RESUMO
KCNQ1 forms K+ channels by assembly with regulatory subunit KCNE proteins and plays a key role in the K+ homeostasis in a variety of tissues. In the heart, KCNQ1 is coassembled with KCNE1 to produce a cardiac delayed rectifier K+ current. In the inner ear, the KCNQ1/KCNE1 complex maintains the high concentration of K+ in the endolymph. In the stomach, KCNQ1 is coassembled with KCNE2 to form the K+ exflux channel that is essential for gastric acid secretion. In the colon and small intestine, KCNQ1 is coassembled with KCNE3 to play an important role in transepithelial cAMP-stimulated Cl- secretion. For further understanding of Kcnq1 function in vivo, an animal model has been required. Here we reported the identification of a coisogenic Kcnq1 mutant rat, named deafness Kyoto (dfk), and the characterization of its phenotypes. WTC-dfk rats carried intragenic deletion at the Kcnq1 gene and showed impaired gain of weight, deafness, and imbalance resulting from the marked reduction of endolymph, prolonged QT interval in the electrocardiogram (ECG), and gastric achlorhydria associated with hypertrophic gastric mucosa. Surprisingly, WTC-dfk rats showed hypertension, which suggested that Kcnq1 might be involved in the regulation of blood pressure. These findings suggest that WTC-dfk rats could represent a powerful tool for studying the physiological functions of KCNQ1 and for the establishment of new therapeutic procedures for Kcnq1-related diseases.
Assuntos
Canal de Potássio KCNQ1/genética , Canal de Potássio KCNQ1/fisiologia , Alelos , Animais , Peso Corporal , Surdez/fisiopatologia , Orelha Interna/anormalidades , Eletrocardiografia , Éxons , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Deleção de Genes , Concentração de Íons de Hidrogênio , Hipertensão/metabolismo , Modelos Animais , Modelos Genéticos , Mutação , Fenótipo , Ratos , Ratos EndogâmicosRESUMO
As a part of the ILSI-HESI Alternative to Carcinogenicity Testing (ACT) program, we performed a 26-week carcinogenetic study of nonmutagenic drug, ampicillin (ABPC) in Tg-rasH2 mice. ABPC was given to Tg-rasH2 mice (0, 350, 1000, 3000 mg/kg, p.o.) and Non-Tg mice (0, 3000 mg/kg, p.o.) daily for 26 weeks. As a positive control, a single dose of MNU was administered once to Tg-rasH2 mice (75 mg/kg, i.p.). In this study, Tg-rasH2 mice did not demonstrate any increases in tumor development in response to ABPC. Thus, ABPC had no carcinogenicity in the 26-week carcinogenesis study in Tg-rasH2 mice or in a 2-year carcinogenesis study in B6C3F1 mice.
