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(Hypertension. 1997;30:22-28.)
© 1997 American Heart Association, Inc.

Articles

Endogenous Endothelin Modulates Blood Pressure, Plasma Volume, and Albumin Escape After Systemic Nitric Oxide Blockade

János G. Filep

From the Research Center, Maisonneuve-Rosemont Hospital, Department of Medicine, University of Montréal (Québec, Canada).

Correspondence to János G. Filep, MD, Research Center, Maisonneuve-Rosemont Hospital, Department of Medicine, University of Montréal, 5415 Boulevard de l'Assomption, Montréal, Québec, Canada H1T 2M4.

Abstract To assess whether acute nitric oxide (NO) blockade could unmask the vascular actions of endogenous endothelin, we tested the effects of the endothelin type A/type B (ET_A/ET_B) receptor antagonist bosentan and the selective ET_A antagonist FR 139317 on blood pressure, plasma volume, and albumin escape after inhibition of NO synthesis with N^G-nitro-L-arginine methyl ester (L-NAME). Conscious, chronically catheterized rats received L-NAME in the absence and presence of 17.4 µmol/kg (10 mg/kg) bosentan or 3.8 µmol/kg (2.5 mg/kg IV, 10 minutes before L-NAME) FR 139317. Red blood cell volume and plasma volume were determined with chromium-51–tagged erythrocytes and iodine-125–labeled albumin, respectively. L-NAME (0.46 to 7.42 µmol/kg [0.125 to 2 mg/kg]) induced a dose-dependent increase in blood pressure, which was attenuated by 60% and 48% with bosentan and FR 139317, respectively (P<.01). L-NAME (7.42 µmol/kg) also increased hematocrit. This effect was associated with an increase in total-body albumin escape, which is reflected by a 14% reduction in plasma volume. Red blood cell volume remained unchanged. L-NAME promoted albumin escape primarily in the lung, heart, liver, kidney, and gastrointestinal tract. Both bosentan and FR 139317 markedly reduced these effects of L-NAME. Furthermore, L-NAME increased plasma levels of immunoreactive endothelin-1 from 8.6±0.4 (n=10) to 14.7±1.4 pg/mL (n=9, P<.01). These results demonstrate that the pressor response, losses in plasma volume, and increase in albumin escape observed after inhibition of NO synthesis are in part the consequence of unmasking the actions of endogenous endothelin, which are mediated predominantly via ET_A receptors. These findings suggest a role for endogenous endothelin in the regulation of vascular functions in conditions when NO formation by endothelial cells is impaired.

Key Words: endothelin • receptors, endothelin • nitric oxide • blood pressure • plasma volume

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