Theses supervised by Prof. Dr. Ömer Bozdoğan
10 theses · Bolu Abant İzzet Baysal University
The effect of carotid artery cannulation and femoral artery cannulation with the cardiac vagal denervation on the ischemia and reperfusion induced arrhythmia
This study, it was aimed to compare the effects of the carotid artery and femoral artery cannulation for blood pressure measurement and right vagal denervation on ischemia-reperfusion-induced arrhythmias in an experimental myocardial infarction model. In the study, 58 male Sprague Dawley rats 6-7 months old were used. A total of 4 groups were produced: two main groups and 2 subgroups. To measure blood pressure in the first group, intravascular cannulation was made from the right carotid artery, and in the second group, from the right femoral artery. The Myocardial Ischemia model was created by ligating the left coronary artery with silk thread, and reperfusion was created by loosening this silk. Vagal denervation was performed in two subgroups, by cutting the N. vagus along the carotid artery. In sham of this procedure, the nerve is not cut, only separated from the carotid artery. During ischemia and reperfusion, blood pressure, heart rate, arrhythmia types, and durations were determined. Comparisons between groups were made using a one-way analysis of variance, one-tailed t-test, and Chi-square test. The blood pressure and the heart rate were lower in the femoral artery group than in the carotid artery group during ischemia and reperfusion. And the arrhythmia score was higher in the femoral artery group than in the carotid artery group. While vagal denervation increased arrhythmias in the carotid artery group, it was not effective in the femoral artery group. In conclusion, femoral artery cannulation performed in experimental myocardial ischemia and reperfusion model in rats increases arrhythmias compared to carotid artery cannulation. Less stimulation of baroreceptors during femoral artery cannulation may play a role in this increase in arrhythmias.
The acute combined effect of Pinacidil and Glimepiride on ischemia and reperfusi̇on i̇nduced arrhythmia. "The role of ATP- dependent potassi̇um channel"
This study was aimed to highlight the role of ATP-dependent-potassium channel on ischemia/reperfusion induced arrhythmia during the acute phase, with the application of Pinacidil as KATP channel opener and Glimepiride as a channel blocker. In this study among 4 groups, 58 male Sprague-Dawley rats 6-7 months old were used. The surgical procedure started with tracheostomy, then femoral cannulation was performed to measure blood pressure during the operation. By using silk thread, coronary artery was ligated and 6 min. ischemia had been performed, and following 6 min. for reperfusion produced by removing the silk. In control group just drugs solvents were administrated at 2 min of ischemia and at the beginning of reperfusion Time of drugs administration among groups did not change. In Pinacidil group, Pinacidil drug were given with Glimepiride solvent, and the same were applied in Glimepiride group with Pinacidil solvent. In combined group both Pinacidil and Glimepiride drugs were given. The type of arrhythmia, the incidence and arrhythmic score were statistically comprised between groups using one way-ANOVA and independent t-test. Pinacidil alone was anti-arrhythmic in reperfusion period, while Glimepiride was pro-arrhythmic. The protective effect of Pinacidil was abolished by Glimepiride in combination group. In conclusion, the expected protective results against I/R injury induce arrhythmia through using channel activator and blocker were not observed. This result might be increasing heterogeneity in action potential duration due to the different effect of two modulators on action potential duration. The protection generated by Pinacidil alone might be depend on its effects on action potential duration instead of its hypotensive effect.
