Pulmonary artery hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to the augmented afterload of the right ventricle (RV), hypertrophy, and heart failure. Oxidative stress and inflammation in the RV may be involved in the physiopathology of PAH. Because of their antioxidant properties, melatonin and sildenafil could be possible therapeutic agents for the treatment of PAH. Therefore, the present study evaluated the protective effects of melatonin against oxidative stress, inflammation, and mitochondrial biogenesis in the RV of rats with PAH. Wistar rats were divided into four groups: control (CTR), monocrotaline (MCT), monocrotaline treated with sildenafil (MCT + SIL), and monocrotaline treated with melatonin (MCT + MEL). PAH was induced using a single dose of MCT (60 mg/kg, i. p.). Sildenafil citrate (50 mg/kg/day) and melatonin (10 mg/kg/day) were then administered by gavage, beginning on the first day of the experimental protocol. On the day 21, echocardiographic, morphometric, oxidative/nitrosative stress and Western blotting analyses were performed. Animals that received melatonin or sildenafil demonstrated an increased tricuspid annular plane systolic excursion (TAPSE) when compared with non-treated animals, indicating an improvement in RV contractility. Both melatonin and sildenafil treatment decreased lipid peroxidation (LPO) and reestablished sulfhydryl levels. Melatonin administration decreased the protein expression level of nuclear factor kappa beta (NF-κB), while sildenafil decreased xanthine oxidase expression. Both treatments increased peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC-1α) expression. Based on our findings, melatonin showed a protective effect similar to sildenafil in the RV of a rats model of PAH.

This study explored the effects of melatonin on cardiac and vascular function, and redox homeostasis in model PAH. Male Wistar rats were divided into: control (CTR), monocrotaline [MCT (60 mg/kg, single dose i.p)], monocrotaline + sildenafil [MCT + SIL (50 mg/kg/day)], and monocrotaline + melatonin [MCT + MEL (10 mg/kg/day)]. This protocol lasted 21 days. Echocardiographic, morphometric, histological, vascular reactivity, and oxidative/nitrosative stress analyses were performed. The reduced diastolic function and AT/ET ratio in the MCT group were partially attenuated by melatonin and sildenafil treatment (p < 0.05). Increased RV hypertrophy and pulmonary congestion were reduced by both treatments (p < 0.05). MCT-induced pulmonary arteriolar muscle layer hypertrophy was also reduced by both treatments (p < 0.05). MCT and MCT + SIL present diminished vasorelaxation as compared to control (p < 0.05). Augmented oxidative/nitrosative stress and reduced glutathione-s-transferase activity in MCT were mitigated by both treatments (p < 0.05). Then, melatonin was as effective as sildenafil against PAH-induced oxidative stress and pathological vascular remodelling.

