Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia.
Hydrochlorothiazide (HCTZ) is used to manage hypertension and heart failure; however, its side effects include mild hypokalemia, metabolic abnormalities, and volume depletion, which might have deleterious effects on renal and endothelial function. We studied whether HCTZ cause renal injury and/or altered vasoreactivity and if these changes are hypokalemia-dependent. Rats were given a normal diet or a diet moderately low in potassium K+ with or without HCTZ. Animals fed either a low K+ diet alone or HCTZ developed mild hypokalemia. There was no significant difference in systolic blood pressure in the different treatment groups. All three groups with hypokalemia had mild proteinuria; low K(+)-HCTZ rats had reduced creatinine clearance. HCTZ-treated rats displayed hypomagnesemia, hypertriglyceridemia, hyperglycemia, insulin resistance, and hyperaldosteronism. No renal injury was observed in the groups without HCTZ; however, increased kidney weight, glomerular ischemia, medullary injury, and cortical oxidative stress were seen with HCTZ treatment. Endothelium-dependent vasorelaxation was reduced in all hypokalemic groups and correlated with reduced serum K+, serum, and urine nitric oxide. Our results show that HCTZ is associated with greater renal injury for the same degree of hypokalemia as the low K+ diet, suggesting that factors such as chronic ischemia and hyperaldosteronism due to volume depletion may be responsible agents. We also found impaired endothelium-dependent vasorelaxation was linked to mild hypokalemia.
Reungjui
S
S
Division of Nephrology, Hypertension and Transplantation, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA. sirirt_a@kku.ac.th
Hu
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Mu
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Roncal
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Croker
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Patel
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Nakagawa
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Srinivas
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Byer
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Simoni
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Wesson
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Sitprija
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Johnson
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D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D004232:Diuretics / Q000633:toxicity*; D006852:Hydrochlorothiazide / Q000633:toxicity*; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007008:Hypokalemia / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008274:Magnesium / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009929:Organ Size; D018384:Oxidative Stress / Q000187:drug effects; D017419:Potassium, Dietary / Q000097:blood / Q000494:pharmacology; D011507:Proteinuria / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D014556:Urine; D014664:Vasodilation / Q000187:drug effects
D004232:Diuretics; D007328:Insulin; D017419:Potassium, Dietary; D006852:Hydrochlorothiazide; D009569:Nitric Oxide; D000450:Aldosterone; D012964:Sodium; D008274:Magnesium