• Publikační typ
• abstrakt z konference MeSH

Pulmonary hypertension is a group of disorders characterized by elevated mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance. To test our hypothesis that combining two drugs useful in experimental pulmonary hypertension, statins and dehydroepiandrosterone sulfate (DHEA S), is more effective than either agent alone, we induced pulmonary hypertension in adult male rats by exposing them to hypoxia (10%O2) for 3 weeks. We treated them with simvastatin (60 mg/l) and DHEA S (100 mg/l) in drinking water, either alone or in combination. Both simvastatin and DHEA S reduced mPAP (froma mean±s.d. of 34.4±4.4 to 27.6±5.9 and 26.7±4.8 mmHg, respectively), yet their combination was not more effective (26.7±7.9 mmHg). Differences in the degree of oxidative stress (indicated by malondialdehydeplasma concentration),the rate of superoxide production (electron paramagnetic resonance), or blood nitric oxide levels (chemiluminescence) did not explain the lack of additivity of the effect of DHEA S and simvastatin on pulmonary hypertension. We propose that the main mechanism of both drugs on pulmonary hypertension could be their inhibitory effect on 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, which could explain their lack of additivity.

• MeSH
• arteria pulmonalis MeSH
• dehydroepiandrosteron farmakologie   terapeutické užití   MeSH
• dehydroepiandrosteronsulfát MeSH
• hypoxie komplikace   farmakoterapie   patologie   MeSH
• krysa rodu rattus MeSH
• plicní hypertenze * farmakoterapie   MeSH
• simvastatin farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthases (NOS). Oxidative stress oxidises BH4 to dihydrobioptein (BH2), resulting in the uncoupling of the two enzymatic domains of NOS and the production of superoxide rather than NO (NOS uncoupling). Oxidative stress is known to be increased in the early stage of chronic hypoxia. This study investigated the participation of NOS uncoupling in the early phase of hypoxia-induced pulmonary hypertension in rats. Rats were exposed to 10% O(2) for 4 days. We investigated the effect of BH4 in vitro on isolated rat lungs and isolated rat peripheral pulmonary blood vessels and in vivo on exhaled NO concentration in exhaled air. BH4 attenuated hypoxic pulmonary vasoconstriction in isolated lungs and its effect was reversed by l-NAME (NOS inhibitor). The main finding of the study is that the effect of BH4 was smaller in rats exposed to 4 days of hypoxia than in normoxic controls. The finding was similar in isolated pulmonary blood vessels. BH4 increased exhaled NO in both normoxic and hypoxic rats. This increase was blunted by l-NIL (specific iNOS inhibitor) and therefore attributable to iNOS. We conclude that BH4 increased NO production in both normoxic and hypoxic rats. The increase was, however, smaller in hypoxic lungs than in controls. We assume that the smaller increase in NO production in hypoxic lungs is due to the decreased BH4/BH2 ratio in chronic hypoxia and NOS uncoupling resulting from this condition.

• MeSH
• biopteriny analogy a deriváty   metabolismus   MeSH
• hypoxie metabolismus   patofyziologie   MeSH
• krysa rodu rattus MeSH
• oxid dusnatý biosyntéza   MeSH
• plíce metabolismus   patofyziologie   MeSH
• plicní hypertenze metabolismus   patofyziologie   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The effect of three-day fasting on cardiac ischemic tolerance was investigated in adult male Wistar rats. Anesthetized open-chest animals (pentobarbitone 60 mg/kg, i.p.) were subjected to 20-min left anterior descending coronary artery occlusion and 3-h reperfusion for infarct size determination. Ventricular arrhythmias were monitored during ischemia and at the beginning (3 min) of reperfusion. Myocardial concentrations of beta-hydroxybutyrate and acetoacetate were measured to assess mitochondrial redox state. Short-term fasting limited the infarct size (48.5+/-3.3 % of the area at risk) compared to controls (74.3+/-2.2 %) and reduced the total number of premature ventricular complexes (12.5+/-5.8) compared to controls (194.9+/-21.9) as well as the duration of ventricular tachycardia (0.6+/-0.4 s vs. 18.8+/-2.5 s) occurring at early reperfusion. Additionally, fasting increased the concentration of beta-hydroxybutyrate and beta-hydroxybutyrate/acetoacetate ratio (87.8+/-27.0) compared to controls (7.9+/-1.7), reflecting altered mitochondrial redox state. It is concluded that three-day fasting effectively protected rat hearts against major endpoints of acute I/R injury. Further studies are needed to find out whether these beneficial effects can be linked to altered mitochondrial redox state resulting from increased ketogenesis.

• MeSH
• acetoacetáty metabolismus   farmakologie   MeSH
• infarkt myokardu metabolismus   veterinární   MeSH
• komorová tachykardie komplikace   MeSH
• krysa rodu rattus MeSH
• kyselina 3-hydroxymáselná metabolismus   farmakologie   MeSH
• mitochondrie metabolismus   MeSH
• oxidace-redukce MeSH
• potkani Wistar MeSH
• reperfuzní poškození myokardu metabolismus   veterinární   MeSH
• srdeční arytmie patofyziologie   veterinární   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH