title: Differentiation of arginine vasopressin antagonistic effects by selective V2 versus dual V2/V1a receptor blockade in a preclinical heart failure model.
abstract: Arginine vasopressin (AVP) is increased in patients with heart failure (HF). Its actions are linked to free water reabsorption (V2-) and arteriolar vasoconstriction (V1a receptor). AVP can exacerbate the cardiorenal syndrome with excess fluid retention and afterload increase. Tolvaptan (TOL; selective V2 antagonist) and Conivaptan (CON; dual V1a/V2 antagonist) are two AVP antagonists that counteract the action of AVP with distinct profiles. We investigated the therapeutic effects of CON and TOL in an acute HF model. Mongrel dogs were paced continuously at 220 beats/min. After 14 days, the animals underwent acute testing. Dogs were instrumented to measure cardiac output, blood pressure, pulmonary artery pressure, and left ventricular dP/dtmax. Additionally, during the acute experiments, vasopressin was infused intravenously (4 mU/kg/min) to achieve constant and controlled pathophysiological levels of AVP. Subsequently, animals received either CON or TOL (n = 6; 0.1-mg/kg bolus). There were no significant differences in effect on mean arterial pressure, dP/dtmax, central venous pressure, and urine output between CON and TOL. In contrast, cardiac output increased by 0.15 l/min after CON and decreased by 0.6 l/min after TOL (P < 0.01). Accordingly, the total peripheral resistance increased after TOL by 250 dyn*s/cm and decreased after CON by 125 dyn*s/cm (P < 0.01). In conclusion, it was demonstrated that in an acute HF model, CON lowered, whereas TOL increased afterload. The results suggest that dual V1a/V2 blockade in the acute HF setting could be beneficial compared with selective V2 blockade. Chronic experiments are needed to determine whether this finding can translate into a sustained clinical advantage.
authors.affiliation: Bayer Health Care, Cardiovascular Research Institute, Wuppertal, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mondritzki
authors.forename: Peter
authors.initials: P
authors.lastname: Kolkhof
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.forename: Chantal
authors.initials: C
authors.lastname: Fürstner
authors.forename: Carsten
authors.initials: C
authors.lastname: Schmeck
authors.forename: Harald
authors.initials: H
authors.lastname: Siedentop
authors.forename: Stefan
authors.initials: S
authors.lastname: Schaefer
authors.forename: Hubert
authors.initials: H
authors.lastname: Truebel
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D006333:Heart Failure / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects; D010138:Pacemaker, Artificial; D000077602:Tolvaptan; D014563:Urodynamics / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; C106389:conivaptan; D001127:Arginine Vasopressin; D000077602:Tolvaptan