Efeitos cardiovasculares do treinamento físico combinado associado a terapias medicamentosas antihipertensivas em um modelo experimental de hipertensão
Data
2022-09-29
Autores
Araujo, Amanda Aparecida de [UNIFESP]
Orientadores
De Angelis, Kátia [UNIFESP]
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Objetivo: Avaliar os efeitos cardiovasculares e neurohumorais do treinamento
físico combinado (aeróbico + resistido) de moderada intensidade associado a terapia
medicamentosa anti-hipertensiva em ratos machos espontaneamente hipertensos
(SHR). Métodos: Foram utilizados 48 ratos machos SHR com 3 meses de idade,
divididos em 6 grupos: CS e CT – Controle Sedentário e Treinado; HS e HT –
Hidroclorotiazida Sedentário e Treinado e ES e ET – Enalapril Sedentário e Treinado.
O tratamento medicamentoso foi de 3 mg/kg/dia para o Enalapril e 30 mg/kg/dia para
a Hidroclorotiazida. O treinamento físico combinado (TFC) foi realizado 3 vezes na
semana, em esteira e escada adaptada para ratos, de 40-60% da capacidade máxima
aferida em testes de capacidade máxima. Foi realizada medida indireta da pressão
arterial (PA) por pletismografia caudal, bem como ao final do protocolo os animais
foram submetidos a canulação da artéria aorta e veia julgular para análise direta da
PA e frequência cardíaca (FC), a avaliação da sensibilidade barorreflexa (SBR) pela
infusão de drogas vasoativas e para realização do bloqueio sequencial dos sistemas
pressores, com a infusão de antagonista do receptor de vasopressina V1 (aAVP),
Losartana potássica e hexametônio. Foram realizadas análises de mediadores
inflamatórios, fator de necroso tumoral (TNF) alfa, interleucina 6 (IL-6) e de
marcadores de estresse oxidativo, peróxido de hidrogênio, nicotinamida adenina
dinucleótido fosfato (NADPH) oxidase, glutationa peroxidase (GPx), catalase (CAT),
superóxido dismutse (SOD), oxidação de lipídeos e de proteínas em tecido cardíaco,
bem como nitritos plasmáticos. Resultados: Houve redução da PA sistólica (PAS) na
pletismografia caudal nos animais tratados com hidroclorotiazida (HS e HT) e com
enalapril (ES e ET), além de redução da PAS, PA diastólica (PAD) e PA média (PAM)
pela medida direta nos grupos tratados com hidroclorotiazida; no entanto, para ambos
os grupos tratados com enalapril somente houve redução da PAD e da PAM. A PAS
reduziu apenas no grupo ET comparado aos grupos controles. Houve bradicardia de
repouso na associação dos medicamentos ao TFC (HT e ET). Para a SBR, os grupos
CT, HS, HT e ET apresentaram aumento da resposta bradicárdica, sem alteração da
resposta taquicárdica. O tratamento com hidroclorotiazida, associado ou não ao TFC,
reduziu a variação de PA quando realizado bloqueio do sistema nervoso simpático
(SNS). Já o tratamento com enalapril (ES e ET) reduziu a hipotensão quando
x
bloqueado o sistema renina angiotensina e, de forma expressiva, somente no grupo
ET com o bloqueio do SNS. Ambos os grupos tratados com enalapril (ES e ET)
reduziram TNF alfa e IL-6 comparados ao CS, com redução adicional do grupo ET
comparado ao CT para o TNF alfa, o que não foi observado com a hidroclorotiazida.
Houve redução de peróxido de hidrogênio em ambas as abordagens
medicamentosas, com maior ênfase para o enalapril, porém sem alteração em
marcadores de dano tecidual. Foi observado aumento da CAT e da concentração de
nitritos plasmáticos no grupo HT, mas não no HS. Houve aumento de nitritos
plasmáticos nos grupos tratados com enalapril, com aumento adicional no ET.
