Long-term effects of nonpeptide vasopressin V2 antagonist OPC-31260 in heart failure in the rat.
The hormone arginine vasopressin (AVP) contributes to water retention and vasoconstriction in congestive heart failure (CHF) through effects at the V2 and V1a receptors, respectively. The effect of long-term V2 receptor (V2R) blockade using OPC-31260 was assessed in a rat model of postinfarction-induced CHF. Rats underwent coronary artery ligation or sham operation and were treated for 6 mo with oral OPC-31260 (10 mg . kg-1 . day-1) or vehicle. CHF was characterized by left ventricular remodeling and impaired systolic function, increased cardiac and lung weight, and elevated plasma atrial natriuretic peptide; plasma AVP and plasma renin activity were not increased. Chronic V2R blockade increased urine volume (P < 0.01) and decreased urine osmolality (P < 0.01) but had no natriuretic effects. V2R blockade did not activate the renin-angiotensin system but increased plasma AVP in CHF (P < 0.01). V2R blockade did not influence cardiac remodeling, cardiac function, or survival. These results suggest that AVP plays a major role in water retention through the renal V2R in a rat model of CHF. V2R blockade using OPC-31260 may represent an alternative to standard diuretic therapy in the management of water retention that characterizes heart failure.
Burrell
L M
LM
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg 3084, Victoria, Australia.
Phillips
P A
PA
Risvanis
J
J
Chan
R K
RK
Aldred
K L
KL
Johnston
C I
CI
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000097:blood; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System; D016019:Survival Analysis; D013599:Systole
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D001127:Arginine Vasopressin; C076251:mozavaptan