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ISSN Печать: 2155-014X
ISSN Онлайн: 2155-0158
Biochemical Mechanisms of Cardioprotective Action of the Drug Product Flocalin, ATP-Sensitive K+ Channel Opener, in Myocardial Ischemia −Reperfusion
Краткое описание
In experiments on the anaesthetized dogs with experimental myocardial ischemia (90min) and reperfusion (180 min), the biochemical changes in the arterial blood samples following intragastric introduction of a medicinal form flocalin (tablets) (2.2 mg/kg), a fluorinecontaining opener of ATP-sensitive potassium channels (KATP-channels), were studied. The analysis of the results allowed us to define several possible mechanisms of flocalin-induced cardioprotective action. They involve an activation of the constitutive de novo nitric oxide synthesis (an increase in cNOS activity 1.6 times at the end of reperfusion, and limitation of L-arginine degradation by arginase (3.7 and 11.5 times) at the end of ischemia and reperfusion, respectively; as well as suppression of inducible nitric oxide de novo synthesis by inducible NO-synthase (iNOS) (a decrease 2.4 times on the 60th min of ischemia, and 5 times on the 120th min of reperfusion). An increase in nitrite anion content 1.3 times on the 60th min of ischemia and 1.7 times on the 120th min of reperfusion suggests a strong anti-ishemic effect of flocalin, since nitrite anion is formed spontaneously from nitric oxide only in oxygenated solutions. Limited generation of active forms of nitrogen and oxygen (oxidative and nitrosative stress) should be considered another possible cardioprotective mechanism due to the inhibition of superoxide generation, in particular, by xanthine oxidase (uric acid as a marker), lipoxygenase (LTC4 as a marker) and cyclooxygenase (TxB2 as a marker). Since LTC4 exerts coronary contractile, arrhythmogenic and chemoattractory action in myocardial ischemia, an inhibition of its production may be another mechanism of flocalin- induced cardioprotection. Powerful anti-ischemic action of flocalin (nitrite anion as a marker) to provide cardioprotection is also possible, as well as an inhibition of ATP and GTP degradation and, possibly, stimulation of haem oxygenase-induced reaction (total bilirubin and Fe in the blood as markers). A decrease in the level of free arachidonic acid in the arterial blood samples (threefold decrease in ischemia, and twofold decrease in reperfusion) can testify to an inhibition of phospholipid degradation in cellular membranes, possibly, by phospholipase A2 suppression, and it indicates possible membrane-stabilizing action of KATP − channel activation under ischemia and reperfusion of the myocardium.
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Filipets N.D., Gozhenko A.I., Filipets O.O., Gozhenko O.A., Sirman V.M., The antiproteinuric effect of ATP-sensitive potassium channel activator flocalin on the models of experimental nephropathies, Fiziolohichnyĭ zhurnal, 64, 2, 2018. Crossref