RESUMO

ABSTRACT: The P-glycoprotein (P-gp) is a transmembrane protein encoded by the MDR1 gene that functions as a biological barrier by extruding toxins and xenobiotics out of cells. The MDR1 gene can carry a mutation called nt230(del4), which is a deletion of four base pairs resulting in the formation of a non-functional protein that may predispose to severe toxicosis, as observed in dogs with sensitivity to ivermectin. Several breeds have been described as carriers of the mutation, including German Shepherds (GS). However, the presence of the mutant allele in this breed has not been described in Brazil. This study aimed to determine the genotypic and allelic frequency of the nt230(del4) mutation in the MDR1 gene in GS from Southern Brazil. Blood samples were collected from 79 GS in the state of Rio Grande do Sul and genotype for the MDR1 gene was performed. Seventy-eight (98.7%) dogs were dominant homozygous genotype (wild) and one (1.3%) was heterozygous. This study showed that there is a low frequency (0.6%) of the mutant allele while the frequency of the wild allele is high (99.4%) in this specific population. This is the first report of the presence of the nt230(del4) mutation in the MDR1 gene in GS in Brazil. This information is important for breeders to prevent dissemination of the mutant allele in the national breeding population and international exchange of animals for breeding; for owners and veterinarians to be aware when dispensing and administering medications for GS dogs in Brazil.

RESUMO: A Glicoproteína-P é uma proteína transmembrana codificada pelo gene MDR1 que atua como uma barreira fisiológica através da extrusão de toxinas e xenobióticos para fora das células. O gene MDR1 pode carregar uma mutação chamada nt230(del4) que é uma deleção de quatro pares de bases, resultando na formação de uma proteína não-funcional que pode predispor à toxicoses graves, como as observadas em cães sensíveis à ivermectina. Diversas raças de cães foram descritas como portadoras da mutação nt230(del4), incluindo Pastores Alemães (PA). Entretanto, a presença do alelo mutante nessa raça não foi descrita em cães no Brasil. O objetivo desse estudo foi determinar a frequência genotípica e alélica da mutação nt230(del4) em PA no sul do Brasil. Amostras de sangue foram coletadas de 79 PA no estado do Rio Grande do Sul e o genótipo dos cães para o gene MDR1 realizado. Setenta e oito (98.7%) cães foram homozigotos dominantes (selvagem) e um (1.3%) tinha genótipo heterozigoto. A frequência do alelo mutante foi baixa (0.6%), enquanto a frequência do alelo selvagem foi alta (99.4%) nesta população. Este é o primeiro relato da presença desta mutação nt230(del4) no gene MDR1 em PA no Brasil. Esta informação é importante para criadores a fim de prevenir a disseminação do alelo mutante na população de criadores da raça no Brasil e programas internacionais de troca de animais para criação, para tutores e veterinários estarem conscientes quando prescreverem e administrarem medicações para cães PA no Brasil.

RESUMO

The P-glycoprotein (P-gp) is a transmembrane protein encoded by the MDR1 gene that functions as a biological barrier by extruding toxins and xenobiotics out of cells. The MDR1 gene can carry a mutation called nt230(del4), which is a deletion of four base pairs resulting in the formation of a non-functional protein that may predispose to severe toxicosis, as observed in dogs with sensitivity to ivermectin. Several breeds have been described as carriers of the mutation, including German Shepherds (GS). However, the presence of the mutant allele in this breed has not been described in Brazil. This study aimed to determine the genotypic and allelic frequency of the nt230(del4) mutation in the MDR1 gene in GS from Southern Brazil. Blood samples were collected from 79 GS in the state of Rio Grande do Sul and genotype for the MDR1 gene was performed. Seventy-eight (98.7%) dogs were dominant homozygous genotype (wild) and one (1.3%) was heterozygous. This study showed that there is a low frequency (0.6%) of the mutant allele while the frequency of the wild allele is high (99.4%) in this specific population. This is the first report of the presence of the nt230(del4) mutation in the MDR1 gene in GS in Brazil. This information is important for breeders to prevent dissemination of the mutant allele in the national breeding population and international exchange of animals for breeding; for owners and veterinarians to be aware when dispensing and administering medications for GS dogs in Brazil.(

