title: Chronic vasopressin V(1A) but not V(2) receptor antagonism prevents heart failure in chronically infarcted rats.
abstract: Evidence is increasing that therapeutic modulation of neurohormonal activation with vasopressin receptor antagonists via V(1A) and V(2) receptors may favourably affect prognosis of heart failure. This study was designed to compare in vivo hemodynamic effects of early treatment (1-21 days after infarction) with a V(1A) (SR-49059 or ((2S)1-[(2R3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide); 0.3 mg/kg/day) and a V(2) (SR-121463B or (1-[4-(N-tert-Butylcarbamoyl)-2-methoxybenzene sulfonyl]-5-ethoxy-3-spiro-[4-(2-morpholinoethyoxy)-cyclo-hexane]indol-2one,furmate; 0.5 mg/kg/day) receptor antagonist in myocardial infarcted rats, chronically instrumented for hemodynamic measurements. Left ventricular dysfunction in conscious myocardial infarcted rats, which was evidenced by a significantly decreased cardiac output (myocardial infarction: 70+/-3 vs. sham: 81 +/- 3 ml/min) and stroke volume (myocardial infarction: 190 +/- 10 vs. sham: 221 +/- 7 microl), was restored by the vasopressin V(1A) (81+/-2 ml and 224 +/- 5 microl, respectively) but not V(2) receptor antagonist. Improved cardiac output with the vasopressin V(1A) receptor antagonist resulted from an increased stroke volume at a reduced myocardial infarction induced tachycardia. In addition to the hemodynamic measurements, left ventricular hypertrophy and capillary density were determined, histologically measured as the cross-sectional area of Gomori-stained myocytes and Lectin-stained capillaries per tissue area, respectively. The observed left ventricular concentric hypertrophy (myocardial infarction: 525 +/- 38 vs. sham: 347 +/- 28 microm(2); P < 0.05) and reduced capillary density (myocardial infarction: 2068 +/- 162 vs. sham: 2800 +/- 250 number/mm(2); P<0.05) in the spared myocardium of myocardial infarcted rats, remained unaffected by the vasopressin V(1A) or V(2) receptor antagonist. Thus, chronic vasopressin V(1A) but not V(2) receptor blockade prevents heart failure in 3-week-old infarcted rats. Moreover, the improved cardiac function could not attributed to changes in left ventricular hypertrophy and/or capillary density.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. vankerckhoven@farma.fgg,eur.nl
authors.forename: Roeland
authors.initials: R
authors.lastname: Van Kerckhoven
authors.forename: Inge
authors.initials: I
authors.lastname: Lankhuizen
authors.forename: Richard
authors.initials: R
authors.lastname: van Veghel
authors.forename: Pramod R
authors.initials: PR
authors.lastname: Saxena
authors.forename: Regien G
authors.initials: RG
authors.lastname: Schoemaker
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D002196:Capillaries / Q000473:pathology; D002302:Cardiac Output / Q000502:physiology; D002496:Central Venous Pressure / Q000502:physiology; D003326:Coronary Circulation / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000503:physiopathology; D007091:Image Processing, Computer-Assisted; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000502:physiology; D020257:Ventricular Remodeling
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists