ANALYSIS OF EICOSANOID MEDIATION OF THE RENAL FUNCTIONAL-EFFECTS OF HYPERCHLOREMIA

Depression of GFR and antinatriuresis in response to high chloride has been linked to a cyclooxygenase (COX)-dependent mechanism involving t hromboxane A(2) (TxA(2)) and prostaglandin endoperoxide (PGH(2)), beca use inhibition of COX prevented the fall in GFR and antinatriuresis pr oduced by hyperchloremia. However, hyperchloremia did not increase, bu t unexpectedly decreased, renal prostaglandin and TxA(2) efflux (Yin e t al., 1995). To resolve questions regarding the role of eicosanoids i n mediating the renal functional effects of high chloride (117 mM), by stimulating either TxA(2) synthesis or TxA(2)/PGH(2) receptors, we co mpared the ability of indomethacin to block high-chloride effects in t he rat isolated kidney with that of BMS 180291 and SQ 29548, antagonis ts of the TxA(2)/PGH(2) receptor. These antagonists differ in terms of their selectivity and their capacity to inhibit isoforms of the TxA(2 )/PGH(2) receptor. Indomethacin and SQ 29548 had identical actions, pr eventing the decrease of GFR and antinatriuresis evoked by hyperchlore mia, e.g., sodium excretion rate in the SQ 29548 and indomethacin grou ps increased to 7.2 +/- 1.3 and 7.1 +/- 1.2 mu Eq/min, respectively, c ompared with 2.6 +/- 0.7 mu Eq/min in the control group. In contrast, neither EMS 180291 nor the TxA(2) synthase inhibitors, OKY 046 and CGS 13080, modified the negative effects of high chloride on GFR or sodiu m excretion. These results argue against either TxA(2) or PGH(2) actin g as mediator of the effects of high chloride on renal function and su ggest a product of COX activity such as a 20-HETE analog of prostaglan din endoperoxide. Evidence to support this proposal was obtained: 1) H yperchloremia increased 20-HETE release from the rat kidney by 2-fold when compared with low-chloride conditions of renal perfusion. 2) The renal vasoconstrictor action of 20-HETE was shown to be dependent on C OX activity and to be antagonized by blockade of the TxA(2)/PGH(2) rec eptor.