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1.
Mol Med ; 23: 120-133, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28598489

RESUMO

Reperfusion injury following acute myocardial infarction is associated with significant morbidity. Activation of neuronal or non-neuronal cholinergic pathways in the heart has been shown to reduce ischemic injury and this effect has been attributed primarily to muscarinic acetylcholine receptors. In contrast, the role of nicotinic receptors, specifically alpha-7 subtype (α7nAChR) in the myocardium remains unknown which offers an opportunity to potentially repurpose several agonists/modulators that are currently under development for neurologic indications. Treatment of ex vivo and in vivo rat models of cardiac ischemia/reperfusion (I/R) with a selective α7nAChR agonist (GTS21) showed significant increases in left ventricular developing pressure, and rates of pressure development without effects on heart rate. These positive functional effects were blocked by co-administration with methyllycaconatine (MLA), a selective antagonist of α7nAChRs. In vivo, delivery of GTS21 at the initiation of reperfusion, reduced infarct size by 42% (p<0.01) and decreased tissue reactive oxygen species (ROS) by 62% (p<0.01). Flow cytometry of MitoTracker Red stained mitochondria showed that mitochondrial membrane potential was normalized in mitochondria isolated from GTS21 treated compared to untreated I/R hearts. Intracellular ATP concentration in cultured cardiomyocytes exposed to hypoxia/reoxygenation was reduced (p<0.001), but significantly increased to normoxic levels with GTS21 treatment, and this was abrogated by MLA pretreatment. Activation of stress-activated kinases, JNK and p38MAPK, were significantly reduced by GTS21 in I/R. We conclude that targeting myocardial 17nAChRs in I/R may provide therapeutic benefit by improving cardiac contractile function through a mechanism that preserves mitochondrial membrane potential, maintains intracellular ATP and reduces ROS generation, thus limiting infarct size.


Assuntos
Traumatismo por Reperfusão Miocárdica/fisiopatologia , Receptor Nicotínico de Acetilcolina alfa7/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Animais Recém-Nascidos , Linhagem Celular , Coração/fisiologia , Humanos , Masculino , Potencial da Membrana Mitocondrial , Mitocôndrias Cardíacas/fisiologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
2.
Physiol Rep ; 10(10): e15136, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35582996

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) increases right ventricular (RV) workload and decreases myocardial oxygen reserve, eventually leading to poor cardiac output. This study created and assessed a novel model of RV work output based on RV hemodynamics and oxygen supply, allowing new insight into causal mechanisms of RV dysfunction. METHODS: The RV function model was built upon an earlier, left ventricular model and further adjusted for more accurate clinical use. The model assumes that RV total power output (1) is the sum of isovolumic and stroke power and (2) is linearly related to its right coronary artery oxygen supply. Thus, when right coronary artery flow is limited or isovolumic power is elevated, less energy is available for producing cardiac output. The original and adjusted models were validated via data from patients with idiopathic PAH (n = 14) and large animals (n = 6) that underwent acute pulmonary banding with or without hypoxia. RESULTS: Both models demonstrated strong, significant correlations between RV oxygen consumption rate and RV total power output for PAH patients (original model, R2  = 0.66; adjusted model, R2  = 0.78) and sheep (original, R2  = 0.85; adjusted, R2  = 0.86). Furthermore, the models demonstrate a significant inverse relationship between required oxygen consumption and RV efficiency (stroke power/total power) (p < 0.001). Lastly, higher NYHA class was indicative of lower RV efficiency and higher oxygen consumption (p = 0.013). CONCLUSION: Right ventricular total power output can be accurately estimated directly from pulmonary hemodynamics and right coronary perfusion during PAH. This model highlights the increased vulnerability of PAH patients with compromised right coronary flow coupled with high afterload.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Acidente Vascular Cerebral , Disfunção Ventricular Direita , Animais , Hemodinâmica , Humanos , Oxigênio , Ovinos , Acidente Vascular Cerebral/complicações , Função Ventricular Direita
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