Objective: Increased mitochondrial reactive oxygen species (ROS) is a known contributor to endothelial cell (EC) dysfunction, which plays a major role in the development and progression of pulmonary hypertension (PH). Deficiency of mitochondrial antioxidant MnSOD has been linked to pathological pulmonary vascular remodeling in PH. The objective of this study was to determine whether EC-specific transgenic overexpression of MnSOD attenuates the onset and progression of PH. Hypothesis: MnSOD overexpression in ECs will attenuate the development of PH. Methods: We studied binary conditional transgenic animals with EC-specific MnSOD overexpression inducible by a Tet-OFF system. Mice of both sexes were divided into groups MnSODVE-NE (normal expression of MnSOD in EC) and MnSODVE-OE (overexpression of MnSOD in EC). PH was induced in both groups by weekly subcutaneous injection of monocrotaline (60 mg/kg) for 4 weeks. At the end of this period, echocardiography was performed, and the organs were collected for morphometric and histological analyses. Results: Animals overexpressing MnSOD in EC showed an 11% decrease in RV hypertrophy (0.31±0.01 in MnSOD-NE vs. 0.27±0.006 in MnSOD-OE, p=0.0164) and a 44% decrease in pulmonary vascular remodeling (18.43±0.80 in MnSOD-NE vs. 10.27±0.87 in MnSOD-OE, p=0.0001) compared to control. Echocardiographic assessment showed a 25% increase in PAT/PET ratio (0.24±0.01 in MnSOD-NE vs. 0.30±0.02 in MnSOD-OE, p=0.0276) and a 49% increase in TAPSE (0.74±0.08 in MnSOD-NE vs. 1.1±0.03 in MnSOD-OE, p=0.0020), indicating that EC-specific MnSOD OE was able to attenuate the development of monocrotaline-induced PH. This beneficial effect was related to a 61% increased expression of CPT1A (0.62±0.05 in MnSOD-NE vs. 1.01±0.10 in MnSOD-OE, p=0.006). Conclusion(s): EC-specific MnSOD overexpression was effective in preventing pulmonary vascular remodeling and attenuating the development of PH in mice. R56HL133624, 5P30GM145500, RI fdn 1472420231352; Bray Award-Brown Univ.; T32HL160517, R01HL046716; T32GM065085; CAPES/PRINT 88887.363181/2019-00; CNPq 404484/2021-2 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: Increased mitochondrial ROS is a known contributor to endothelial cell (EC) dysfunction, which plays a major role in the development and progression of pulmonary hypertension (PH). MnSOD deficiency has been linked to pathological pulmonary vascular remodeling in PH, which overloads the right ventricle (RV), causing RV hypertrophy. Hypothesis: We hypothesize that overexpression of MnSOD in ECs is effective in attenuating the progression of pulmonary hypertension and right ventricular hypertrophy. Methods/Approach: We studied transgenic mice with EC-specific MnSOD overexpression inducible by a Tet-OFF system. Mice of both sexes were divided into two groups (n=7/group): MnSODVE-NE (normal expression of MnSOD in EC) and MnSODVE-OE (overexpression of MnSOD in EC). Monocrotaline (60 mg/kg, s.c.) was injected once weekly for four weeks in mice. PH was induced in both groups by weekly subcutaneous injection of monocrotaline (60 mg/kg) for 4 weeks. At the end of this period, RV echocardiogram was assessed, and the heart and lungs were collected for morphometric, histological, and protein expression analyses. Results/Data: MnSODVE-OE animals presenting increased MnSOD expression in EC showed decreased muscularization of pulmonary arterioles (by a 44% decrease in pulmonary vascular remodeling, (18.43±0.80 in MnSODVE-NE vs. 10.27±0.87 in MnSODVE-OE, p=0.0001), 11% decrease in RV hypertrophy (0.31±0.01 in MnSOD-NE vs. 0.27±0.006 in MnSODVE-OE, p =0.0164), and 44% decrease in pulmonary vascular remodeling (18.43±0.80 in MnSOD-NE vs. 10.27±0.87 in MnSOD-OE, p =0.0001). Echocardiographic assessment showed a 25% increase in PAT/PET ratio (0.24±0.01 in MnSODVE-NE vs. 0.30±0.02 in MnSODVE-OE, p =0.0276) and 49% increase in TAPSE (0.74±0.08 in MnSODVE-NE vs. 1.1±0.03 in MnSODVE-OE, p =0.0020), indicating that EC-specific MnSOD-OE was able to attenuate the development of RV hypertrophy in PH. In the RV, this was associated with 22% decreased expression of phospho-PLN (p-PLN Ser16/Thr17 ) (0.621.8±0.057 in MnSODVE-NE vs. 1.014±0.102 in MnSODVE-OE, p =0.010506), 60% increase in calmodulin (1.0±0.22 in MnSODVE-NE vs. 1.6±0.05 in MnSODVE-OE, p =0.0270), and 50% increase in SERCA2 to PLN ratio (1.2±0.10 in MnSODVE-NE vs. 1.8±0.15 in MnSODVE-OE, p =0.0099). Conclusion(s): EC-specific MnSOD-OE is effective in attenuating pulmonary vascular remodeling and RV hypertrophy by modulating expression of calcium handling proteins in PH.