A Glicoproteína-P é uma proteína transmembrana codificada pelo gene MDR1 que atua como uma barreira fisiológica através da extrusão de toxinas e xenobióticos para fora das células. O gene MDR1 pode carregar uma mutação chamada nt230(del4) que é uma deleção de quatro pares de bases, resultando na formação de uma proteína não-funcional que pode predispor à toxicoses graves, como as observadas em cães sensíveis à ivermectina. Diversas raças de cães foram descritas como portadoras da mutação nt230(del4), incluindo Pastores Alemães (PA). Entretanto, a presença do alelo mutante nessa raça não foi descrita em cães no Brasil. O objetivo desse estudo foi determinar a frequência genotípica e alélica da mutação nt230(del4) em PA no sul do Brasil. Amostras de sangue foram coletadas de 79 PA no estado do Rio Grande do Sul e o genótipo dos cães para o gene MDR1 realizado. Setenta e oito (98.7%) cães foram homozigotos dominantes (selvagem) e um (1.3%) tinha genótipo heterozigoto. A frequência do alelo mutante foi baixa (0.6%), enquanto a frequência do alelo selvagem foi alta (99.4%) nesta população. Este é o primeiro relato da presença desta mutação nt230(del4) no gene MDR1 em PA no Brasil. Esta informação é importante para criadores a fim de prevenir a disseminação do alelo mutante na população de criadores da raça no Brasil e programas internacionais de troca de animais para criação, para tutores e veterinários estarem conscientes quando prescreverem e administrarem medicações para cães PA no Brasil.

Assuntos

RESUMO

The P-glycoprotein (P-gp) is a transmembrane protein encoded by the MDR1 gene that functions as a biological barrier by extruding toxins and xenobiotics out of cells. The MDR1 gene can carry a mutation called nt230(del4), which is a deletion of four base pairs resulting in the formation of a non-functional protein that may predispose to severe toxicosis, as observed in dogs with sensitivity to ivermectin. Several breeds have been described as carriers of the mutation, including German Shepherds (GS). However, the presence of the mutant allele in this breed has not been described in Brazil. This study aimed to determine the genotypic and allelic frequency of the nt230(del4) mutation in the MDR1 gene in GS from Southern Brazil. Blood samples were collected from 79 GS in the state of Rio Grande do Sul and genotype for the MDR1 gene was performed. Seventy-eight (98.7%) dogs were dominant homozygous genotype (wild) and one (1.3%) was heterozygous. This study showed that there is a low frequency (0.6%) of the mutant allele while the frequency of the wild allele is high (99.4%) in this specific population. This is the first report of the presence of the nt230(del4) mutation in the MDR1 gene in GS in Brazil. This information is important for breeders to prevent dissemination of the mutant allele in the national breeding population and international exchange of animals for breeding; for owners and veterinarians to be aware when dispensing and administering medications for GS dogs in Brazil.((AU)

