Effects of SR 49059, a non-peptide antagonist of vasopressin V1a receptors, on vasopressin-induced coronary vasoconstriction in conscious rabbits.

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.