Summary—The effect of SR 49059, a new potent non‐peptide vasopressin (AVP) V1areceptor antagonist, was investigated on AVP‐induced electrocardiogram modifications. A high intravenous dose of AVP (0.5 IU or 1.23 μg/animal) produced an important transientt‐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. Thet‐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 ont‐wave elevation and heart rate decrease with ED50's of 95 (95% CL: 168‐22) and 30 (95% CL:54‐6) μg/kg iv, respectively. Complete blockade occurred with doses of 2 mg/kg iv 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 iv, suggesting that protection occurred by interaction with vascular AVP V1areceptors. Thus, SR 49059 is the first specific non‐peptide V1aantagonist 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 pre