| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 87 === Studies on Coronary Blood Flow and Myocardial Protection
Background
Cardiovascular diseases are the leading causes of mortality for Taiwanese population. Myocardial infarction and stunning are the main morbidity and mortality for cardiovascular diseases. Intensive research has been done to provide myocardial protection to reduce myocardial infarct size and enhance recovery from myocardial stunning. Ischemic preconditioning is considered the most powerful myocardial protective method. A lot of studies were done to search medicine to provide "pharmacological preconditioning" to protect myocardium against infarction and stunning. Although several mechanisms of ischemic preconditioning have been elucidated by previous reports, there is little information regarding the changes of coronary blood flow in association with the myocardial protective effects of ischemic or pharmacological preconditioning.
Purpose
The current study was done by carrying out five experiments. The purpose of the study is to investigate the relationship between changes of coronary blood flow and myocardial protection by ischemic or pharmacological preconditioning.
Experiment I
Pre-Coronary Artery Occlusion Myocardial Blood Flow and Myocardial Infarct
Myocardial blood flow may average 1.0 ml/min/g, but ranges from approximately 0.2-2.0 ml/min/g, in different myocardial samples due to spatial heterogeneity. We recently observed that the spatial heterogeneity could predict necrosis in baboons with coronary artery occlusion (CAO) and reperfusion (CAR). The goal of this study was to determine if necrosis could be predicted using spatial heterogeneity either prior to CAO or early after CAR in conscious pigs. Accordingly, the effects of CAO for 60 minutes followed by 3 days of CAR were examined in 9 conscious instrumented with aortic, left atrial catheters and CA occluders. Myocardial blood flow was measured by radioactive microspheres before CAO, during CAO, and after CAR. The left ventricle was cut into small pieces (0.17 * 0.00 g) and separated into non-ischemic (n=2282), or area at risk, which contained infarcted (n=319) or salvaged (n=152) samples. Analysis revealed infarcted tissue had higher pre-CAO myocardial blood flow than salvaged tissue ( 1.25 * 0.02 vs 0.99 * 0.03 ml/min/g, P < 0.01). Conversely, infarcted tissue had lower blood flow at 5 minutes after CAR than Salvaged tissue ( 1.57 * 0.06 vs 3.00 * 0.11 ml/min/g, P < 0.01). Thus spatial heterogeneity of myocardial blood flow in conscious pigs, assessed either prior to CAO or early after CAR, can predict myocardium salvaged by CAR.
Experiment II
Ischemic Preconditioning, Pre-Coronary Artery Occlusion Blood Flow, and Myocardial Infarction
The goal of this study was to determine whether the cardioprotective effects of an adenosine A1-agonist and ischemic preconditioning involve a shift in the pre-coronary artery occlusion spatial distribution of myocardial blood flow, which might shed light on the mechanism of ischemic preconditioning and explain its heterogeneous effects. Accordingly, 60 min coronary artery occlusion followed by 72 hours coronary artery reperfusion was examined in three groups of conscious pigs 10 to 14 days after instrumentation with aortic and left atrial catheters and coronary artery occluders. Myocardial infarct size, expressed as a fraction of the area at risk, was reduced significantly (P < 0.05) by infusion of the adenosine A1-agonist (27.1 * 6.6 %) and to a greater extent (P < 0.05) by ischemic preconditioning (11.6 * 5.1%) compared with the infarct size in vehicle-treated animals (55.1 * 2.9 %). Transmural myocardial blood flow (determined by radioactive microspheres) in the area at risk shifted toward lower levels after infusion of the adenosine A1-agonist (1.27 * 0.19 vs 0.74 * 0.10 ml/min/g) or ischemic preconditioning (1.27 * 0.11 vs 0.96 * 0.09 ml/min/g) but not by infusion of vehicle (1.20 * 0.10 vs 1.23 * 0.09 ml/min/g). This study demonstrated that both intravenous pretreatment with adenosine A1-agonist and also ischemic preconditioning altered the spatial distribution of pre-CAO myocardial blood flow, which might reflect a downregulation of metabolic state and thus play a role in the cardioprotective effects of ischemic preconditioning.
