title: Carvedilol exacerbate gentamicin-induced kidney mitochondrial alterations in adult rat.
abstract: Gentamicin is an aminoglycoside antibiotic widely used to treat many types of bacterial infections. Although its properties, his clinical use is limited due to the occurrence of nephrotoxicity, which has been related to mitochondrial dysfunction. Carvedilol, an antihypertensive drug with strong antioxidant properties, has been tested in order to prevent gentamicin nephrotoxicity. This study aimed to test this hypothesis using a rat model of gentamicin-induced nephrotoxicity. Animals were treated subcutaneously with DMSO (control) (0.4%/kg/24h bw) for 11days; with carvedilol (2mg/kg/24h bw) for 11days; with gentamicin (60mg/kg/24h bw) for the last 8days and with carvedilol (2mg/kg/24h bw) for 11days and with gentamicin (60mg/kg/24h bw) for the last 8days. Estimations of urine creatinine, urine carboxylic acids, blood urea, serum creatinine and glomerular filtration rate were carried out after the last administered dose of gentamicin. Mitochondria functionality was analyzed by monitoring its bioenergetics function and cardiolipin oxidized products were analyzed by ESI-MS. The kidneys were also examined for morphological changes. Gentamicin caused marked nephrotoxicity and mitochondrial dysfunction as evidenced by several mitochondrial parameters. Carvedilol did not induce significant changes while the co-treatment exacerbated the negative effect of gentamicin although maintaining ATP levels and membrane potential. Kidneys from gentamicin treated rats, with and without carvedilol, showed necrosis of tubular cells in renal cortex. Higher values on relative abundance of cardiolipin oxidation products identified as [M-2H]2-ions, at m/z 771 were observed in the groups treated with gentamicin. The observed effects were associated to a possible interaction of carvedilol with F1F0-ATP synthase that merit further investigation. In conclusion, carvedilol may contribute to the exacerbation of renal dysfunction induced by gentamicin, at least in some physiological and biochemical parameters. From a clinical perspective, and until further conclusions, cautious use of both drugs in combination is advised with particular emphasis in patients presenting mitochondrial disorders.
authors.affiliation: Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Institute for Research and Innovation in Health (i3S), University of Porto (UP), Porto, Portugal. Electronic address: lfelix@utad.pt.
authors.forename: Luís
authors.initials: L
authors.lastname: Félix
authors.affiliation: Chemistry Centre of Vila Real (CQVR), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.
authors.forename: M M
authors.initials: MM
authors.lastname: Oliveira
authors.affiliation: REQUIMTE/Laboratory of Pharmacognosy, Department of Chemistry, Faculty of Pharmacy, University of Porto (UP), Porto, Portugal.
authors.forename: Romeu
authors.initials: R
authors.lastname: Videira
authors.affiliation: Mass Spectrometry Center, Department of Chemistry and QOPNA, University of Aveiro (UA), Aveiro, Portugal; Department of Biology and CESAM, University of Aveiro (UA), Aveiro, Portugal.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Maciel
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho (UM), Braga, Portugal.
authors.forename: Nuno D
authors.initials: ND
authors.lastname: Alves
authors.affiliation: Chemistry Centre of Vila Real (CQVR), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.
authors.forename: Fernando M
authors.initials: FM
authors.lastname: Nunes
authors.affiliation: Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.
authors.forename: Anabela
authors.initials: A
authors.lastname: Alves
authors.affiliation: School of Agrarian and Veterinary Sciences (ECAV), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.
authors.forename: José M
authors.initials: JM
authors.lastname: Almeida
authors.affiliation: Mass Spectrometry Center, Department of Chemistry and QOPNA, University of Aveiro (UA), Aveiro, Portugal.
authors.forename: M Rosário M
authors.initials: MR
authors.lastname: Domingues
authors.affiliation: Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal. Electronic address: fpeixoto@utad.pt.
authors.forename: Francisco P
authors.initials: FP
authors.lastname: Peixoto
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004195:Disease Models, Animal; D005839:Gentamicins / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000900:Anti-Bacterial Agents; D000975:Antioxidants; D002227:Carbazoles; D005839:Gentamicins; D011412:Propanolamines; D000077261:Carvedilol
keywords: Carboxylic acid; Cardiolipin; Carvedilol; Gentamicin; Mitochondria; Nephrotoxicity