Effects of SR 49059, a non‐peptide antagonist of vasopressin V_1a 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.

Antiatherogenic and Anti-Ischemic Properties of Traditional Chinese Medicine Xinkeshu via Endothelial Protecting Function

“…At the end of the 12-week experimental period, according to the method of Serradeil-Le Gal et al [22], experimental of coronary vasospastic myocardial ischemia was induced by VP. The standard limb lead II of the ECG was recorded continuously before and 25 min after the administration of VP (2.0 IU/kg, iv. )…”

Complementary Role of Oxytocin and Vasopressin in Cardiovascular Regulation

“…Stimulation of V1aR also plays an essential role in the vasoconstriction of systemic, coronary, and renal vessels [ 237 , 238 , 239 , 240 ]. However, stimulation of V1aR also causes vasodilation of the pulmonary arteries [ 241 ].…”