1.0, P < 0.001), whereas baroreflex sensitivity was significantly lower in rabbits with CHF compared with control (3.09 +/- 0.19 vs. 6.04 +/- 0.73, P < 0.001). L-754,142 caused a time-dependent reduction in arterial pressure and RSNA in rabbits with CHF. In addition, BQ-123 caused a reduction in resting RSNA. For both compounds, RSNA returned to near control levels 24 h after removal of the minipump. These data suggest that ET-1 contributes to sympathoexcitation in the CHF state. Enhancement of arterial baroreflex sensitivity may further contribute to sympathoinhibition after ET-1 blockade in heart failure.
authors.affiliation: Department of Physiology and Biophysics, University of Nebraska College of Medicine, Omaha, Nebraska 68198-4575, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Liu
authors.forename: R U
authors.initials: RU
authors.lastname: Pliquett
authors.forename: E
authors.initials: E
authors.lastname: Brewer
authors.forename: K G
authors.initials: KG
authors.lastname: Cornish
authors.forename: Y T
authors.initials: YT
authors.lastname: Shen
authors.forename: I H
authors.initials: IH
authors.lastname: Zucker
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001158:Arteries / Q000503:physiopathology; D017704:Baroreflex / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002303:Cardiac Output, Low / Q000503:physiopathology*; D002908:Chronic Disease; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000294:innervation*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011817:Rabbits; D044022:Receptor, Endothelin A; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D000081:Acetamides; D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; C097296:L 754142; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C072247:cyclo(Trp-Asp-Pro-Val-Leu)