Ovariektomize sıçanlarda bitkisel östrojenin iskemi-reperfüzyon aritmileri üzerine etkileri
More than 50% of sudden death in human occurring due to heart attack is caused by occlusion of coronary arteries. Ventricular arrhythmias that occurs due to the myocardial ischemia is the main reason of the sudden death. In most of the experimental researches, studies focus on these lethal arrhythmias and many chemical agents have been researched for the prevention of these arrhythmias. According to the previous researches, arrhythmia generation has been observed in females less than males. This difference has been based on gender differences which results from endogenous estrogen. There are many experimental studies that show protective effects of estrogen on ischemia and reperfusion induced arrhythmias. In recent years, plant derived substances that have a similar structure and function with estrogen have been used to prevent menopausal symptom in human being. Phytoestrogens are one of the examples of these substances. They are soy-derived substances which have a similar molecular shape with the endogenous estrogen. Genistein is the most known type of phytoestrogen and it has been used in the many experimental and clinical studies. Due to its similarity with estrogen, it was aimed to be researched whether it has a protective effect on ischemia and reperfusion induced arrhythmias in this study. Spraque-Dawley female rats weighing 225 - 290 g and in 6 - 7 months old were used. Myocardial ischemia were made by ligation of left coronary artery and reperfusion were made by releasing of this artery. Ovariectomy were made in two groups (ovx group). Genistein were given intraperitoneally in a dose of 100 µg / kg for 4 weeks in all groups except their control. Electrocardiogram (ECG) and arterial blood pressure were recorded during ischemia and reperfusion. It was found that plasma estradiol level significantly decreased in ovx group than the other group (p < 0,05). In genistein-treated group, no significant changes was observed in plasma estradiol level. There were no significant effect of genistein found on the total duration of arrhythmia and the incidence of ventricular tachycardia, ventricular premature contraction or ventricular fibrillation and arrhythmia score in unovariectomized and ovariectomized rats during 6 minutes of reperfusion. The effect of ovariectomy and genistein on the ischemia reperfusion induced arrhythmia was found similar as like previous studies. The nonsignificant different effect of genistein in the unovariectomised rats and ovariectomized rats was thought to be depend on the changes of its affinity to the estrogen receptor or the changes in the number of estrogen receptor after ovariectomy. More research is required to clarify the relation of genistein effect with the number of estrogen receptor and its affinity to the estrogen receptor.
Sıçanlarda egzersiz ve beslenmenin iskemi ve reperfüzyon aritmileri üzerine etkisi
The risk of coronary artery disease(CAD) increases with aging and death occurs due to the arrhythmias following coronary artery occlusion. In recent years, researchers have focused on the effects of physical exercise and diet for decreasing of these deaths. However, the effect of nutrition together with physical exercise and food restriction (FR) on the arrhythmias induced by ischemia and reperfusion was not studied more in experimentally produced myocardial infarction. That is why in this research the effect of exercise, different nutrition and food restriction alone and together on ischemia reperfusion (I/R) induced arrhythmia in male and female was aimed to be studied. 148 Male and 142 female Sprague-Dawley rats were used in this study. Exercise was made by swimming in 45min/ day, food restriction by decreasing food in %50 during six weeks. Animals were fed by two different food; standard food and protein rich food. Ischemia was produced by the ligation of left coronary artery in 6 minutes and reperfusion by releasing of this artery in 15 minutes. The score of arrhythmia, ventricular premature contraction and the duration of total arrhythmia decreased during ischemia in male having exercise and also in exercised combined with food restriction in rats fed with standard diet (P <0.05). However in females, this effect was only seen in combination group (P<0.05). The amount of superoxide dismutase (SOD) increased in male groups that applied exercise and combination (P<0.05). Otherwise, there was no difference in ATP dependent potassium (KATP) channel protein in exercise and exercise with food restriction male group in respect to control male,but in females it was increased in both condition. No changes in arrhythmia during reperfusion period were observed in male and female in exercise or exercise and food restriction groups in respect to their control. Different effect of protein rich diet on the ischemia-induced arrhythmia was observed. Protein rich diet was not effective on the ischemia-induced arrhythmia in male but it increased the arrhythmia in female following exercise combined with food restriction group. Otherwise, in reperfusion period, protein rich diet increased the arrhythmia in male having exercise, but no change in arrhythmia was observed in female in this period. The amount of SOD was not significantly increased either in male and female having exercise alone or together with the food restriction in protein rich diet. But KATP channel protein increased in exercised alone and with food restriction applied groups only in male. Increasing in the amount of SOD was effective alone in reducing the arrhythmias during ischemia without increasing KATP channels in males. This result supports the previous studies. In female, the increase of SOD was not effective on arrhythmias alone but this time the increasing number of KATP channel was effective in reducing the arrhythmias occurred during ischemia. The protein-rich feeding eliminates the protectiveeffect against arrhythmia in male and female having long-term exercise firstly, was found in this study. KEYWORDS:Ischemia, Reperfusion, Arrhythmia, Diet, Food restriction, Exercise.
