Preservation of the glomerular capillary ultrafiltration coefficient during rat nephrotoxic serum nephritis by a specific leukotriene D4 receptor antagonist

Leukotriene D₄, a potent biologically active lipoxygenase derivative of arachidonic acid in activated leukocytes, depresses the glomerular capillary ultrafiltration coefficient (K(f)) and contracts mesangial cells in culture. We therefore investigated its potential role in mediating the reduction in nephron filtration rate seen after induction of experimental nephrotoxic serum (NTS)-induced glomerulonephritis in the rat. Micropuncture measurements were performed in euvolemic Munich-Wistar rats 2 h after i.v. administration of 0.8 ml of rabbit serum (group 1, n = 6), 0.8 ml of rabbit anti-rat glomerular basement membrane antibody in the absence (group 2, n = 8), or presence (group 3, n =7) of the new highly specific LTD₄ receptor antagonist SK&F 104353. Quantitation of antibody binding and neutrophil infiltration revealed no differences between groups 2 and 3. Antagonism of endogenous LTD₄ actions, however, was associated with prevention of the NTS-induced fall in SNGFR because of the abrogation of the fall in K(f) which characterizes this form of experimental glomerulonephritis. Antagonism of endogenous LTD₄ had no effect on the NTS-induced increases in pre- and postglomerular arteriolar resistances, and did not affect nephron plasma flow rate or net transcapillary hydraulic pressure difference. The observed highly localized protective action of the LTD₄ antagonist on the glomerular capillary points to a possibly major functional role for intraglomerularly released LTD₄, likely originating from infiltrating leukocytes, in the pathophysiology of this form of glomerulonephritis.