ABSTRACT:Adrenergic overstimulation is detrimental to the left ventricle. However, its effects on the right ventricle (RV) are not clear. Because adrenergic overload increases metabolic demand and oxidative stress, boldine could be a therapeutic option in the treatment of cardiovascular disease because of its antioxidant role. This study aimed to investigate the impact of adrenergic overload on RV remodeling and the cardioprotective effect of boldine. Animals were divided into 4 groups: control (C), boldine (25 mg/kg i. P .) (B), isoproterenol (ISO) (5 mg/kg subcutaneously), and boldine+isoproterenol (B+ISO). Echocardiography, Fulton index (FI), histology, oxidative stress, inflammation, and β-adrenergic receptor (ADR) were analyzed. The diastolic parasternal length [C 0.698 (0.623-0.724) versus ISO 0.77 (0.73-0.81)], FI [C 0.268 (0.231-0.275) versus ISO 0.340 (0.280-0.353)], inflammatory infiltration (∼40%), and ADR [C 0.78 (0.71-0.84) versus ISO 1.74 (1.52-2.00)] were increased in the ISO group ( P < 0.05). Boldine treatment (B+ISO) reduced the FI [0.240 (0.228-0.263)], lipid peroxidation [2.07 (2.01-2.61)], and ADR [0.71(0.62-0.80)]. Boldine increased total SH levels in B+ISO [C 2.4 (1.78-2.71); ISO 4.01 (2.95-4.66) versus B+ISO 6.77(5.15-8.60)] ( P < 0.05). There was a positive correlation between lipid peroxidation and the FI, and a negative correlation between total SH and the FI ( P < 0.05). This is the first study to explore the effects of adrenergic overstimulation on RV and the protective effect of boldine. Such data pave the way for further research involving RV remodeling, such as in pulmonary hypertension, and a new therapeutic option.

Several studies have linked low levels of testosterone with increased symptoms of cardiac disease and cardiovascular mortality; however, the effects of testosterone deficiency on cardiac systolic function and morphology are still not completely elucidated. The present study aims to evaluate the influence of testosterone deprivation on cardiac systolic function and morphology. Male Wistar rats were divided into two groups: Sham operation group (Sham): animals underwent sham operation and Orchiectomized group (Orchiec): animals underwent bilateral orchiectomy. The experimental protocol lasted 60 days after the surgery. All animals were weighted and blood samples collected to serum testosterone analysis, determined by chemiluminescence, on first (before orchiectomy) and on 60th days. One day before euthanasia (on the 59th day) echocardiographic parameters were assessed to evaluate left ventricle (LV) systolic function and morphology. Statistical significant difference was set at≤0.05. Orchiec rats presented reduced LV fractional shortening (p=0.032), increased myocardial performance index (MPI) (p=0.043), prolonged mitral valve closure time (p=0.013) and decreased heart rate (p=0.049) when compared to Sham. No statistically significant difference was found in the ejection fraction (p=0.666) between groups. Besides that, heart weight was lower in Orchiec group (p=0.035) when compared to Sham group. Testosterone deprivation reduced cardiac systolic function, changing contraction and relaxation parameters. Testosterone deficiency also changed heart rate and heart weight. The present study demonstrated for the first time that castrated levels of testosterone could alter parameters such as mitral valve closing time and MPI.