Conclusões: os resultados evidenciam que apesar da associação dos tratamentos
não induzirem efeito adicional de redução da PA, somente a associação das
abordagens induziu benefícios na capacidade física e bradicardia de repouso. Os
mecanismos neurohumorais de manutenção da PA que se adaptam ao TFC +
hidroclotiazida parecem em parte mediados pelo SNS como nessa monoterapia
isolada, porém com efeito potencializador na biodisponibilidade do óxido nítrico (NO).
Na associação de TFC + enalapril os mecanismos neurohumorais diferem pela
redução do SNS, melhora da SBR e aumento adicional de NO, que se somam ao
efeito do bloqueio do eixo pressor do SRA e a melhora de mediadores inflamatórios
observados nessa monoterapia isolada. Os efeitos aditivos da associação das
terapias podem ter importante impacto no manejo de risco remanescente e na
qualidade de vida de hipertensos.
Objective: To evaluate cardiovascular and neurohumoral effects of combined exercise training (aerobic + resistance) of moderate intensity associated with antihypertensive drug therapy in spontaneously hypertensive male rats (SHR). Methods: Forty-eight male SHR rats (3 month) were used, divided into 6 groups: CS and CT – Sedentary and Trained Control; HS and HT – Sedentary and Trained Hydrochlorothiazide and ES and ET – Sedentary and Trained Enalapril. Drug treatments were 3 mg/kg/day for Enalapril and 30 mg/kg/day for Hydrochlorothiazide. Combined exercise training (CET) was performed 3 times a week, on a treadmill and ladder adapted for rats, at 40-60% of the maximum capacity measured in tne exercise maximum tests. Indirect blood pressure was measured by caudal plethysmography, and at the end of the protocol, the animals were submitted to cannulation of the aorta and jugular vein for direct blood pressure (BP) and heart rate (HR) recording and evaluation of baroreflex sensitivity (BRS), by the infusion of vasoactive drugs, and sequential block of the BP systems, by the infusion of vasopressin V1 receptor antagonist (aAVP), losartan potassium and hexamethonium. Inflammation mediators, tumor necrosis factor (TNF) alpha and interleukin 6 (IL-6), and and oxidative stress markers, hydrogen peroxide, NADPH nicotinamide adenine dinucleotide reduced phosphate (NADPH) oxidase, glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), lipid, and protein oxidation, were evaluated in cardiac tissue, as well as we analysed plasma nitrites. Results: There was a reduction in systolic BP (SBP) by caudal plethysmography in animals treated with hydrochlorothiazide and enalapril. Reduction in SBP, diastolic BP (DBP) and mean BP (MBP) were observed in the groups treated with hydrochlorothiazide; however, in both groups treated with enalapril there was only a reduction in DBP and MAP. SBP reduced only in the ET group compared to the control groups. There was resting bradycardiain both groups that associated drugs with CET (HT and ET). For SBR, the CT, HS, HT and ET groups showed an increase in the bradycardic response, with no change in the tachycardic response. Treatment with hydrochlorothiazide, associated or not with CET, reduced the BP variation when the sympathetic nervous system (SNS) was blocked. On the other hand, treatment with enalapril (ES and ET) reduced the hypotension when the renin angiotensin system was blocked and, significantly, only in the ET group with SNS blockade. Both enalapril- xii treated groups (ES and ET) reduced TNF alpha and IL-6 compared to CS, with an additional reduction in the ET group compared to CT for TNF alpha, which was not observed with hydrochlorothiazide. There was a reduction in hydrogen peroxide in both drug approaches, with greater emphasis on enalapril, but with no change in tissue damage markers. An increase in CAT and plasma nitrite concentration was observed in the HT group, but not in the HS. There was an increase in plasma nitrites in the enalapril-treated groups, with an additional increase in ET. Conclusions: the results show that the association of treatments does not induce an additional effect of BP reduction, only the association of approaches induced benefits in physical capacity and restriction bradycardia. The neurohumoral mechanisms of BP maintenance that adapt to CET+hydrochlothiazide through the SNS-mediated part as this isolated monotherapy, but with a potentiating effect on the bioavailability of NO. The additional association of CET+enalapril the neurohumoral mechanisms by the reduction of the SNS, improvement of BR and increase of NO, which is an additional effect of the blockade of the RAS somapressor axis and the improvement of the altered media observe these mechanisms monotherapy alone. Additive additives in combination therapies can have a major impact on the remaining risk and quality of life in hypertensive patients.
