EFFECTS OF SR-49059, A NONPEPTIDE ANTAGONIST OF VASOPRESSIN V-1A RECEPTORS, ON VASOPRESSIN-INDUCED CORONARY VASOCONSTRICTION IN CONSCIOUS RABBITS

The effect of SR 49059, a new potent non-peptide vasopressin (AVP) V-1 a receptor antagonist, was investigated on AVP-induced electrocardiogr am modifications. A high intravenous dose of AVP (0.5 IU or 1.23 mu g/ 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 (0.12 5 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 elevati on and heart rate decrease with ED(50)'s of 95 (95% CL:168-22) and 30 (95% CL:54-6) mu g/kg iv, respectively. Complete blockade occurred wit h doses of 2 mg/kg iv and upwards. By the oral route, SR 49059 was rap idly absorbed and a dose of 10 mg/kg displayed a protective effect las ting more than 6 hours on both electrocardiogram parameters. Moreover, SR 49059 exerted a high stereospecific inhibitory effect since its en antiomer was totally inactive at 0.5 mg/kg iv, suggesting that protect ion occurred by interaction with vascular AVP V-1a receptors. Thus, SR 49059 is the first specific non-peptide V-1a antagonist with long-las ting oral activity on AVP-induced coronary vasoconstriction and bradyc ardia. With this original profile, SR 49059 could be a promising thera peutical antivasospastic agent for preventing AVP-induced cardiac dama ge.