The effect of estrous cycle on ischemia reperfusion induced arrhythmias in rats
Arrhythmia caused by coronary artery occlusion is a major cause of sudden death both in women and men. Ventricular tachycardia and fibrillation are lethal arrhythmias that may cause sudden death due to ischemia-reperfusion injury. The incidences of these arrhythmias show differences in women and men. There is a cardioprotective difference between women and men. Women are more resistant to heart attack than men. However the cardioprotective effect disappears after menopause in women. Since estrogen diminishes after menopause in women, and it is well known that the administration of estrogen have a cardioprotective effect against ischemia-reperfusion induced arrhythmias, it is thought that the cardioprotective effect in pre-menopausal women is caused by estrogen levels. However, the estrogen levels are fluctuating during menstrual cycle in women and during the estrous cycle in rats. It was shown that there is a difference between phases of estrous cycle in the maintaining of cardiac function after injury. That is why in the present study the effect of estrous cycle on ischemia-reperfusion induced arrhythmias and the role of endogenous estrogen were researched. In the present study 6-7 months old 28 female Sprague Dawley rats were used. The phases of estrous cycle were determined by the observation of the cells present in the vaginal smears. Four groups were created according to the phases of estrous cycle; proestrus, estrus, metestrus, diestrus. Left anterior descending coronary artery was occluded to create ischemia for 6 minutes, and the artery was released for reperfusion for 6 minutes. Electrocardiogram and blood pressure are recorded during ischemia and reperfusion. Blood samples were collected after reperfusion, and serum 17ß-Estradiol levels were determined. After occlusion, blood pressures decreased and ST segment elevation or depression were observed in all animals. There were no differences in arrhythmia score, the incidences of arrhythmias, and arrhythmic periods among the groups. Higher blood pressures were observed in proestrus group, however the difference was not statistically significant. Lower heart rates were observed in estrus group during 6 minutes of ischemia and 6 minutes of reperfusion (P<0.05). 17ß-Estradiol level of proestrus was found higher than the other groups (P<0.05). In conclusion, in the present study it was found that the estrous cycle and endogenous estrogen do not have an effect on ischemia-reperfusion induced arrhythmias, however they may have an effect on the heart rate and blood pressure during ischemia-reperfusion.
Kısa ve uzun dönem deneysel diyabette iskemi ve reperfüzyon aritmileri üzerine resveratrol, berberin ve glibenklamid kombinasyonunun etkisi; atp bağımlı potasyum kanalının rolü
In the present study, it was aimed to investigate the effect of resveratrol, berberine and glibenclamide combination on ischemia/reperfusion induced arrhythmias and in relation with KATP channel in streptozotocin-induced diabetic rats. In this study, 210 male Sprague Dawley rats, 5-6 months age, were used. Diabetes was induced by intraperitoneal injection of streptozotocin (65 mg/kg). Resveratrol (5 mg/kg), berberine (10 mg/kg) and glibenclamide (5 mg/kg) were freshly prepared and daily administrated for 2 and 6 weeks. Six minutes ischemia and six minutes reperfusion were performed for evaluating arrhythmias. Short-term diabetes significantly decreased the incidence of other types of arrhythmias (Ventricular premature contraction, salvo, bigeminy) induced by reperfusion. However, combination of berberine and glibenclamide significantly increased the incidence of other types of arrhythmias. In long-term diabetes, resveratrol alone and its combination with glibenclamide significantly decreased the arrhythmia score, arrhythmic period, duration and incidence of other types of arrhythmia during reperfusion. Short-term diabetes did not change protein expression level of Kir 6.2 subunit; however, long-term diabetes significantly decreased protein expression level of Kir 6.2 subunit. Resveratrol, berberine and glibenclamide combinations significantly increased protein expression of Kir 6.2 subunits in long-term diabetes. In conclusion, short-term diabetes increased the resistance of diabetic hearts against reperfusion-induced arrhythmias. As the duration of diabetes increased, the resistance against the arrhythmias disappeared. Resveratrol alone and its combination with glibenclamide were effective in decreasing reperfusion-induced arrhythmias. Long-term diabetes resulted in decreased protein expression of Kir 6.2 subunit, which might be a reason for decreased resistance of diabetic heart to arrhythmias in long-term diabetes. Upstream and downstream signaling pathways for the effect of resveratrol and diabetes mellitus on myocardial KATP channel and arrhythmias should be determined in future studies.
