title: Effects of SR 49059, a non-peptide antagonist of vasopressin V1a receptors, on vasopressin-induced coronary vasoconstriction in conscious rabbits.
abstract: The effect of SR 49059, a new potent non-peptide vasopressin (AVP) V1a receptor antagonist, was investigated on AVP-induced electrocardiogram modifications. A high intravenous dose of AVP (0.5 IU or 1.23 micrograms/animal) produced an important transient t-wave elevation (from 4.7 +/- 0.2 to 8.9 +/- 0.7 mm) and heart rate decrease (from 199 +/- 5 to 99 +/- 6 bpm) in conscious rabbits. The t-wave increase was a significant index of coronary vasoconstriction-induced cardiac ischemia. SR 49059 had potent protective effects in this model both by intravenous (0.125 to 0.5 mg/kg) and oral (2.5 to 10 mg/kg) routes. After a 30-min pre-treatment, SR 49059 showed dose-dependent protection on t-wave elevation and heart rate decrease with ED50's of 95 (95% CL:168-22) and 30 (95% CL:54-6) micrograms/kg i.v., respectively. Complete blockade occurred with doses of 2 mg/kg i.v. and upwards. By the oral route, SR 49059 was rapidly absorbed and a dose of 10 mg/kg displayed a protective effect lasting more than 6 hours on both electrocardiogram parameters. Moreover, SR 49059 exerted a high stereospecific inhibitory effect since its enantiomer was totally inactive at 0.5 mg/kg i.v., suggesting that protection occurred by interaction with vascular AVP V1a receptors. Thus, SR 49059 is the first specific non-peptide V1a antagonist with long-lasting oral activity on AVP-induced coronary vasoconstriction and bradycardia. With this original profile, SR 49059 could be a promising therapeutical antivasospastic agent for preventing AVP-induced cardiac damage.
authors.affiliation: Sanofi Recherche, Exploratory Research Department, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Serradeil-Le Gal
authors.forename: G
authors.initials: G
authors.lastname: Villanova
authors.forename: M
authors.initials: M
authors.lastname: Boutin
authors.forename: J P
authors.initials: JP
authors.lastname: Maffrand
authors.forename: G
authors.initials: G
authors.lastname: Le Fur
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004562:Electrocardiography; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D011817:Rabbits; D013237:Stereoisomerism; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D011759:Pyrrolidines; D001127:Arginine Vasopressin; C082134:relcovaptan