Experiment III
the Effects of Dipyridamole, Nitroglycerin and Nitroprusside on Coronary Blood Flow
Dipyridamole, nitroglycerin and nitroprusside have been shown to be effective vasodilators. However, there are few data comparing their in vivo coronary vasodilatation effects. The purpose of the current study is to compare their vasodilatation effects on the coronary vascular resistance in anesthetized, open-chest rabbits. Fifty-nine male New Zealand white rabbits were anesthetized. A 3 mm suction-type pulsed Doppler velocimeter probe was applied to the proximal part of the left anterior descending coronary artery after median sternotomy. The rabbits received infusion of different doses of dipyridamole, nitroglycerin or nitroprusside. The percentage change of coronary blood flow velocity and coronary vascular resistance were examined. All three vasodilators increased coronary blood flow velocity significantly and decreased coronary vascular resistance dose-dependently. The dose response curves of dipyridamole, nitroglycerin and nitroprusside were significantly different (P < 0.01). 10 mg/kg of dipyridamole was the most effective in increasing coronary blood flow velocity and reducing coronary vascular resistance in anesthetized, open-chest rabbits.
Experiment IV
the Myocardial Protective Effect of Magnolol
Effect of magnolol, an antioxidant, on myocardial stunning was investigated by evaluating the recovery of regional myocardial function after 10-minute coronary artery occlusion in anesthetized, open-chest rabbits. There was no significant hemodynamic change after intravenous infusion of magnolol. Systolic wall thickening fraction measured with an epicardial Doppler sensor in animals pretreated with normal saline and vehicle solution remained significantly depressed (60 * 7 % and 77 * 4% of baseline, respectively) 3 hours after coronary artery reperfusion (CAR). Pretreatment with magnolol (10-7 and 10-6 g/kg, intravenous infusion) significantly enhanced the recovery of systolic wall thickening fraction (98 * 1 and 99 * 1 % of baseline, respectively) 60 minutes after CAR. This study demonstrated that intravenous pretreatment with magnolol protected myocardium against stunning.
Experiment V
the Effect of Magnolol on Coronary Blood Flow
Magnolol is an active component purified from Magnolia officinalis. It was reported to protect myocardium against ischemia and reperfusion. The purpose of the current study is to investigate the effect of magnolol on the coronary circulation and to determine whether a change in coronary vascular resistance (RTC) could be the mechanism underlying the myocardial protective effect of magnolol. Male New Zealand white male rabbits were anesthetized with pentobarbital. A 3 mm suction-type pulsed Doppler velocimetry probe was applied to the proximal part of LAD after median sternotomy. Twenty-one rabbits received intravenous injection of vehicle, magnolol of 10-6, 10-5, or 10-4 g/kg. Eighteen rabbits received intravenous injection of nitroglycerin (NTG) of 10-5, 10-4, or 10-3 g/kg. Phasic and mean arterial pressure, heart rate, EKG, phasic and mean coronary blood flow (CBF) velocity were recorded simultaneously. NTG increased CBF velocity and decreased RTC in a dose-dependent manner. Although magnolol didn*t change blood pressure and CBF velocity, it reduced coronary vascular resistance (RTC) in anesthetized, open-chest rabbits at high concentration (10-4 g/kg). However, its effect is modest, compared with that of NTG. Since magnolol protects myocardium at relatively low doses, coronary vasodilatation is unlikely the underlying mechanism for the myocardial protective effects of magnolol.
Conclusions
The current study showed ischemic preconditioning and infusion of the adenosine A1-agonist protected myocardium and reduced the myocardial infarct size after 60-minute coronary artery occlusion. The myocardial protection was associated with alternation of spatial distribution of myocardial blood flow. On the other hand, intravenous pretreatment with magnolol also protected the myocardium and enhanced the recovery of myocardial thickening from myocardial stunning after 10-minunte coronary artery occlusion. However, the infusion of magnolol did not cause significant change of coronary blood flow. The change of coronary vascular resistance induced by infusion of magnolol was modest, either. Therefore, changes of coronary blood flow might be associated with some myocardial protective maneuver. Other manipulations provide myocardial protection by other mechanisms, e.g., anti-oxidant effects, without association with changes of coronary blood flow.
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