ABSTRACT
Imatinib and bosutinib were administered to rats for up to 6 months at clinically relevant exposures to investigate the effects on the cardiovascular system. Imatinib treatment resulted in increased volume, wall thickness and mass suggesting a hypertrophic heart in male and female rats at one and fivefold clinical exposures, respectively. Bosutinib treatment resulted in milder cardiac hypertrophy in female rats only at fivefold clinical exposures. Analysis of excised hearts and cultured myocytes demonstrated increased expression of hypertrophic genes with imatinib or analogs, but not bosutinib or c-Abl RNAi treatment. The current dataset suggests that cardiovascular liability of imatinib and bosutinib are differentiated preclinically and c-Abl independent.
Subject(s)
Aniline Compounds/adverse effects , Benzamides/adverse effects , Cardiovascular System/drug effects , Nitriles/adverse effects , Piperazines/adverse effects , Pyrimidines/adverse effects , Quinolines/adverse effects , Aniline Compounds/administration & dosage , Aniline Compounds/pharmacokinetics , Animals , Benzamides/administration & dosage , Benzamides/pharmacokinetics , Cardiomyopathy, Hypertrophic/chemically induced , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/pathology , Cardiovascular System/pathology , Echocardiography , Female , Gene Expression , Gene Knockdown Techniques , Heart/drug effects , Heart/physiopathology , Imatinib Mesylate , Male , Myocardium/metabolism , Myocardium/pathology , Nitriles/administration & dosage , Nitriles/pharmacokinetics , Organ Size , Piperazines/administration & dosage , Piperazines/pharmacokinetics , Proto-Oncogene Proteins c-abl/genetics , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Quinolines/administration & dosage , Quinolines/pharmacokinetics , Rats , Sex FactorsABSTRACT
Peroxisome-proliferator-activated receptor (PPAR-gamma) agonists improve insulin sensitivity, but are associated with edema. Increased distal tubule sodium and water reabsorption through the epithelial sodium channel (ENaC) and aquaporin-2 (AQP-2) have been suggested to play mechanistic roles. To determine the molecular regulation of these proteins, we treated male, Sprague-Dawley rats daily by gavage with either vehicle, rosiglitazone (RGZ, 50mg/kg bw), or PD168 (a test compound causing marked edema, 10mg/kg bw), for 1, 3, or 5 days (n=6/treatment/time). On day 1, urine sodium excretion was significantly reduced by RGZ with a strong trend for PD168 (p-values 0.047 and 0.053, respectively) indicating early sodium retention. Blood pressure was lowered by RGZ- or PD168 treatment by 12h. Immunoblotting of whole kidney homogenates (WKHs) and a membrane-enriched fraction (MF) revealed increased band densities for AQP-2 in WKH (29 kDa and glycosylated bands) by both drugs at 1 day. However, at 5 days, the 29-kDa band was significantly decreased ( approximately 30% of vehicle). alpha-ENaC was increased by RGZ at 3 days; however both agents decreased alpha-ENaC by 5 days. In contrast, beta- and gamma-ENaC (85 kDa) were unchanged or decreased at all times by both agents. However, the 70-kDa band of gamma-ENaC (active band) in MF was increased in density (120-600%) by both agents on days 3-5. Overall, both agents resulted in early alterations in banding patterns for AQP-2 and ENaC subunits, many of which are described as activating changes. However, later reduction in AQP-2 and alpha-ENaC may represent an attempt to re-establish sodium and water balance.
