The novel compound SR142948A was compared with SR48692 as an antagonist of neurotensin-induced cardiovascular effects both in vitro and in vivo. SR142948A inhibited [125I]-neurotensin binding [median inhibitory concentration (IC50) = 0.24 ± 0.01 nM], neurotensin-induced cytosolic free Ca2+ increase (IC50 = 19 ± 6 nM), and prostacyclin production in human umbilical vein endothelial cells (IC50 = 17 ± 3 nM) at much lower concentrations than did SR48692 (respective IC50 values, 14 ± 5, 41 ± 16, and 86 ± 16 nM). Oral administration of SR142948A (10 μg/kg) resulted in significant inhibition of neurotensin-induced blood pressure changes, whereas SR48692 was active only at 10-fold higher doses. Furthermore, SR142948A administered i.v. in μg/kg quantities 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 concentrations as low as 10 pmol/site, whereas 1,000 pmol/site of SR48692 were necessary to reach a significant inhibition. These data show that SR142948A is a novel, extremely potent antagonist of neurotensin-induced cardiovascular responses both in vitro and in vivo. SR142948A and SR48692 constitute a pair of nonpeptide neurotensin antagonists of different potency, which may be used to probe for the implication of neurotensin receptors in physiologic or pathologic phenomena.