Objective: To evaluate cardiovascular and neurohumoral effects of combined exercise training (aerobic + resistance) of moderate intensity associated with antihypertensive drug therapy in spontaneously hypertensive male rats (SHR). Methods: Forty-eight male SHR rats (3 month) were used, divided into 6 groups: CS and CT – Sedentary and Trained Control; HS and HT – Sedentary and Trained Hydrochlorothiazide and ES and ET – Sedentary and Trained Enalapril. Drug treatments were 3 mg/kg/day for Enalapril and 30 mg/kg/day for Hydrochlorothiazide. Combined exercise training (CET) was performed 3 times a week, on a treadmill and ladder adapted for rats, at 40-60% of the maximum capacity measured in tne exercise maximum tests. Indirect blood pressure was measured by caudal plethysmography, and at the end of the protocol, the animals were submitted to cannulation of the aorta and jugular vein for direct blood pressure (BP) and heart rate (HR) recording and evaluation of baroreflex sensitivity (BRS), by the infusion of vasoactive drugs, and sequential block of the BP systems, by the infusion of vasopressin V1 receptor antagonist (aAVP), losartan potassium and hexamethonium. Inflammation mediators, tumor necrosis factor (TNF) alpha and interleukin 6 (IL-6), and and oxidative stress markers, hydrogen peroxide, NADPH nicotinamide adenine dinucleotide reduced phosphate (NADPH) oxidase, glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), lipid, and protein oxidation, were evaluated in cardiac tissue, as well as we analysed plasma nitrites. Results: There was a reduction in systolic BP (SBP) by caudal plethysmography in animals treated with hydrochlorothiazide and enalapril. Reduction in SBP, diastolic BP (DBP) and mean BP (MBP) were observed in the groups treated with hydrochlorothiazide; however, in both groups treated with enalapril there was only a reduction in DBP and MAP. SBP reduced only in the ET group compared to the control groups. There was resting bradycardiain both groups that associated drugs with CET (HT and ET). For SBR, the CT, HS, HT and ET groups showed an increase in the bradycardic response, with no change in the tachycardic response. Treatment with hydrochlorothiazide, associated or not with CET, reduced the BP variation when the sympathetic nervous system (SNS) was blocked. On the other hand, treatment with enalapril (ES and ET) reduced the hypotension when the renin angiotensin system was blocked and, significantly, only in the ET group with SNS blockade. Both enalapril- xii treated groups (ES and ET) reduced TNF alpha and IL-6 compared to CS, with an additional reduction in the ET group compared to CT for TNF alpha, which was not observed with hydrochlorothiazide. There was a reduction in hydrogen peroxide in both drug approaches, with greater emphasis on enalapril, but with no change in tissue damage markers. An increase in CAT and plasma nitrite concentration was observed in the HT group, but not in the HS. There was an increase in plasma nitrites in the enalapril-treated groups, with an additional increase in ET. Conclusions: the results show that the association of treatments does not induce an additional effect of BP reduction, only the association of approaches induced benefits in physical capacity and restriction bradycardia. The neurohumoral mechanisms of BP maintenance that adapt to CET+hydrochlothiazide through the SNS-mediated part as this isolated monotherapy, but with a potentiating effect on the bioavailability of NO. The additional association of CET+enalapril the neurohumoral mechanisms by the reduction of the SNS, improvement of BR and increase of NO, which is an additional effect of the blockade of the RAS somapressor axis and the improvement of the altered media observe these mechanisms monotherapy alone. Additive additives in combination therapies can have a major impact on the remaining risk and quality of life in hypertensive patients.