SR142948A IS A POTENT ANTAGONIST OF THE CARDIOVASCULAR EFFECTS OF NEUROTENSIN

The novel compound SR142948A was compared with SR48692 as an antagonis t of neurotensin-induced cardiovascular effects both in vitro and in v ivo. SR142948A inhibited [I-125]-neurotensin binding [median inhibitor y concentration (IC50) = 0.24 +/- 0.01 nM], neurotensin-induced cytoso lic free Ca2+ increase (IC50 = 19 +/- 6 nM), and prostacyclin producti on in human umbilical vein endothelial cells (IC50 = 17 +/- 3 nM) at m uch lower concentrations than did SR48692 (respective IC50 values, 14 +/- 5, 41 +/- 16, and 86 +/- 16 nM). Oral administration of SR142948A (10 mu g/kg) resulted in significant inhibition of neurotensin-induced blood pressure changes, whereas SR48692 was active only at 10-fold hi gher doses. Furthermore, SR142948A administered i.v. in mu g/kg quanti ties in the rat was as active as mg/kg doses of SR48692 on neurotensin -induced increase in hematocrit. SR142948A injected intradermally also significantly inhibited neurotensin-induced plasma extravasation at c oncentrations as low as 10 pmol/site, whereas 1,000 pmol/site of SR486 92 were necessary to reach a significant inhibition. These data show t hat SR142948A is a novel, extremely potent antagonist of neurotensin-i nduced cardiovascular responses both in vitro and in vivo. SR142948A a nd SR48692 constitute a pair of nonpeptide neurotensin antagonists of different potency, which may be used to probe for the implication of n eurotensin receptors in physiologic or pathologic phenomena.