Mitochondrial ATP-Sensitive Potassium Channel And Antiischemic Effects Of Opener

Ischemic heart disease (coronary heart disease) is one of the disease that are endangering human health, whose machanism as well as the prevention and the cure has long been a hot spot in the field of medicine. The mortality of cardiovascular disease is the highest in Occident, more than half of which is ischemic heart disease. Though the mortality of cardiovascular disease in our country is not so high as that in Occident, the trend of gradual increase has appeared in this years. Therefore we are in high demand of effective therapy.At present, antiischemic agent is the chief therapy of ischemic heart disease. The antiischemic agent can regulate the supply of oxygen by dilating coronary artery so as to increase coronary flow. The action of antiischemic agent can also be realized by decreasing cardiac consumption of oxygen to improve the relationship between supply and demand. The medicines used commonly are nitrates, β-adrenoceptor antagonists and Ca²⁺ antagonists. Although these medicines have the action of antiischemia to some extent, the cardioprotection of antiischemia is not so perfect. The reason is that some side effects may be found in these medicines, e.g. tolerance of nitrate, negative inotropic effect and hypotention of p-adrenoceptor antagonist and Ca²⁺ antagonist. So it is one of the key tasks in the field of cardiovascular research to develop an antiischemic agent with potential action and less side effect.In early 1980s, Noma firstly reported the existence of ATP-sensitive potassium channel (Katp) in cardiac sarcolemma. K_Atp is theinwardly-rectifying potassium channel. It is testified by later research that the channel opening could generate cardioprotection. It has been found in the research work in these years that the target of Katp may be intracellular, and also mitochondrial Katp may be a new target of cardioprotection. The opening mitochondrial Katp induces membrane depolarization and K+ influx. As a result, the volume of mitochondria may increase and therefore it may enhance respiration. Consequently, the tolerance to hypoxia of myocyte would be improved and the ability of endogenetic antiischemia would be strengthened.Diazoxide is a benzothiadiazine derivative, which was synthesized and put into market in U.S. in early 1960s. It was been applied in the therapy of hypertensive crises. It is indicated that diazoxide is a mitochondrial Katp opener in current study. It is not only a dialator of vessel but also a cardioprotective agent to ischemia. In order to further evaluate the pharmacological property of protection of diazoxide, in this research, different kinds of animals were studied and also the relationship between the protection and hemodynamics were discussed. The possible protection mechanism was presented so as to provide theory basis of the clinical application of diazoxide, which made both a theoretical and an experimental foundation for the development of novel antiischemic agent. In this study, the followings are indicated:Firstly, diazoxide has the following effects with the model of rabbit myocardial ischemia-reperfusion injury.1. Pretreatment with diazoxide (3⁵mg/kg) could reduce the myocardial infarct size, decrease the activity of serum LDH, CK and a-HBDH.2. Moderate or low dose of diazoxide (l³mg/kg) had no effect on systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterialpressure (MAP) and heart rate (HR), while high dose could decrease SBP, DBP and MAP significantly. Obvious fall of blood pressure could be observed 1 minute after the treatment. The SBP, DBP and MAP start to recover after about 10 minute. When treated after 30 minute, SBP, DBP and MAP recover to the level of untreated.Secondly, diazoxide has the following effects in the model of isoproterneol-induced cardiac cell injury of the rat.1. Pretreatment with diazoxide could minimize the change of ischemic injury on electrcardiogram (ECG) and decrease the activity of serum LDH, CK and a-HBDH.2. Observed under light microscope, reduced myocardial infarct size was seen.3. Observed under electron microscope, ultrastructural changed caused by hypoxia was found to be improved which exhibits both the decreasing injury degree of mitochondria and myofilament.Thirdly, diazoxide has the following effects in the model of ischemia -reperfusion injury of isolated rat heart.1. Diazoxide of 10¹00umol/L dialated coronary artery, increased coronary flow significantly and had no effect on heart rate.2. Reducesd the activity of perfusion LDH, suggesting that diazoxide could attenuate degree of ischemia-reperfision injury.3. Decreased the content of MDA significantly in cardiac tissue elevated due to ischemia-reperfusion injury, suggesting that diazoxide has an anti-oxidative effect. Decreased the content of lactic acid in cardiac tissue, suggesting that diazoxide can improve the metabolism of the myocardium.Fourthly, with an in vitro model of myocardial ischemia of isolated ratmyocyte. Diazoxide could reduce motality of myocyte and improve viability.Finally, with the model of isoproterneol-induced cardiac cell injury of the rat, the effects of diazoxide on the structures and functions of the membrane of mitochondria was observed as follows:1. Pretreatment with diazoxide improved the membrane lipid fluidity (LFU) and activity of Ca2+-ATPase. On the other hand, it inhibited the activity of phospholipase A2 (PLA2), which slowed down the degragation rate of phospholipid (PL).2. Improved the mitochondrial function of oxidative phosphorylation after hypoxia injury, which increased the rate of state 3 in the present of Succinate and respiration contrl rate (RCR).In general, diazoxide has the cardioprotection on different ischemic model of animal, the mechanism of which may realized by protecting the structure and the function of mitochondria. Diazoxide can also enhance the ability of endogenetic protection, improve the metabolism of the myocardium and reduce the production of free radical. This king of protection is independent of hemodynamic effects.