Role of chloride in the variable response of the kidney to cyclooxygenase inhibition

The role of prostanoids in renal function remains unclear, as inhibitors of cyclooxygenase (COX) have contrasting effects. We postulated that these inconsistencies were related to differential effects of the prevailing chloride concentration on COX-dependent mechanisms. In oncotically perfused rat kidneys, in the presence of either high (117 mM) or low (87 mM) chloride with sodium held constant, low chloride resulted in a higher glomerular filtration rate (GFR) than with high chloride, i.e., 1.2 +/- 0.2 and 0.5 +/- 0.1 ml/min, respectively, for the last clearance period. Water and electrolyte excretion and levels of immunoassayable prostaglandins were higher with low chloride. Indomethacin (10 microM) had opposite effects on renal function depending on the chloride levels, although prostaglandin release was inhibited similarly. For example, indomethacin substantially reduced the elevated urine flow and sodium excretion in the low-chloride group, which, by the last period, were reduced from 111 +/- 32 to 37 +/- 3 microliters/min and 8.3 +/- 2.9 to 3.1 +/- 0.6 mu eq/min, respectively, whereas the lower urine flow and sodium excretion in the high-chloride group increased from 32 +/- 8 to 109 +/- 15 microliters/min and 2.5 +/- 0.8 to 7.1 +/- 1.6 mu eq/min, respectively. In summary, inhibition of COX has differential effects depending on the prevailing chloride concentration, or conversely, high and low chloride have contrasting effects on renal function, which are reversed by COX inhibition. We suggest that prohypertensive and antihypertensive COX-dependent mechanisms are linked to chloride; the latter is an integral component in the development of salt-sensitive hypertension.