EFFECTS OF SYSTEMIC COMPLEMENT ACTIVATION ON RENAL CIRCULATION OF RATS

In a variety of immunopathological diseases activation of the compleme nt cascade occurs either systemically or localized in the kidney. To e lucidate the functional impact of complement activation upon the renal microcirculation, we administered cobra venom factor of Naja naja kao uzhia (CVF) i.v. into thiobarbital anaesthetized female rats. CVF is a potent activator of the alternative pathway of complement by forming the C3-convertase CVF, Bb which cannot be downregulated by the natural inhibitor factors H and I and thereby leads to generation of the anap hylatoxins C3a and C5a and formation of the membrane attack complex (M AC). We utilized creatinine clearance and flowmeter measurements in th e normal kidney and intravital microscopy of the split hydronephrotic rat kidney model to observe the microvascular changes. Bolus injection of CVF (100 U kg(-1)) resulted in an immediate reduction of RBF (-68% after 10 min), which remained decreased during the entire experiment (90 min). Systemic blood pressure was significantly reduced only in th e early period (-23% of control: 126 mmHg after 10 min). After an init ial anuric phase of 30 min duration, the glomerular filtration rate wa s significantly diminished by 47%. White cell count was decreased by a bout 50% after the experiments. Application of the competitive thrombo xane At-antagonist, BM 13505, reversed all renal and systemic CVF-effe cts. Continuous infusion of the competitive leukotriene D-4-antagonist , ICI 198615, attenuated the late renal CVF-effects (i.e. 30 min after injection of CVF). Depletion of polymorphonuclear cells (PMN) attenua ted the CVF-effects similar to BM 13505. Intravenous administration of CVF in the hydronephrotic kidney model resulted in a massive constric tion of the interlobar and arcuate artery, with a fail in glomerular b lood flow comparable to the reduction of RBF in the normal kidney. Dia meters of the afferent arterioles-most sensitive to many vasoconstrict ing agents-were not significantly altered. Our results suggest that in jection of CVF and the liberation of high amounts of the anaphylatoxin s, C3a and C5a, induces the release of TXA(2), which contributes to th e early renal effects and the formation of cysteinyl-leukotrienes whic h play an important role in the late phase of systemic complement acti vation. Utilizing the split hydronephrotic kidney model we demonstrate d the predominant action of complement activation on the large preglom erular vessels for the first time. PMN are seemingly involved in the l iberation of secondary mediators which appear to reduce renal blood fl ow and glomerular filtration.