title: Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia.
abstract: 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.
authors.affiliation: Division of Nephrology, Hypertension and Transplantation, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA. sirirt_a@kku.ac.th
authors.forename: S
authors.initials: S
authors.lastname: Reungjui
authors.forename: H
authors.initials: H
authors.lastname: Hu
authors.forename: W
authors.initials: W
authors.lastname: Mu
authors.forename: C A
authors.initials: CA
authors.lastname: Roncal
authors.forename: B P
authors.initials: BP
authors.lastname: Croker
authors.forename: J M
authors.initials: JM
authors.lastname: Patel
authors.forename: T
authors.initials: T
authors.lastname: Nakagawa
authors.forename: T
authors.initials: T
authors.lastname: Srinivas
authors.forename: K
authors.initials: K
authors.lastname: Byer
authors.forename: J
authors.initials: J
authors.lastname: Simoni
authors.forename: D
authors.initials: D
authors.lastname: Wesson
authors.forename: V
authors.initials: V
authors.lastname: Sitprija
authors.forename: R J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: 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
chemical_list: D004232:Diuretics; D007328:Insulin; D017419:Potassium, Dietary; D006852:Hydrochlorothiazide; D009569:Nitric Oxide; D000450:Aldosterone; D012964:Sodium; D008274:Magnesium