Introduction: Extracellular vesicles (EV) mediate intercellular communication and may have effects on disease processes. Research question: Can intravenous (IV) treatment with human bone-marrow mesenchymal stem-cell-derived (hBM-MSC) EV improve monocrotaline (MCT)-induced pulmonary hypertension (PH) in mice? Methods: WT Mice (male/female, 6 weeks-old) were randomly divided into four groups: Control (n= 8), MCT (n= 10), Control+EV (n= 7) and MCT+EV (n= 10). MCT and MCT+EV groups received weekly SC injections of MCT (60 mg/kg, 100 µl, Sigma, St. Louis, USA) diluted in 1x DPBS over 4 weeks, while Control and Control+EV received vehicle. Twenty-four hours after each SC injection, Control+EV and MCT+EV received IV injection (100 µl) of 3 x 10 6 hBM-MSC-derived EV diluted in 1x DPBS, while Control and MCT received vehicle. PH was characterized by morphometry, echocardiography, and lung histology. Blood samples (100 µl) were collected from the submandibular vein, centrifuged to purify EV in the serum by Total Exosome Isolation Kit (Invitrogen™), and analyzed by proteomics. Results: There was an attenuation of pulmonary vascular remodeling in MCT+EV mice (decreased by 41.2%, p= 0.0005) compared to the MCT group. MCT+EV mice also presented improved right ventricular (RV) function measured by Tricuspid Annular Plane Systolic Excursion (TAPSE), which increased by 51.7% in the MCT+EV vs the MCT group (p= 0.0004). MCT+EV mice also presented an attenuation of RV hypertrophy (decreased by 19.4%, p= 0.0115) along with an increase in expression of calsequestrin (increased by 33.5%, p= 0.0401) and calreticulin (increased by 29.8%, p= 0.0125) in RV compared to the MCT group. A KEGG pathway analysis of purified EV from mouse blood showed upregulation of proteasome and autophagy in MCT as compared with the Control group after 21 days. The same pathways were downregulated in MCT+EV in comparison with MCT. Further analysis revealed 7 overlapping proteins upregulated in MCT vs control and downregulated with MCT+EV vs MCT. Of the proteins downregulated in MCT vs control and upregulated with MCT+EV vs MCT, 9 overlapping proteins were found. Conclusion: EV treatment attenuated pulmonary vascular remodeling and RV hypertrophy, and improved parameters of RV cardiac function in mice with PH. This research identified 16 proteins in circulating EV that may be involved in the attenuation of PH. Future research investigating them may reveal new biomarkers or targets for treatment of PH.

BACKGROUND:Adrenergic overload is a central feature of cardiovascular diseases, contributing to right ventricular (RV) injury. Although widely studied, limited data are available on melatonin's impact on the RV and extracardiac tissues. OBJECTIVE:To investigate the effects of melatonin on RV remodeling, inflammation, and oxidative stress in the lung and gastrocnemius muscle of rats subjected to isoproterenol (ISO)-induced adrenergic stress. METHODS:Male Wistar rats were divided into Control, ISO, and ISO + melatonin groups. ISO (5 mg/kg, s.c.) was administered for 7 days, and ISO + M received ISO plus melatonin (10 mg/kg/day, gavage). Control animals received saline (s.c) and the non-treated groups received only saline by gavage. Cardiac function and hypertrophy was assessed by echocardiography and morphometric analyses, respectively. RV inflammation and fibrosis were examined histologically, while protein expression in the RV (TLR4, NF-κB, Bax) and lungs (eNOS, ETAR) was analyzed by western blotting. Oxidative stress markers (ROS, TBARS, sulfhydryl groups, nitrite) were measured in lung and gastrocnemius. RESULTS:ISO reduced cardiac output and heart rate, effects preserved by melatonin. RV hypertrophy induced by ISO was not prevented, but inflammatory infiltrate, fibrosis, and upregulation of TLR4, NF-κB, and Bax were attenuated by melatonin. In the lungs, no significant alterations were observed, except for increased nitrite levels in ISO + M. Gastrocnemius oxidative stress was unchanged. CONCLUSIONS:Melatonin attenuates RV inflammation and apoptosis under adrenergic overload without preventing hypertrophy or markedly affecting lungs and skeletal muscle, supporting its potential as adjunctive therapy in cardiac diseases.

Spinal cord injury (SCI) represents a debilitating condition with no effective treatments currently available. Previous research demonstrated that galantamine improves functional outcomes in SCI models. However, systemic administration results in limited target tissue bioavailability. This study aimed to develop and evaluate the therapeutic potential of galantamine-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles for SCI treatment. Galantamine-containing PLGA particles (PG) were synthesized via electrospraying, yielding nanoparticles with 568 nm average diameter, − 23 mV zeta potential, 12.87

