Tackling reperfusion injury after cardiopulmonary bypass with tetrahydrobiopterin: new therapeutic potentials for this phenylketonuria drug?†
| Autor: | Natascha L. Assman, An L. Moens, Yanti Octavia |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Pulmonary and Respiratory Medicine
medicine.drug_class Ischemia Drug Evaluation Preclinical Biopterin Myocardial Reperfusion Injury Pharmacology Ventricular Function Left chemistry.chemical_compound Dogs Atrial natriuretic peptide Enos Coronary Circulation medicine Natriuretic peptide Animals Letters to the Editor Cyclic GMP Postoperative Care Cardiopulmonary Bypass biology business.industry Extracorporeal circulation Hemodynamics General Medicine Tetrahydrobiopterin medicine.disease biology.organism_classification Oxygen Vasodilation Disease Models Animal chemistry Anesthesia Heart Arrest Induced Surgery Endothelium Vascular Cardiology and Cardiovascular Medicine business Reperfusion injury medicine.drug |
| Popis: | Szabo et al. [1] demonstrated that administration of tetrahydrobiopterin (BH4) during early reperfusion improves cardiopulmonary recovery after cardioplegic arrest and extracorporeal circulation in dogs. Application of BH4 restored myocardial, endothelial, and pulmonary function and increases plasma cyclic guanosine monophosphatase (cGMP) levels. Szabo et al. concluded that the beneficial effect of BH4 on reperfusion injury after cardiopulmonary bypass can be explained by recoupling of endothelial nitric oxide synthase (eNOS), as supported by increased cGMP levels measured by radioimmunoassay. However, there are many factors that can cause induction of cGMP other than NO, such as carbon monoxide and natriuretic peptides [2], which are also released in ischemia/reperfusion damage [3]. In addition, plasma arterial cGMP is correlated with atrial natriuretic peptide levels, and its production is secondary to an enhancement of the local tissue cGMP of the vascular bed [4]. It is required to measure natriuretic peptide to exclude this as another factor of cGMP production. Moreover, there are several more direct ways to evaluate eNOS coupling, such as eNOS monomer/dimer analysis, eNOS activity, eNOS- dependent superoxide generation, and quantification of BH4 and BH2 levels [5]. In addition, it is not clear whether the dose of BH4 that is used in the study of Szabo et al. increases myocardial and endothelial levels of BH4. Subsequently, it is unclear whether the improved left-ventricular function is due to improved myocyte function or is secondary to improved endothelial function. Furthermore, administration of BH4 results in increased BH2 levels, which have been described to have an inhibitory role on eNOS function. Therefore, measurement of myocardial and endothelial levels of both BH4 and BH2 is recommended from both a safety and a mechanistic point. Szabo et al. have paved the way to further reduce reperfusion injury after cardioplegic arrest and extracorporeal circulation. However, more focused molecular analysis is needed to further unravel the mechanism of action and optimize of the use of this eNOS-modulator (BH4), which is already approved as phenylketonuria (PKU) drug, in this clinical relevant model of reperfusion injury. |
| Databáze: | OpenAIRE |
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