Dişi sıçanlarda ATP bağımlı potasyum kanallarının bloke edilmesi ya da açılmasının sol koroner arterin kısmi tıkanmasını takiben oluşan aritmiler üzerine etkisi
In this study, the effect of both ATP dependent potassium channel blocker (glibenclamide) and opener (pinacidil) on ischemia induced arrhythmia produced by ligation of smaller branch of left coronary arteries was researched.In the research, 30 Female Spraque-Dawley rats weighing 215 - 245 g. in 7-8 month old were used. Glibenclamide was given in 0, 5 mg/kg/100ul dose intraperitoneally 20 minute before coronary ligation and pinacidil was given in 0, 01 mg/kg/100ul dose intravenously from cocygeal tail vein 10 minute before coronary ligation. Electrocardiogram (ECG) and arterial blood pressure was recorded during the 30 minute of coronary ligation.Blood pressure decreased (P<0.05) immediately after the ligation in all group of animals. Glibenclamide decreased the incidence of ventricular tachycardia (VT) (P<0.05) but pinacidil did not in respect to control. The score of arrhythmia calculated by using the type and duration of arrhythmia observed during 30 minutes of ligation was decreased by glibenclamide which was significantly different from both control and pinacidil group.As a result, ATP dependent potassium channel blockage with glibenclamide is found to be effective to decrease arrhythmia occuring 30 minutes ischemia in rats. This effect of glibenclamide to decrease arrhythmia may depend on decreasing electrical heterogenity between nonischemic and ischemic area. This heterojenity may increase in pinacidil group because of pinacidil opens ATP dependent potassium channel in normal myocardial cells.
Sarkolemmal ve mitokondriyal ATP bağımlı potasyum kanallarının erkek ve dişi sıçanlarda iskemi ve reperfüzyon aritmilerine etkisi; Endojen östrojenin rolü
The role of ATP dependent potassium channel in ischemia reperfusion induced injury and arrhythmias have been investigated intensively, however the effect of sarcolemmal and mitochondrial ATP dependent potassium channel modulation by drugs on these arrhythmias remains controversial. Therefore, the aim of the present study is to investigate the role of sarcolemmal and mitochondrial KATP channel modulation on ischemia and reperfusion induced arrhythmias.In this study 143 Sprague-Dowley rats in male and female aged 7-8 months old were used. Six minutes ischemia and six minutes reperfusion was generated by the ligation and releasing of left coronary artery. The effect of pinacidil, HMR 1098, 5-HD and diazoxide on ischemia reperfusion induced arrhythmia have been examined.The score of arrhythmia in reperfusion and total duration of arrhythmias in ligation was found to be lower in female and ovariectomized female than in male rats (P<0.05). The score of arrhythmias and total length of arrhythmias in males during reperfusion was lower in pinacidil, HMR 1098, 5-HD and diazoxide groups compared to control (P<0.05). Pinacidil did not decrease the score of arrhythmia in males during reperfusion when it was combined with 5-HD (P<0.05). In females, the combination of Pinacidil and HMR 1098 decreased total length of arrhythmias during reperfusion (P<0.05). In ovariectomized females, HMR 1098 decreased the score of arrhythmias during reperfusion while 5-HD increased duration of total arrhythmias during ligation (P>0.05).The lower arrhythmia scores observed in female did not depend on the circulating estrogen levels. The ovariectomy changed the response of females to HMR 1098 and 5-HD. It may indicate estrogen involvement in the modulation of KATP channel by selective drugs. Both activation and inhibition of mitochondrial or sarcolemmal KATP channel produced antiarrhythmia in males. The protective effect of pinacidil against arrhythmia was abolished by the combination of pinacidil with mitochondrial KATP channel blocker, That may suggest that pinacidil decreases arrhythmia through mitochondrial potassium channel opening.As a conclusion, both the blockage of sarcolemmal KATP dependent channel and opening of mitochondrial KATP channel at the same time may be effective to decrease ischemia reperfusion induced arrhythmia.Key Words: Ischemia reperfusion, Arrhythmias, Rat, Sex, ATP dependent potassium channels, Estrogen, Pinacidil, HMR 1098, 5-HD, Diazoxide.