Myocardial performance index (MPI) has been used in the estimation of ventricular function in a non-invasive way through echocardiography. This index has presented relevant results in clinical and experimental studies. However, there are no studies evaluating whether this index correlates with other cardiac parameters in experimental models of heart disease, such as monocrotaline-induced pulmonary artery hypertension (PAH) and acute myocardial infarction (AMI). In view of that, the present study evaluated rats submitted to PAH and perform a broad analysis of echocardiographic, hemodynamic and morphometric parameters of the right ventricle (RV) and pulmonary artery (PA). Besides that, the present study also evaluated rats submitted to experimental AMI and performed a broad echocardiographic evaluation of left ventricle (LV). Subsequently, it was analyzed whether the parameters collected presented correlation with the MPI. In PAH model, monocrotaline was administrated and the animals were divided into the following groups: control and PAH. In AMI model, infarction was induced by coronary artery ligation and the groups were as follows: SHAM and AMI. In PAH model, MPI presented correlation with RV functional parameters, as well as with parameters that evaluate flow and resistance in the PA. In addition, this index also presented correlation with LV parameters in infarcted rats. To our knowledge, this is the first study that evaluates the correlation of MPI with parameters of the RV in rats with PAH induce by monocrotaline. Besides that, this is the first study that compares the use of this index in two different experimental models of cardiac diseases.

The objective of this study was to explore the therapeutic effect of blueberries on hematological parameters, oxidative stress, and interleukin-10 levels in acute hemolytic anemia induced by the administration of an intraperitoneal injection of 40 mg/kg phenylhydrazine. Male Wistar rats were divided into three groups: Control, anemia (PHZ), and anemia plus blueberries (PHZ+BB). Blueberries were administered via oral gavage (250 mg/day). The erythrocyte osmotic fragility, splenomegaly, iron metabolism, hematological analysis, reactive oxygens species, sulfhydryl group, and interleukin-10 levels were evaluated. The erythrocyte osmotic fragility (in 0.85% and 0.55% sodium chloride solution) and spleen weight-to-body weight ratio (∼400%) were elevated in the PHZ and PHZ+BB Groups compared to the controls (p-value < 0.05). Increased transferrin and reactive oxygens species levels were found in the PHZ (15%) compared to the Control Group (p-value < 0.05). There was an immune inflammatory response in the PHZ Group due to increases in the total leukocyte (300%), lymphocyte (100%), and neutrophil (400%) counts compared to the Control Group (p-value < 0.05); the PHZ Group showed increased interleukin-10 levels (100%) compared to the Control Group (p-value < 0.05). Blueberries showed a partial protective effect on these parameters, since there were lower neutrophil and lymphocyte counts and diminished interleukin-10 levels in the PHZ+BB Group compared to the PHZ Group (p-value < 0.05). In addition, blueberries increased sulfhydryl group levels (p-value < 0.05). These data suggest a protective role of blueberries against inflammatory response and oxidative stress in an acute hemolytic anemia model.

Resumo Fundamento A remodelação adversa dos vasos pulmonares eleva a pressão pulmonar e provoca hipertensão arterial pulmonar (HAP). A HAP resulta em aumento da pós-carga do ventrículo direito (VD), causando hipertrofia ventricular e consequente insuficiência cardíaca. Não existe um tratamento específico para o remodelamento desadaptativo do VD secundário à HAP. Objetivos Este estudo tem como objetivo explorar duas abordagens terapêuticas, o suco de uva (SU) e os hormônios tireoidianos (HT), no tratamento do estresse oxidativo induzido pela HAP e nas alterações funcionais cardíacas. Métodos Parâmetros ecocardiográficos relacionados à resistência dos vasos pulmonares (relação TA/TE), contratilidade do VD (ESPAT) e função diastólica do VD (relação dos picos E/A) foram avaliados. Além disso, foram medidos ROS totais, peroxidação lipídica, enzimas antioxidantes, proteínas de manipulação de cálcio, expressão de proteínas pró-oxidantes e antioxidantes. Valores de p<0,05 foram considerados estatisticamente significativos. Resultados Ambos os tratamentos, com SU e HT, demonstraram uma redução na resistência pulmonar (~22%), além de melhorias na ESPAT (inotropismo ~11%) e na relação TA/TE (~26%) (p<0,05). Não houve alterações entre os grupos na relação do pico de E/A. Embora ROS e TBARS não tenham sido estatisticamente significativos, os tratamentos com SU e HT diminuíram os níveis de xantina oxidase (~49%) e normalizaram a expressão de HSP70 e proteínas de manipulação de cálcio (p<0,05). No entanto, apenas o tratamento com HT melhorou a função diastólica (~50%) e aumentou o imunoconteúdo de NRF2 (~48%) (p<0,05). Conclusões Até onde sabemos, este estudo é pioneiro ao mostrar que o HT administrado em conjunto com o SU promoveu melhorias funcionais e bioquímicas em um modelo de HAP. Além disso, nossos dados sugerem que os tratamentos com SU e HT se mostraram cardioprotetores, sejam combinados ou não, e exibiram seus benefícios ao modular o estresse oxidativo e as proteínas de manipulação do cálcio.

