动物造模 z-bo 2020-09-08 470

　　Introduction: We perform pharmacological characterization of this animal under halothane anesthesia as an in vivo experimental model for safety pharmacology research. The degree of cardiovascular response induced by drugs is usually greater in minipigs than dogs. Due to its unique pharmacokinetic curve, including the smaller effective volume of the drug and lower body fat content, the greater the basal sympathetic tone, the greater the reflex. The greater the mediated increase, the smaller the repolarization reserve. We encountered some minor cases of reversible ST-segment elevation/depression, which occasionally caused fatal arrhythmia episodes during the study. Since these phenomena are not observed under the same anesthesia conditions, the coronary artery regulation of miniature pigs and Beagle dogs may be different. The application of dipyridamole stress test in the diagnosis of coronary heart disease. The infusion of dipyridamole inhibits intracellular adenosine reuptake, thereby increasing the plasma concentration of adenosine. Adenosine then expands the coronary arteries of the healthy heart muscle and increases blood flow. But conversely, blood flowing into the diseased coronary artery will be "stolen", causing ischemia of the damaged myocardium. Dipyridamole stress test does not affect ST-segment changes in healthy people, but it has a certain effect on ST-segment elevation or depression in patients with coronary artery disease. In this study, on the basis of ECG monitoring, the dipyridamole stress test was used to compare and analyze the coronary circulation between healthy miniature pigs and dogs.

　　The effect of dipyridamole on the cardiovascular function of dogs: The experiment used 2 male and 2 female beagle dogs, weighing 10.7±0.6 kg. The dogs were initially anesthetized with thiopental sodium (30 mg/kg, IV). After the tracheal tube is intubated, inhale 1% halothane with 100% oxygen through a respirator. The tidal volume and breathing rate were set at 20 mL/kg and 15 breaths/min. Two clinically usable catheter sheaths, one was placed in the right femoral artery and the other was placed in the right femoral vein. To prevent blood clotting, heparin calcium (100 IU/kg) is placed in the venous sheath of the right femoral vein through a catheter. Measure blood pressure on the flush line of the right femoral artery catheter sheath. The double product is calculated with the following equation: double product = systolic blood pressure x heart rate, reflecting the myocardial oxygen consumption rate. The ratio of the double product to the diastolic blood pressure is also calculated to estimate the balance between the heart's oxygen supply and demand (demand/supply ratio = double product/diastolic blood pressure). Continuously monitor ECG leads I, II, and III. Lead II is used for ECG analysis. Calculate the QT interval (QTc) with the Van de Water formula: QTC=QT-0.087×(RR-1000), where the unit of the RR interval is ms. The ST segment depression is measured 80 milliseconds after the J point and the bottom of the T wave .

　　The effect of dipyridamole on the cardiovascular function of miniature pigs: The experiment used 4 male miniature pigs, weighing 9.2±0.3 kg. Pre-anaesthesia with ketamine (16 mg/kg, I.M) and xylazine (1.6 mg/kg, I.M). A 24G cannula was inserted into the superficial auricular vein and anesthetized with 1 mg/kg propofol injection. After the tracheal tube is intubated, inhale 1% halothane with 100% oxygen through a respirator. The tidal volume and respiratory rate were set at 10 mL/kg and 15 breaths/min. Two sets of catheter sheaths are used; one is placed in the right or left femoral artery and the other is placed in the right or left femoral vein. To prevent blood clotting, heparin calcium (100 IU/kg) is administered intravenously through the flush line of the catheter sheath placed in the femoral vein. Analyze cardiovascular variables in the same way as dogs.

　　Monitor heart rate, blood pressure and electrocardiogram, and use real-time automatic data analysis system for analysis. Each ECG measurement is based on the average of three complexes recorded continuously. Since the preliminary experiment in halothane anesthetized dogs (2), dipyridamole significantly inhibited the ST segment when the infusion of 0.56 mg/kg exceeded 10 min. The doses of 0.056 and 0.56 mg/kg were selected for this study. After the basic evaluation, dipyridamole was infused intravenously for 10 minutes at a dose of 0.056 mg/kg. Each variable of the Beagle dog was recorded 10, 20, and 30 minutes after the administration. Each variable of the minipig was recorded at 5, 10, 15, 20 and 30 minutes after administration. Dipyridamole was infused intravenously over 10 minutes at a dose of 0.56 mg/kg. Each variable of the Beagle dog was recorded 10, 20, and 30 minutes after the administration. Each variable of the minipig was recorded at 5, 10, 15, 20, 30, 45 and 60 minutes after administration. After completing the assessment of the cardiovascular effects of dipyridamole, their hearts were removed to macroscopically examine the morphology of the coronary arteries.

