• 대한약리학회지
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• 제19권1호
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• pp.15-35
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• 1983

Although it has been well known that ventricular fibrillation is the most important complication during hypothermia, much investigation has failed to show the exact nature of the etiology of ventricular fibrillation. Recently, there has been considerable research on the relationship between sympathetic activity and ventricular fibrillation under hypothermia. Cardiac muscle normally contains a certain amount of norepinephrine and the dramatic effect of this catecholamines on the cardiac muscle is well documented. It is, therefore, conceivable that cardiac catecholamines might exert an influence on the susceptibility of heart muscle to tachycardia, ventricular fibrillation and arrhythmia, under hypothermia. Hypothermia itself is stress enough to increase tonus of sympatheticoadrenal system. The normal heart is supplied by an autonomic innervation and is subjected to action of circulating catecholamines which may be released from the heart. If the reaction of the heart associated with a variable amount of cardiac catecholamines is. permitted to occur in the induction of hypothermia, the action of this agent on the heart has not to be differentiated from the direct effects of cooling. The studies presented in this paper were designed to provide further information about the cardio-physiological effects of reduced body temperature, with special reference to the role of catecholamines in ventricular fibrillation. Healthy cats, weighing about 3 kg, were anesthetized with pentobarbital(30 mg/kg) intraperitoneally. The trachea was intubated and the endotracheal tube was connected to a C.F. Palmer type A.C. respirator. Hypothermia was induced by immersing the cat into a ice water tub and the rate of body temperature lowering was $1^{\circ}C$ per 5 to 8 min. Esophageal temperature and ECG (Lead II) were simultaneously monitored. In some cases the blood pH and serum sodium and potassium were estimated before the experiment. After the experiment the animals were killed and the hearts were excised. The catecholamines content of the cardiac muscle was measured by the method of Shore and Olin (1958). The results obtained are summarized as follows. 1) In control animal the heart rate was slowed as the temperature fell and the average pulse rates of eight animals were read 94/min at $31^{\circ}C$, 70/min at $27^{\circ}C$ and 43/min at $23^{\circ}C$ if esophageal temperature. Ventricular fibrillation was occurred with no exception at a mean temperature of $20.3^{\circ}C(21-l9^{\circ}C)$. The electrocardiogram revealed abnormal P waves in each progressive cooling of the heart. there was, ultimately, a marked delay in the P-R interval, QRS complex and Q-T interval. Inversion of the T waves was characteristic of all animals. The catecholamines content of the heart muscle excised immediately after the occurrence of ventricular fibrillation was about thirty percent lower than that of the pre-hypothermic heart, that is, $1.0\;{\mu}g/g$ wet weight compared to the prehypothermic value of $1.41\;{\mu}g/g$ wet weight. The changes of blood pH, serum sodium and potassium concentration were not remarkable. 2) By the adrenergic receptor blocking agent, DCI(2-3 mg/kg), given intramuscularly thirty minutes before hypothermia, ventricular fibrillation did not occur in one of five animals when their body temperature was reduced even to $16^{\circ}C$. These animals succumbed at that low temperature, and the changes of heart rate and loss of myocardial catecholamines after hypothermia were similar to those of normal animals. The actual effect of DCI preventing the ventricular fibrillation is not predictable. 3) Administration of reserpine(1 mg/kg, i.m.) 24 hours Prior to hypothermia disclosed reduced incidence of ventricular fibrillation, that is, six of the nine animals went into fibrillation at an average temperature of $19.6^{\circ}C$. By reserpine myocardial catecholamines content dropped to $0.045\;{\mu}g/g$ wet weight. 4) Bretylium pretreatment(20 mg/kg, i.m.), which blocks the release of catecholamines, Prevented the ventricular fibrillation under hypothermia in four of the eight cats. The pulse rate, however, was approximately the same as control and in some cases was rather slower. 5) Six cats treated with norepinephrine(2 mg/kg, i.m.) or DOPA(50 mg/kg) and tranylcypromine(10 mg/kg), which tab teen proved to cause significant increase in the catecholamines content of the heart muscle, showed ventricular fibrillation in all animals under hypothermia at average temperature of $21.6^{\circ}C$ and the pulse rate increased remarkably as compared with that of normal. Catecholamines content of cardiac muscle of these animals markedly decreased after hypothermia but higher than control animals. 6) The functional refractory periods of isolated rabbit atria, determined by the paired stimulus technique, was markedly shortened by administration of epinephrine, norepinephrine and isoproterenol. 7) Adrenergic beta-blocking agents, such as pronethalol, propranolol and sotalol(MJ-1999), inhibited completely the shortening of refractory period induced by norepinephrine. 8) Pretreatment with either phenoxftenbamine or phentolamine, an adrenergic alphatlocking agent, did not modify the decrease in refractory period induced by norepinephrine. From the above experiment it is possible to conclude that catecholamines play an important role in producing ventricular fibrillation under hypothermia. The shortening of the refractorf period of cardiac muscle induced by catecholamines mar be considered as a partial factor in producing ventriculr fibrillaton and to be mediated by beta-adrenergic receptor.