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance (PVR), right ventricular (RV) failure and premature death. Compounds with vasodilatory characteristics, such as ll-caryophyllene, could be promising therapeutics for PAH. This study aimed to determine the effects of free and nanoemulsified ll-caryophyllene in lung oxidative stress and heart function in PAH rats. Male Wistar rats (170 g, n = 6/group) were divided into four groups: control (CO), monocrotaline (MCT), monocrotaline + ll-caryophyllene (MCT-Bcar) and monocrotaline + nanoemulsion with ll-caryophyllene (MCT-Nano). PAH was induced by MCT (60 mg/kg i.p.), and 7 days later, treatment with ll-caryophyllene, either free or in a nanoemulsion (by gavage, 176 mg/kg/day) or vehicle was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and after, the RV was collected for morphometry and the lungs for evaluation of oxidative stress, antioxidant enzymes, total sulfhydryl compounds, nitric oxide synthase (NOS) activity and endothelin-1 receptor expression. RV hypertrophy, increased PVR and RV systolic and diastolic pressures (RVSP and RVEDP, respectively) and increased mean pulmonary arterial pressure (mPAP) were observed in the MCT group. Treatment with both free and nanoemulsified ll-caryophyllene reduced RV hypertrophy, mPAP, RVSP and lipid peroxidation. The reduction in RVSP was more pronounced in the MCT-Nano group. Moreover, RVEDP decreased only in the MCT-Nano group. These treatments also increased superoxide dismutase, catalase and NOS activities and decreased endothelin-1 receptors expression. Both ll-caryophyllene formulations improved mPAP, PVR and oxidative stress parameters. However, ll-caryophyllene in a nanoemulsion was more effective in attenuating the effects of PAH.

Resumo Fundamento A disfunção vascular constitui a etiologia de diversas doenças, incluindo infarto do miocárdio e hipertensão, diante da ruptura da homeostase oxi-redutiva (“redox”), desempenhando um papel no desequilíbrio do mecanismo de controle vasomotor. Nosso grupo demonstrou anteriormente que os hormônios tireoidianos melhoram a sinalização da angiogênese, exercendo efeitos protetores sobre o tecido aórtico de ratos infartados. Objetivos Investigar o papel da triiodotironina (T3) na resposta vascular, explorando seus efeitos em aortas isoladas e a presença de mecanismos redox vasculares. Métodos Anéis aórticos isolados (endotélio intacto e desnudado) pré-contraídos com fenilefrina foram incubados com T3 (10-8, 10-7, 10-6, 10-5 e 10-4 M) e a tensão foi registrada usando um transdutor de deslocamento de força acoplado a um sistema de coleta. Para avaliar o envolvimento do estresse oxidativo, os anéis aórticos foram pré-incubados com T3 e posteriormente submetidos a um sistema de geração de espécies reativas de oxigênio (ROS) in vitro. O nível de significância adotado na análise estatística foi de 5%. Resultados A T3 (10-4 M) promoveu o vasorrelaxamento dos anéis aórticos pré-contraídos com fenilefrina em endotélio intacto e desnudado. Os anéis aórticos pré-incubados na presença de T3 (10-4 M) também mostraram diminuição da vasoconstrição provocada pela fenilefrina (1 µM) em preparações de endotélio intacto. Além disso, o efeito vasorrelaxante da T3 (10-4 M) persistiu em anéis aórticos pré-incubados com éster metílico de NG-nitro-L-arginina (L-NAME, 10 µM), um inibidor inespecífico da NO sintase (NOS). Por fim, a T3 (10-4 M) exibiu, in vitro, um papel antioxidante ao reduzir a atividade da NADPH oxidase e aumentar a atividade da SOD nos homogenatos aórticos. Conclusão A T3 exerce efeitos dependentes e independentes de endotélio, o que pode estar relacionado ao seu papel na manutenção da homeostase redox.

