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

Abstract

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.

Chloride-Dominant Salt Sensitivity in the Stroke-Prone Spontaneously Hypertensive Rat

“…33,34 In the SHR, pharmacological inhibition of the angiotensin converting enzyme dose-dependently attenuates hypertension and the narrowing of the renal afferent arteriole, 33,34 the extent of narrowing varying directly with the severity of pharmacologically attenuated hypertension. 33 Even in the normal rat, Cl Ϫ selectively loaded either in the diet 13,14 or in the isolated perfused kidney 35 induces renal vasoconstriction and amplifies that induced by angiotensin II, 14,36 likely by constricting the renal afferent arteriole 37 such that glomerular filtration rate is reduced. 35 An increased delivery of Cl Ϫ to the macula densa of the thick ascending limb of the renal tubule, as presumably occurred with the chlorureses currently induced in the SHRSP, elicits dose-dependent constriction of the renal afferent arteriole as part of the normal tubuloglomerular feedback (TGF) response.…”

“…33 Even in the normal rat, Cl Ϫ selectively loaded either in the diet 13,14 or in the isolated perfused kidney 35 induces renal vasoconstriction and amplifies that induced by angiotensin II, 14,36 likely by constricting the renal afferent arteriole 37 such that glomerular filtration rate is reduced. 35 An increased delivery of Cl Ϫ to the macula densa of the thick ascending limb of the renal tubule, as presumably occurred with the chlorureses currently induced in the SHRSP, elicits dose-dependent constriction of the renal afferent arteriole as part of the normal tubuloglomerular feedback (TGF) response. 38 In the SHR, an angiotensin II-dependent exaggeration of TGF is a likely major determinant of the severity of hypertension.…”

Genetically determined chloride-sensitive hypertension and stroke

“…Renal retention of Na ϩ and water that expands plasma volume is widely believed to initiate the pathogenesis of human ''essential hypertension'' (43,44), and the genetically determined hypertension of the Dahl ''salt-sensitive'' rat (20,45). However, the fact of selective Cl Ϫ sensitivity in the salt-sensitive SHRSP suggests the possibility that a genetically determined mechanism of saltsensitive hypertension might primarily affect the renal tubular transport of Cl Ϫ , or the capacity of Cl Ϫ to stimulate renal vasoconstriction (16,17), which might take the form of an exaggerated tubuloglomerular feedback response (35,38) that reduces medullary blood flow and the capacity of the kidney to excrete salt (46). Whatever the precise mechanism of selective Cl Ϫ sensitivity in the SHRSP, the phenomenon and its demonstration with KCl, a salt well known to have natriuretic and diuretic effects, raise the possibility that an increased renal retention of Na ϩ and water need not be the initial physiological consequence of all genetically determined mechanisms of salt-sensitive hypertension either in rats or humans.…”

Cyclooxygenase-2 Is Required for Tumor Necrosis Factor-α– and Angiotensin II–Mediated Proliferation of Vascular Smooth Muscle Cells

“…Analysis of TXB 2 was performed as previously described. 11 Cellular DNA Content DNA content was assessed using the CyQUANT assay kit (Molecular Probes). Briefly, cells were challenged and then lysed with CyQUANT lysis solution.…”