Neurotensin induces the release of prostacyclin from human umbilical vein endothelial cells in vitro and increases plasma prostacyclin levels in the rat.
Human umbilical vein endothelial cells express high affinity neurotensin receptors which are coupled to phosphoinositide turnover and 45Ca2+ efflux (Schaeffer et al., 1995. J. Biol. Chem. 270, 3409-3413). In order to assess the physiological significance of neurotensin receptor activation in endothelial cells, we have compared the in vitro effect of neurotensin on prostacyclin release and cytosolic free calcium increase ([Ca2+]i) as determined by fura-2 fluorescence experiments to the in vivo effect of neurotensin on blood pressure and haematocrit. Neurotensin increased [Ca2+]i levels at low concentrations (EC50 = 4.2 +/- 0.2 nM, n = 3). At similar concentrations, neurotensin was also able to induce prostacyclin release from human umbilical vein endothelial cells (EC50 = 14 +/- 1 nM, n = 3) as determined by a 6-keto-prostaglandin F1 alpha enzyme immunoassay. The neurotensin (100 nM)-induced [Ca2+]i increase and prostacyclin release were inhibited by the specific non-peptide neurotensin receptor antagonist SR 48692 at similar concentrations (IC50 = 41 +/- 16 nM and 86 +/- 17 nM, respectively, n = 3), confirming that these responses were mediated by high affinity neurotensin receptors. Intravenous injection of neurotensin (1-4 nmol/kg i.v.) in the rat resulted in a drop of blood pressure and increased haematocrit, and nearly doubled the plasma levels of 6-keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin. Whereas indomethacin (10 mg/kg i.v.) pretreatment significantly reduced the effect of neurotensin on blood pressure, it did not alter its effect on haematocrit. These results suggest that prostacyclin release plays a role in the hypotensive effects of neurotensin, but is not involved in its effects on haematocrit.
Schaeffer
P
P
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Laplace
M C
MC
Prabonnaud
V
V
Bernat
A
A
Gully
D
D
Lespy
L
L
Herbert
J M
JM
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D011464:Epoprostenol / Q000097:blood / Q000378:metabolism*; D006400:Hematocrit; D006801:Humans; D008297:Male; D009496:Neurotensin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014471:Umbilical Veins / Q000378:metabolism*
D009496:Neurotensin; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D002118:Calcium