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Individuals born preterm present altered cardiac autonomic function, a risk factor to heart diseases. Neonatal renin-angiotensin-system activation contributes to adult cardiomyopathy in rats exposed to neonatal hyperoxia, a well-established model of preterm birth-related conditions. Central angiotensin II receptor activation is a key modulator of the autonomic drive to the heart. Whether neonatal hyperoxia leads to alteration of the cardiac autonomic function through activation of the angiotensin II receptor type 1 (AT1) is unknown and was examined in the present study. Sprague-Dawley pups were exposed to hyperoxia or room air from postnatal days 3-10. AT1 antagonist losartan or water was given orally postnatal days 8-10. Blood pressure, autonomic function, left ventricular sympathetic innervation, beta-adrenergic-receptors expression, and AT1 expression in the solitary-tract-nucleus were examined in adult rats. Neonatal hyperoxia led to loss of day-night blood pressure variation, decreased heart rate variability, increased sympathovagal balance, increased AT1 expression in the solitary-tract, decreased left ventricle sympathetic innervation, and increased beta 1-adrenergic-receptor protein expression. Losartan prevented the autonomic changes and AT1 expression in the solitary-tract but did not impact the loss of circadian blood pressure variation nor the changes in sympathetic innervation and in beta 1-adrenergic-receptor expression. In conclusion, neonatal hyperoxia leads to both central autonomic and cardiac sympathetic changes, partly programmed by neonatal activation of the renin-angiotensin system.

ABSTRACT:Myocardial infarction (MI) and pulmonary arterial hypertension (PAH) are 2 prevalent cardiovascular diseases. In both conditions, oxidative stress is associated with a worse prognosis. Pterostilbene (PTE), an antioxidant compound, has been studied as a possible therapy for cardiovascular diseases. This study aims to evaluate the effect of PTE on oxidative stress in the hearts of animals with MI and in the lungs of animals with PAH. Male Wistar rats were used in both models. In the MI model, the experimental groups were sham, MI, and MI + PTE. In the PAH model, the experimental groups were control, PAH, and PAH + PTE. Animals were exposed to MI through surgical ligation of the left coronary artery, or to PAH, by the administration of monocrotaline (60 mg/kg). Seven days after undergoing cardiac injury, the MI + PTE animals were treated with PTE (100 mg/kg day) for 8 days. After this, the heart was collected for molecular analysis. The PAH + PTE animals were treated with PTE (100 mg/kg day) for 14 days, beginning 7 days after PAH induction. After this, the lungs were collected for biochemical evaluation. We found that PTE administration attenuated the decrease in ejection fraction and improved left ventricle end-systolic volume in infarcted animals. In the PAH model, PTE improved pulmonary artery flow and decreased reactive oxygen species levels in the lung. PTE administration promoted protective effects in terms of oxidative stress in 2 experimental models of cardiac diseases: MI and PAH. PTE also improved cardiac function in infarcted rats and pulmonary artery flow in animals with PAH.

Sustained adrenergic overload in the heart causes maladaptive cardiac remodelling, which involves oxidative stress. Boldine (BOL) has antioxidant activity and represents a novel therapeutic approach. This study explored the cardioprotective role of BOL in adverse left ventricular remodelling induced by isoproterenol. The rats were divided into four groups: control; BOL (25 mg/kg daily); isoproterenol (ISO) (5 mg/kg daily), and ISO + BOL. Morphometric, echocardiographic, and oxidative stress parameters were evaluated. BOL attenuated both cardiac hypertrophy and increased diastolic volume caused by adrenergic overstimulation (P < 0.05). BOL treatment reduced lipid peroxidation induced by ISO (ISO vs. ISO + BOL; P < 0.05), and this effect was associated with increased superoxide dismutase (SOD) (ISO vs. ISO + BOL; P < 0.05) and glutathione-S-transferase levels (GST) (ISO vs. ISO + BOL; P < 0.05). This data suggest that BOL may improve cardiac oxidative stress and attenuate some parameters of adverse cardiac remodelling.