A Glicoproteína-P é uma proteína transmembrana codificada pelo gene MDR1 que atua como uma barreira fisiológica através da extrusão de toxinas e xenobióticos para fora das células. O gene MDR1 pode carregar uma mutação chamada nt230(del4) que é uma deleção de quatro pares de bases, resultando na formação de uma proteína não-funcional que pode predispor à toxicoses graves, como as observadas em cães sensíveis à ivermectina. Diversas raças de cães foram descritas como portadoras da mutação nt230(del4), incluindo Pastores Alemães (PA). Entretanto, a presença do alelo mutante nessa raça não foi descrita em cães no Brasil. O objetivo desse estudo foi determinar a frequência genotípica e alélica da mutação nt230(del4) em PA no sul do Brasil. Amostras de sangue foram coletadas de 79 PA no estado do Rio Grande do Sul e o genótipo dos cães para o gene MDR1 realizado. Setenta e oito (98.7%) cães foram homozigotos dominantes (selvagem) e um (1.3%) tinha genótipo heterozigoto. A frequência do alelo mutante foi baixa (0.6%), enquanto a frequência do alelo selvagem foi alta (99.4%) nesta população. Este é o primeiro relato da presença desta mutação nt230(del4) no gene MDR1 em PA no Brasil. Esta informação é importante para criadores a fim de prevenir a disseminação do alelo mutante na população de criadores da raça no Brasil e programas internacionais de troca de animais para criação, para tutores e veterinários estarem conscientes quando prescreverem e administrarem medicações para cães PA no Brasil.(AU)

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RESUMO

Background: The drugs that promote sedation, analgesia, and anesthesia, as inhalatory agents, phenothiazines, benzodiazepines, alpha-2 adrenergic agonists, and opioids, can promote different kinds of side effects. The concept of a balanced anesthesia in equine was developed in order to minimize adverse effects inherent to anesthesia, creating a combination of lower doses of these drugs in comparison with the doses of each one used alone. Alpha-2-adrenoceptor agonists such as xylazine, detomidine, and others, are drugs used for standing sedation, analgesia, and reduction of volatile anesthetic requirement in the equine as well as an agent used to maintenance of arterial blood pressure during anesthesia. Alpha-2 agonists works stimulating receptors of autonomic neurons inducing reduction of heart rate, cardiac output and vascular resistance, hypertension, behavioral changes, and inhibition of insulin secretion. This reduction in insulin levels increases blood glucose concentration in horses due to its lower utilization in insulin-dependent tissues, as muscular and adipose tissues. Muscular tissue is capable to maintain a constant lactate production even in a well oxygenated environment in order to maintain its cellular activity, especially in cases when glucose is not available. To evaluate the effect on blood glucose and lactate, horses were submitted to one hour of detomidine constant rate infusion during sevoflurane inhalatory anesthesia with controlled ventilation, in order to assess blood concentration of glucose and lactate. Materials, Methods & Results: Four adult horses were studied. Detomidine 20 µg.kg-¹ was used as premedication followed by an association of ketamine and diazepam intravenously as anesthetic induction. After intubation, sevoflurane was vaporized at approximately 2.3 V%. Mechanical ventilation was established. After stabilization, an intravenous continuous rate infusion (CRI) of detomidine 5 µg.kg.h-¹ was started. Venous blood samples were collected before premedication, prior to detomidine continuous infusion, 20, 40, and 60 min after beginning of infusion, in order to determination of glucose and lactate serum concentrations. After 60 min of detomidine infusion, the horses were allowed to recovery. There was statistical significant hyperglycemia in the horses under CRI of detomidine. There was no significant increase in blood lactate, despite of the hyperlactatemia in some animals. Discussion: Detomidine CRI of 5 µg.kg.h-¹ does increase blood glucose levels over normal values but not to levels that could be toxic to tissues, mainly CNS. With low levels of serum insulin, body tissues, mainly muscular and adipose tissues, are unable to capture this available blood glucose and these cells depend on lactate metabolism. The lactate serum concentrations below normal range observed in studied horses suggest that all lactate produced by the tissues is being utilized in the energetic metabolism. In according to many authors, lactate is produced and utilized for mitochondrias as energetic source even in fully oxygenated tissues, which seems to be what happened in this experiment. The present study helps to understand energetic metabolism in horses under general inhaled anesthesia with detomidine CRI, a selective alpha-2-adrenoceptor agonist. In order to better evaluate energetic metabolism during inhaled anesthesia under detomidine influence, other studies are suggested, as prolonged anesthesia duration to evaluate a longer adrenergic stimulus induced by detomidine. Besides, other investigations with detomidine CRI in horses submitted to surgical procedures could provide different responses in energetic metabolism.

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