　　Results: During the experiment, no cardiodynamic collapse or fatal ventricular arrhythmia was observed in dogs or mini-pigs. No coronary stenosis was detected in the left anterior descending coronary artery, left coronary artery or right coronary artery. It is worth noting that Beagle dogs have more and larger epicardial coronary arteries and collateral networks than miniature pigs.

　　The effect of heart rate, blood pressure, double product and supply-demand ratio on heart rate and blood pressure: the time course of the changes in dog and miniature pig heart rate, systolic blood pressure, diastolic blood pressure, double product and supply-demand ratio is shown in the figure. The pre-drug control values (C) for Beagle dogs were 119±3 times/min, 139±12/99±9 mmHg, 16592±1552 mmHg·times/min, 169±9. The mini-pigs were 87±5 times/min, 84±6 and 58±6 mmHg, 7255±677 mmHg·times/min and 126±9. The pre-drug control values of Beagle dogs and miniature pigs are within the range of our previous studies, and each value of miniature pigs is smaller than that of dogs. Canine dipyridamole low-dose 0.056 mg/kg infusion did not change any of these variables. The high dose of 0.56 mg/kg can reduce systolic blood pressure for 10-20 minutes, diastolic blood pressure for 10-30 minutes, and double product for 10-20 minutes. No significant changes were found in the heart rate or the demand/supply ratio. On the other hand, in miniature pigs, low and high doses reduced systolic blood pressure and diastolic blood pressure, respectively, with double products of 5-30 minutes and 5-60 minutes, respectively, while no significant changes were observed in heart rate or demand/supply rate. The double product of the maximum change in systolic/diastolic blood pressure (percentage) and the pre-drug control value was observed in the two animals within 10 minutes after the high dose. Dogs were -12 to -16 mmHg (-8/-16%) ) And -1867 mmHg·sub-minute (-11%), -25～-20 mmHg. Miniature pigs are -25～-20 mmHg (-31/-34%) and -2903 mmHg·sub-minute (-40%).

　　The influence of ECG variables: The PR interval, QRS width, QT interval and QTc time course of Beagle dogs and miniature pigs were summarized. The pre-drug control values (C) for dogs were 97±6, 66±8, 271±11, and 314±10 ms, while the drug control values for miniature pigs were 114±3, 92±3, 374±7 and 400, respectively ±8 ms. The pre-drug control values of Beagle dogs and mini-pigs are within the range of our previous studies. Miniature pigs are longer than Beagle dogs, but no significant difference in PR interval was found. The low dose prolonged dog QTC by 10-20 minutes, while other variables did not change significantly. The high dose prolonged the QT interval and QTc by 10-30 minutes, while other variables did not change significantly. In miniature pigs, the PR interval was extended by 20-30 minutes and 5-60 minutes at low dose and high dose, respectively, and no significant changes were found in other variables.

　　Effect of ST segment: In dogs, 2 of the 4 bars show the downhill form of the ST segment, while the other two show up or horizontal on the basic control. The low dose hardly changes the ST-segment level, while the high dose reduces it significantly for 10-30 minutes. At the same time, in minipigs, 3 out of 4 showed the horizontal morphology of ST segment. The other tilts downward. Low or high doses did not significantly change ST-segment levels. No ST segment depression was observed in other limb leads of minipigs.

　　Conclusion: The dipyridamole stress test showed that in minipigs, the ST segment was not depressed, suggesting that dipyridamole has a good resilience and similarity to the anatomical structure and function of the coronary artery. At the same time, dipyridamole inhibits the ST segment of normal dogs, which is different from miniature pigs. It suggests that the well-developed canine coronary collateral circulation may play a role in the pathogenesis of myocardial ischemia.