Fowler 2019 Int J Mol Sci

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Fowler ED, Hauton D, Boyle J, Egginton S, Steele DS, White E (2019) Energy metabolism in the failing right ventricle: limitations of oxygen delivery and the creatine kinase system . Int J Mol Sci 20:1805.

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Fowler ED, Hauton D, Boyle J, Egginton S, Steele DS, White E (2019) Int J Mol Sci

Abstract: Pulmonary arterial hypertension (PAH) results in hypertrophic remodeling of the right ventricle (RV) to overcome increased pulmonary pressure. This increases the O2 consumption of the myocardium, and without a concomitant increase in energy generation, a mismatch with demand may occur. Eventually, RV function can no longer be sustained, and RV failure occurs. Beta-adrenergic blockers (BB) are thought to improve survival in left heart failure, in part by reducing energy expenditure and hypertrophy, however they are not currently a therapy for PAH. The monocrotaline (MCT) rat model of PAH was used to investigate the consequence of RV failure on myocardial oxygenation and mitochondrial function. A second group of MCT rats was treated daily with the beta-1 blocker metoprolol (MCT + BB). Histology confirmed reduced capillary density and increased capillary supply area without indications of capillary rarefaction in MCT rats. A computer model of O2 flux was applied to the experimentally recorded capillary locations and predicted a reduction in mean tissue PO2 in MCT rats. The fraction of hypoxic tissue (defined as PO2 < 0.5 mmHg) was reduced following beta-1 blocker (BB) treatment. The functionality of the creatine kinase (CK) energy shuttle was measured in permeabilized RV myocytes by sequential ADP titrations in the presence and absence of creatine. Creatine significantly decreased the KmADP in cells from saline-injected control (CON) rats, but not MCT rats. The difference in KmADP with or without creatine was not different in MCT + BB cells compared to CON or MCT cells. Improved myocardial energetics could contribute to improved survival of PAH with chronic BB treatment.

Keywords: Myocardial hypoxia, Creatine kinase, Pulmonary artery hypertension, Beta blocker, Monocrotaline, Right ventricle failure, Heart failure Bioblast editor: Plangger M O2k-Network Lab: UK Leeds Peers C


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cardiovascular 

Organism: Rat  Tissue;cell: Heart  Preparation: Permeabilized cells 

Regulation: ADP  Coupling state: OXPHOS 

HRR: Oxygraph-2k 

Labels, 2019-04