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 neurotens in receptors which are coupled to phosphoinositide turnover and Ca-45( 2+) efflux (Schaeffer et al., 1995. J. Biol. Chem. 270, 3409-3413). In order to assess the physiological significance of neurotensin recepto r activation in endothelial cells, we have compared the in vitro effec t of neurotensin on prostacyclin release and cytosolic free calcium in crease ([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 (EC(50) = 4.2 +/- 0.2 nM, n = 3). At similar concentrations, neurotensin was al so able to induce prostacyclin release from human umbilical vein endot helial cells (EC(50) = 14 +/- 1 nM, n = 3) as determined by a 6-keto-p rostaglandin F-1 alpha enzyme immunoassay. The neurotensin (100 nM)-in duced [Ca2+](i) increase and prostacyclin release were inhibited by th e specific non-peptide neurotensin receptor antagonist SR 48692 at sim ilar concentrations (IC50 = 41 +/- 16 nM and 86 +/- 17 nM, respectivel y, n = 3), confirming that these responses were mediated by high affin ity neurotensin receptors. Intravenous injection of neurotensin (1-4 n mol/kg i.v.) in the rat resulted in a drop of blood pressure and incre ased haematocrit, and nearly doubled the plasma levels of 6-keto-prost aglandin F-1 alpha, the stable metabolite of prostacyclin. Whereas ind omethacin (10 mg/kg i.v.) pretreatment significantly reduced the effec t of neurotensin on blood pressure, it did not alter its effect on hae matocrit. These results suggest that prostacyclin release plays a role in the hypotensive effects of neurotensin, but is not involved in its effects on haematocrit. (C) Elsevier Science B.V.