SR142948A is a potent antagonist of the cardiovascular effects of neurotensin.
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 microg/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 microg/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.
Schaeffer
P
P
Department of Haemobiology Research, Sanofi Recherche, Toulouse, France.
Laplace
M C
MC
Bernat
A
A
Prabonnaud
V
V
Gully
D
D
Lespy
L
L
Herbert
J M
JM
D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D011464:Epoprostenol / Q000378:metabolism; D006400:Hematocrit; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007271:Injections, Intradermal; D007457:Iodine Radioisotopes; D008297:Male; D009496:Neurotensin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors*; D014471:Umbilical Veins / Q000187:drug effects* / Q000378:metabolism
D007093:Imidazoles; D007457:Iodine Radioisotopes; D011720:Pyrazoles; D011804:Quinolines; D018028:Receptors, Neurotensin; C104418:SR 142948A; C079087:SR 48692; D009496:Neurotensin; D011464:Epoprostenol; D000218:Adamantane; D002118:Calcium