Efeitos cardiovasculares da infusão de exendin-4 no núcleo paraventricular do hipotálamo em um modelo experimental de hipertensão induzida por L-NAME
Data
2023-02-24
Autores
Moraes, Yaslle Andrade Cavalcante 
Orientadores
Nishi, Erika Emy
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
O aumento do tônus vasomotor simpático está envolvido em várias doenças cardiometabólicas, como hipertensão arterial (HA), diabetes do tipo II, obesidade e doença renal crônica (DRC). O peptídeo semelhante ao Glucagon-1 (GLP-1) é um incretinomimético amplamente utilizado no tratamento do diabetes do tipo II e obesidade. Nos últimos anos, a literatura científica tem reportado uma associação entre agonistas do receptor de GLP-1 (GLP-1r) e efeitos cardiovasculares. Adicionalmente, diversos estudos clínicos demonstram efeitos cardiorrenais benéficos com a utilização crônica desses fármacos, incluindo ações anti-hipertensivas. No presente trabalho, avaliamos os efeitos cardiovasculares agudos da infusão de um agonista de GLP-1r (Exendin-4) em uma região pré-motora do simpático, o núcleo paraventricular do hipotálamo (PVN), em um modelo experimental de HA. Para obter um quadro hipertensivo, ratos Wistar foram tratados oralmente por 7 dias consecutivos com L-NAME (20 mg/kg/dia). Uma microinjeção bilateral de Exendin-4 (0,03μg/100 nL) foi realizada no PVN de animais hipertensos (L-NAME) e controles normotensos, seguida por registro da frequência cardíaca (FC), pressão arterial média (PAM), atividade nervosa simpática esplâncnica (ANSe) e renal (ANSr). A expressão gênica de GLP-1r foi quantificada no hipotálamo, bulbo, rim e ceco. A infusão de Exendin-4 no PVN foi capaz de elicitar respostas taquicardíacas em animais normotensos e hipertensos (L-NAME). No entanto, apenas o grupo normotenso apresentou uma resposta pressórica transiente e simpatoexcitação para o território esplâncnico (aumento da ANSe), sem alterações na ANSr. Curiosamente, no grupo hipertenso (L-NAME) não houve alterações significativas em relação a ANSe e ANSr. Paralelamente, os resultados apontaram aumento na expressão de GLP-1r no hipotálamo de animais hipertensos (L-NAME), sem alterações em relação à expressão no bulbo. De forma oposta, houve uma diminuição notável na expressão de GLP-1r no rim de animais hipertensos (L-NAME), mas sem alterações significativas no ceco. Coletivamente, os resultados indicam que a ativação central aguda de GLP-1r é capaz de ativar respostas cronotrópicas, pressóricas e simpatoexcitatórias em animais normotensos, mas esse mecanismo parece atenuado ou ausente em animais hipertensos (L- NAME).
Increased sympathetic vasomotor tone is involved in several cardiometabolic diseases, including hypertension, type II diabetes, obesity, and chronic kidney disease (CKD). Glucagon-like peptide-1 (GLP-1) is an incretin hormone widely used to treat type II diabetes and obesity. In recent years, the scientific literature has reported an association between GLP-1 receptor (GLP-1r) agonists and cardiovascular effects. Additionally, several clinical studies demonstrate beneficial cardiorenal effects with the chronic use of these drugs, including antihypertensive actions. In the present study, we evaluated the acute cardiovascular effects of infusion of a GLP- 1r agonist (Exendin-4) in a sympathetic premotor region, the paraventricular nucleus of the hypothalamus (PVN), in an experimental model of hypertension. To obtain a hypertensive state, male Wistar rats were orally treated for seven consecutive days with L-NAME (20 mg/kg/day). A bilateral microinjection of Exendin-4 (0,03μg/100 nL) was performed in the PVN of hypertensive (L-NAME) and normotensive controls rats, followed by heart rate (HR), mean arterial pressure (MAP), splanchnic (eSNA) and renal (rSNA) sympathetic nerve activity recording. GLP-1r gene expression was quantified in the hypothalamus, medulla, kidney, and cecum. Infusion of Exendin-4 into the PVN was able to elicit tachycardia responses in normotensive control and hypertensive (L-NAME) animals. However, only the normotensive control group showed a transient pressure response and sympathoexcitation for the splanchnic territory (increased eSNA) without altering rSNA. Interestingly, there were no significant alterations in the hypertensive (L-NAME) group concerning eSNA and rSNA. At the same time, the results showed upregulation of GLP-1r in the hypothalamus of hypertensive (L- NAME) animals without alterations regarding the expression in the medulla. Contrarily, there was a notable downregulation of GLP-1r expression in the kidney of hypertensive (L-NAME) animals, but without significant changes in the cecal tissue. The results indicate that acute central activation of GLP-1r can trigger chronotropic, pressure, and sympathoexcitatory responses in normotensive animals, but this mechanism seems attenuated or absent in hypertensive (L-NAME) animals.
Increased sympathetic vasomotor tone is involved in several cardiometabolic diseases, including hypertension, type II diabetes, obesity, and chronic kidney disease (CKD). Glucagon-like peptide-1 (GLP-1) is an incretin hormone widely used to treat type II diabetes and obesity. In recent years, the scientific literature has reported an association between GLP-1 receptor (GLP-1r) agonists and cardiovascular effects. Additionally, several clinical studies demonstrate beneficial cardiorenal effects with the chronic use of these drugs, including antihypertensive actions. In the present study, we evaluated the acute cardiovascular effects of infusion of a GLP- 1r agonist (Exendin-4) in a sympathetic premotor region, the paraventricular nucleus of the hypothalamus (PVN), in an experimental model of hypertension. To obtain a hypertensive state, male Wistar rats were orally treated for seven consecutive days with L-NAME (20 mg/kg/day). A bilateral microinjection of Exendin-4 (0,03μg/100 nL) was performed in the PVN of hypertensive (L-NAME) and normotensive controls rats, followed by heart rate (HR), mean arterial pressure (MAP), splanchnic (eSNA) and renal (rSNA) sympathetic nerve activity recording. GLP-1r gene expression was quantified in the hypothalamus, medulla, kidney, and cecum. Infusion of Exendin-4 into the PVN was able to elicit tachycardia responses in normotensive control and hypertensive (L-NAME) animals. However, only the normotensive control group showed a transient pressure response and sympathoexcitation for the splanchnic territory (increased eSNA) without altering rSNA. Interestingly, there were no significant alterations in the hypertensive (L-NAME) group concerning eSNA and rSNA. At the same time, the results showed upregulation of GLP-1r in the hypothalamus of hypertensive (L- NAME) animals without alterations regarding the expression in the medulla. Contrarily, there was a notable downregulation of GLP-1r expression in the kidney of hypertensive (L-NAME) animals, but without significant changes in the cecal tissue. The results indicate that acute central activation of GLP-1r can trigger chronotropic, pressure, and sympathoexcitatory responses in normotensive animals, but this mechanism seems attenuated or absent in hypertensive (L-NAME) animals.