• 대한약리학회지
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• 제19권1호
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• pp.37-60
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• 1983

The uterus receives adrenergic terminals from the mesenteric ganglia and considerably large amount of catecholamines have been shown to be contained in this organ. On the other hand, the activities of epinephrine, norepinephrine or adrenergic nerve on uterine motility is so complicated that many controversial results have been reporter. Recently, a large number of reports concerning the changes of uterine catecholamines content have appeared, but little is known about the role of uterine catecholamines in their activities on uterine motility. The present experiments were undertaken to determine the significance of the intrinsic uterine catecholamines in the physiology of uterus. Female albino rabbits weighing approximately 2 kg were employed in this experiment. uterine strip3 were prepared and suspended in a constant temperature $bath(38^{\circ}C)$ containing 100 ml of Locke's solution aerated with 95% oxygen and 5% carbon dioxide. Spontaneous motility was recorded on a smoked drum with an isotonic lever. The catecholamines concentration of the uterus was determined according to the Procedure described of Shore and Olin (1958). Human uterus obtained from patients was also used to determine the catecholam ines content of myometrium. Followings are summarized results. 1) On the non-pregnant rabbit uterine strips, epinephrine and norepinephrine significantly elevated the tonus and stimulated the spontaneous motility. Pretreatment with dichloroisoproterenol(DCI), an adrenergic beta-receptor blocker, enhanced the stimulatory activity of epinephrine or norepinephrine. On the other hand, pretreatment with dibenamine, an adrenergic alpha-receptor blocker, rendered the uterine muscle to exhibit inhibition after the administration of epinephrine or norepinephrine. Following the treatment with both DCI and dibenamine, epinephrine or norepinephrine produced no appreciable effects on the spontaneous motility of the uterus. These results suggest there exist both alpha and beta-adrenergic receptors in the uterine muscle and the response to epinephrine of the former is predominant over that of latter in the non-pregnant uterus of rabbits. The total catecholamines concentration of the non-pregnant uterus was $351\;m{\mu}g/g$ and the fractional concentrations of epinephrine and norepinephrine were $125\;m{\mu}g/g(35.7%)$ and $226\;m{\mu}g/g$ respectively. It is interesting to note that the catecholamines content of uterus was characterized by a high fractional corcentration of epinephrine relative to norepinephrine. 2) On the pregnant rabbit uterine strips, the effects of epinephrine and norepinephrine varied according to the period of pregnancy. The response to epinephrine of adrenergic beta receptor of uterus increased during pregnancy, and the effect of catecholamine was inhibitory in the early pregnancy but became stimulatory as the pregnancy progressed. This stimulating action on the uterine motility was found to occur through the action of norepinephrine. The uterine catecholamines concentration was markedly reduced during pregnancy. The catecholamines concentration was started to decrease in the early pregnancy, reached the lowest level in the mid-pregnancy and then started to increaae again in the late pregnancy when the total catecholamines content became the highest level of all. This increase of catefholamines in late pregnancy was chiefly due to the increase of norepinephrine. These results suggest that the uterine motility may be related to the catecholamines content, especially norepinephrine content in the uterus. 3) Bilateral oophorectomy of rabbits results in a marked shrink of the uterus in size. The spontaneous motility of the uterine segment of these animals was very weak and irregular. Norepinephrine produced inhibitory effect, whereas epinephrine was stimulatory or inhibitory effect on the uterine segment. The total catecholamines tontent in whole uterus was markedly reduced. The injection of estrogen into the oophorectornized rabbit increased the weight of uterus to approximately three times of that of oophorectornized animal. The apontaneous motility and the response to epinephrine and norepinephrine of the uterine segment were greatly enhanced. Both epinephrine and norepinephrine produced a marked stimulatory effects of the uterine motility. The uterine content of catecholamines, particularly epinephrine, was markedly increased. The injection of progesterone into the oophorectornized rabbit increaeed the weight of uterus to approximately 2.5 times of that of eophorectornized animal. The spontaneous motility of the uterine segment was weak and irregular. Epinephrine produced stimulatory effect at high concentrations but norepinephrine always prcdnced inhibitory effect on the uterine segment. The uterine content of catecholamines, particularly of norepinephrine, was markedly reduced. These results suggested that ovarian hormones play an important role not only on the growth and spontaneous norepinephrine of uterus but also on the catecholamines content and responee to epinephrine and norepinephrine of the uterus. 4) The intraperitoneal injection of reserpine(3 mg/kg) into the non-pregnant, pregnant and oophorectornieed rabbits markedly decreased the uterine content of catecholamines, particularly of the norepinephrine. The stimulatory response to epinephrine and. norepinephrine of the uterine segment of these reserpinized ratbits was markedly reduced whereas the inhibitory response to these catecholamines was enhanced. This finding further support the close relationship between the uterine catecholamines content and uterine response to epineptrire and norepinephrine. 5) In the human uterus, the concentration of epinephrine was actrally greater than that of norepinephrine and it was significantly greater during the proliferative phase of the menstrtal cycle. In the human pregnant uterus, the concentrations of toth epinephrine and ncrefinephrine were markedly reduced and showed about 45 percent rednction after 6-8 weeks of ectopic Pregnancy. At full term ana during labor, the concentrations of epinephrine and norepinephrine at placental sites were less than those found in the non-pregnant group. Of interest was the finding that the norepinephrine concentration of uterus from toxemic patients was two and half times higher than that of lower uterine segment of the nontoxemic pregnant individuals. Also the epinephrine concentraticn was slightly increaeed.