Erkek sıçanlarda kısmi sol koroner arter tıkanmasını takiben oluşan aritmiler üzerine ATP bağımlı potasyum kanal bloker ve açıcılarının etkisi
More than 50 % of Sudden Death in human being occurs due to heart attack that is generated by occlusion of coronary arteries. The reason of these sudden death is ventricular arrhythmia that occurs due to the myocardial ischemia. That?s why experimental studies have been done for the prevention or decreasing of these arrhythmias. Researches were concentrated on the ATP dependent potassium channels that have role in the generation of these arrhythmias. In this study, unlike previous studies; the effect of both ATP dependent potassium channel blocker and opener on ischemia induced arrhythmia were researched in rats having smaller infarct size.In the present study, 280-377 g weight, 8-9 months old, 21 Spraque-Dawley male rats were used. Pinacidil was given intravenously and glibenclamide was given intraperitoneally before coronary ligation. Electrocardiogram and blood pressure were recorded during 30 minutes of coronary ligation.Blood pressure decreased in all animals after coronary ligation. Glibenclamide increased the incidence of arrhythmia during 30 minutes of coronary ligation but there was no statistical difference observed. Similar insignificant effect was seen in pinacidil treated groups. Similarly arrhythmia score calculated from duration and type of arrhythmia was not significantly different in pinacidil and glibenclamide treated group according to control rats.As a result, the effect of pinacidil and glibenclamide on the arrhythmias induced by smaller ischemic area in male rats were different as it compared with larger ischemic model. This different effect may be due to the presence of less number of ATP dependent potassium channels and the appearance of less arrhythmia in males than females.
Sıçanlarda aralıklı açlığın ve susuzluğun iskemi-reperfüzyon ile uyarılan aritmiler üzerine etkisi
Ischemia and reperfusion induced arrhythmias such as ventricular tachycardia or ventricular fibrillation are one of the most important causes of death in myocardial ischemia. That is why, it is important to find factors increasing resistance against myocardial ischemia induced by sudden occlusion of coronaries in human being. The changing of life style or feeding habit may be more effective in the reduction or prevention of death from cardiovascular disease instead of using drug. Dietary restriction, including caloric restriction, intermittent fasting or alternative day fasting may be protective in the decreasing the incidence of death due to the coronary artery disease in human being. Recently, researchers have focused on the various effects of intermittent fasting. It has been shown that intermittent fasting can reduce cardiovascular disease. In literature, there could not found any research related with the effect of both intermittent fasting and water restriction on the ischemia and reperfusion induced arrhythmias in rats. Thirty male rats in 8-9 months old were used in this study. Six minutes ischemia was produced by ligation of left coronary artery which was followed by six minute reperfusion by releasing of this artery. Control group was fed ad libitum. IFW1 group was subjected to intermittent fasting and water restriction for one month. IFW2 group was maintained one month intermittent fasting and water restriction followed by one month normal feeding.ECG and arterial blood pressure were recorded during ischemia and reperfusion. Blood glucose level was also measured before ligation. The blood pressure and heart rate during ischemia and reperfusion did not show a significant difference among groups. Similarly, there was no significant difference in arrhythmia score calculated from duration and type of arrhythmia. But arrhythmic period during ischemia in IFW1 was longer in respect to other groups. Blood glucose level significantly decreased in animals maintained on food and water intermitted restriction. In conclusion, it was found that the intermittent fasting and water restriction that is experimental model of Ramadan fasting did not have any effect on the severity of arrhythmia induced by ischemia and reperfusion. Further studies should be made to research the effect of other restriction models on the ischemia or reperfusion induced arrhythmia and the survival rate of animals after acute coronary artery occlusion.