TUMOR-NECROSIS-FACTOR-ALPHA ANGIOTENSIN INTERACTIONS AND REGULATION OF BLOOD-PRESSURE

Objectives To compare the levels of tumor necrosis factor-alpha (TNF) produced by medullary thick ascending limb tubules (MTAL) obtained fro m normotensive and angiotensin II (Ang II)-dependent hypertensive rats and determine whether TNF participates in a mechanism that opposes el evation of blood pressure by Ang II. Design We have previously demonst rated that in-vitro administration of Ang II increases production of T NF and prostaglandin E-2 (PGE(2)) by the MTAL. We hypothesize that pro duction of TNF and PGE(2) by the MTAL is elevated in in-vivo models of Ang II-dependent hypertension and acts to modulate the pressor effect s of Ang II. Thus, inhibition of TNF should disclose whether this cyto kine acts to modulate Ang II-induced hypertension. Methods MTAL tubule s obtained from normotensive and Ang II-dependent hypertensive rats we re isolated by enzymatic digestion and sieving. Tubules were cultured in the absence of exogenous Ang II. TNF and PGE(2) levels were measure d by enzyme-linked immunosorbent assay. Anti-TNF antiserum was adminis tered intravenously to normotensive and Ang II-dependent hypertensive rats and their mean arterial pressures were measured. Results Producti on of TNF and PGE(2) was significantly greater in MTAL tubules isolate d from Ang II hypertensive rats than it was in those from normotensive controls. Administration of anti-TNF antiserum exacerbated the Ang II -mediated increase in mean arterial pressure. Conclusions The higher l evels of production of TNF and PGE(2) by MTAL tubules isolated from An g II hypertensive rats compared with those of normotensive controls ar e consistent with results of in-vitro experiments showing that adminis tration of Ang II increases production of TNF and PGE(2) by the MTAL. TNF and PGE(2) participate in a counter-regulatory mechanism that oppo ses the pressor actions of Ang II.