EFFECTS OF RC5A ON THE CIRCULATION OF NORMAL AND SPLIT HYDRONEPHROTICRAT KIDNEYS

Systemic release of complement-derived anaphylatoxin C5a is suggested to be involved in the pathogenesis of renal failure during endotoxic o r severe traumatic shock. In the present study we analyzed renal hemod ynamic effects of recombinant human complement 5a (rC5a) and examined whether these effects are mediated by the secondary release of other i nflammatory mediators. Intravenous infusion of rC5a (0.5 mug/min) in t hiobarbital-anesthetized rats decreased renal blood flow (RBF) by 20 a nd 34% after 20 and 60 min, respectively. Glomerular filtration rate ( GFR) was reduced by 45%, whereas filtration fraction and blood pressur e were not significantly changed by rC5a. Hematocrit (Hct) increased b y 11%, whereas white blood cell count decreased by 40%. Renal rC5a eff ects were completely inhibited by the competitive leukotriene D4/E4 an tagonist ICI-198615, whereas the competitive thromboxane A2 (TxA2) ant agonist daltroban only partly reversed rC5a effects on RBF and GFR. Th e competitive platelet-activating factor (PAF) antagonist L-695989 did not influence renal or systemic rC5a effects. These results point to an rC5a-mediated synthesis and release of cysteinyl leukotrienes and T xA2, whereas PAF does not seem to be released after intravenous rC5a i n rats. To determine the cellular source of cysteinyl-leukotriene synt hesis, rats were depleted of polymorphonuclear cells (PMN) by intraper itoneal injection of anti-rat PMN antibodies, which abrogated renal an d systemic hemodynamic rC5a effects, suggesting that PMN participate i n the synthesis and release of cysteinyl leukotrienes. The exact local ization of renovascular rC5a effects was performed on the model of the split hydronephrotic rat kidney. Intravenous infusion of rC5a (0.5 mu g/min) induced a constriction of arcuate (-18%) and interlobular (-12% ) arteries as well as proximal efferent arterioles (-14%); glomerular blood flow decreased by 34%. Our results in normal and hydronephrotic kidneys demonstrate a predominant preglomerular and, to a lesser exten t, postglomerular constriction after intravenous infusion of rC5a medi ated by cysteinyl leukotrienes and TxA2, which are synthesized and rel eased by PMN.