Effects of high intensity interval training on neuro-cardiovascular dynamic changes and mitochondrial dysfunction induced by high-fat diet in rats.

BACKGROUND AND AIMS: Mitochondrial swelling is involved in the pathogenesis of many human diseases associated with oxidative stress including obesity. One of the strategies for prevention of deleterious effects related to obesity and overweight is engaging in regular physical activity, of which high intensity interval training (HIIT) is efficient in promoting biogenesis and improving the function of mitochondria. Therefore, our aims were to investigate the effects of HIIT on metabolic and neuro-cardiovascular dynamic control and mitochondrial swelling induced by high-fat diet (HFD). METHODS AND RESULTS: Twenty-three male Wistar rats (60 - 80g) were divided into 4 subgroups: control (C), HIIT, HFD and HFD+HIIT. The whole experimentation period lasted for 22 weeks and HIIT sessions were performed 5 days a week during the last 4 weeks. At the end of the experiments, fasting glucose and insulin tolerance tests were performed. Cerebral microcirculation was analyzed using cortical intravital microscopy for capillary diameter and functional density. Cardiac function and ergoespirometric parameters were also investigated. Mitochondrial swelling was evaluated on brain and heart extracts. HFD promoted an increase on body adiposity (p<0.001), fasting glucose levels (p<0.001), insulin resistance index (p<0.05), cardiac hypertrophy index (p<0.05) and diastolic blood pressure (p<0.05), along with worsened cardiac function (p<0.05), reduced functional cerebral capillary density (p<0.05) and its diameter (p<0.01), and heart and brain mitochondrial function (p<0.001). HFD did not affect any ergoespirometric parameter. After 4 weeks of training, HIIT was able to improve cardiac hypertrophy index, diastolic blood pressure, cerebral functional capillary density (p<0.01) and heart and brain mitochondrial swelling (p<0.001). CONCLUSION: In animals subjected to HFD, HIIT ameliorated both cerebral mitochondrial swelling and functional capillary density, but it did not improve cardiovascular function suggesting that the cardiovascular dysfunction elicited by HFD was not due to heart mitochondrial swelling.

N-acylhydrazone derivative ameliorates monocrotaline-induced pulmonary hypertension through the modulation of adenosine AA2R activity.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a disease that results in right ventricular (RV) dysfunction. While pulmonary vascular disease is the primary pathological focus, RV hypertrophy and RV dysfunction are the major determinants of prognosis in PAH. The aim of this study was to investigate the effects of (E)-N'-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), an N-acylhydrazone derivative, on the lung vasculature and RV dysfunction induced by experimental PAH. METHODS: Male Wistar rats were injected with a single dose (60mg/kg, i.p.) of monocrotaline (MCT) and given LASSBio-1386 (50mg/kg, p.o.) or vehicle for 14 days. The hemodynamic, exercise capacity (EC), endothelial nitric oxide synthase (eNOS), adenosine A2A receptor (A2AR), sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), phospholamban (PLB) expression, Ca(2+)-ATPase activity and vascular activity of LASSBio-1386 were evaluated. RESULTS AND CONCLUSIONS: The RV systolic pressure was elevated in the PAH model and reduced from 49.6 ± 5.0 mm Hg (MCT group) to 27.2 ± 2.1 mm Hg (MCT+LASSBio-1386 group; P<0.05). MCT administration also impaired the EC, increased the RV and pulmonary arteriole size, and promoted endothelial dysfunction of the pulmonary artery rings. In the PAH group, the eNOS, A2AR, SERCA2a, and PLB levels were changed compared with the control; in addition, the Ca(2+)-ATPase activity was reduced. These alterations were related with MCT-injected rats, and LASSBio-1386 had favorable effects that prevented the development of PAH. LASSBio-1386 is effective at preventing endothelial and RV dysfunction in PAH, a finding that may have important implications for ongoing clinical evaluation of A2AR agonists for the treatment of PAH.

Beneficial effects of a novel agonist of the adenosine A2A receptor on monocrotaline-induced pulmonary hypertension in rats.

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on monocrotaline (MCT)-induced pulmonary hypertension in rats. EXPERIMENTAL APPROACH: PAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mg·kg(-1)) and 2 weeks later, oral LASSBio-1359 (50 mg·kg(-1)) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed. KEY RESULTS: MCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio-1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre-contracted arterial rings, and this dysfunction was reversed by LASSBio-1359. In pulmonary artery rings from normal Wistar rats, LASSBio-1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio-1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio-1359 and the A2A receptor agonist, CGS21680, were very similar. CONCLUSION AND IMPLICATIONS: In rats with MCT-induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio-1359, most probably through the activation of adenosine A2A receptors.