Contribution of de novo synthesis of acetylcholinesterase to spontaneous recovery of neuromuscular transmission following soman intoxication.

The role of the de novo synthesis of acetylcholinesterase in the spontaneous recovery of neuromuscular transmission was studied in diaphragms isolated from soman-intoxicated rats. Ten minutes after soman (3 X LD50 i.v.), the acetylcholinesterase activity and the neuromuscular transmission appeared to be completely blocked. Acetylcholinesterase activity in endplate and endplate-free regions recovered linearly during a 3 h experiment (1.5 and 2.9%h, respectively); and neuromuscular transmission was also improved. Since both inhibition of the de novo synthesis of acetylcholinesterase by cycloheximide and the re-inhibition of acetylcholinesterase in vitro by soman did not affect the improvement of neuromuscular transmission, it was concluded that this recovery of neuromuscular transmission can not be attributed to synthesis of new acetylcholinesterase.

A method for hemorrhagic shock in the rat.

Normovolemic hemorrhagic shock was induced in unanesthetized as well as anesthetized rats. The animals were bled according to predetermined schedules followed by reinfusion of all shed blood. In these models mortality during the hypovolemic phase was avoided, while practically 100% mortality ensued a number of hours after the reinfusion. To this end, a certain individualization of the bleeding procedure was necessary. The pathology induced was very similar in the two models. The survival time as well as the course of the plasma-glucose concentration (a tendency to a high degree of hypoglycemia) and the plasma-K+ concentration (extreme hyperkalemia) were also very similar. The causes of the hypoglycemia and hyperkalemia are not elucidated.

Effect of naloxone on blood pressure and survival in different shock models in rats.

The effect of naloxone on a number of experimental shock models, using the anaesthetized rat, was studied with special emphasis on mean arterial blood pressure (MABP) and chance of survival. Only a slight increase in MABP was noted in haemorrhagic shock models whereas survival was not affected. Naloxone was without effect in endotoxin shock (i.p. administration of endotoxin). In endotoxin shock (i.v. administration) naloxone increased MABP especially at a high dose of endotoxin. Although survival time was prolonged, the chance of permanent survival was not improved. Naloxone had practically no effect in anaphylactic shock and intestinal ischaemia shock. It is concluded that if naloxone has any effect it is relatively slight. However, this does not exclude the possibility that naloxone might still be considered as an adjunct to other forms of shock treatment at least in certain types of shock.

Studies on hyperkalemia as a cause of death in intestinal ischemia shock in rats.

Intestinal ischemia shock was induced either by temporary occlusion of the three splanchnic arteries for 40 min (SAO-shock) or by temporary occlusion of the portal vein for 35-40 min (PVO-shock). In both types of shock, life can be considerably prolonged (5-8-fold) by treatment with rat plasma plus glucose. Eventually, death is caused by heart failure due to hyperkalemia (plasma K+ concentration greater than 10 mmol/l). The amount of K+ causing this hyperkalemia is estimated at roughly 10% of the total body K+. Acidosis, low blood pressure, reduced kidney function, and disintegration of erythrocytes in the gastrointestinal (GI) tract probably are of no or minor importance in causing this extreme hyperkalemia. No indication was found that the liver, the skeletal muscles, or the erythrocytes release K+. Although the K+ concentration of the contents of the GI tract as well as the K+ transport by the portal vein were increased, the source of the excess K+ remains obscure. Removal of the contents of the stomach and small intestine, followed by flushing of the gastrointestinal tract, may have a favorable effect on the course of plasma K+ (and plasma glucose) concentration, indicating that toxic products from the damaged intestines may be important lethal factors.

Studies on the site of the block in gluconeogenesis causing severe hypoglycemia in intestinal ischemia shock in rats.

Intestinal ischemia shock was induced by 35 to 40-min portal vein occlusion (PVO). After treatment with rat plasma a severe hypoglycemia ensues which is caused by a block in gluconeogenesis. This hypoglycemia is not affected by treatment with adrenaline, glucagon, nicotinadenine dinucleotide (NAD), adenosine triphosphate (ATP) alanine (A), or pyruvate (P), while fructose (F) and dihydroxyacetone (DHA) slightly increase the plasma glucose concentration. If F or DHA are combined with NAD a considerable hyperglycemic effect is observed, but NAD plus A or P is ineffective. A similar marked rise in plasma glucose is observed if F is combined with nicotinamide, adenylic acid, or histamine. NAD causes vasodilatation in the splanchnic area and an increased portal flow. It is concluded that the effect of NAD is the result of an increased uptake of suitable substrates of gluconeogenesis from the peritoneal cavity and/or an increased availability of these substrates to the liver. During the development of PVO shock, portal venous flow diminishes considerably. This reduced flow may be the result of vasoconstriction caused by the high level of plasma adrenaline.

The effect of dopamine on the occurrence of kidney lesions caused by hypotension in rats.

Dopamine at dose rates varying from 80 micrograms/kg/min to 0.3 micrograms/kg/min was infused i.v. in rats anesthetized with ketamine, during a period of 60 min while the rats were bled into a reservoir against a pressure of 50 mm Hg. The bleeding was followed by reinfusion of the blood remaining in the reservoir at 60 min. At a dose rate of 80 micrograms/kg/min 5/9 animals died during the bleeding and the remaining 4 died within 24 hr. In all 9 animals the time at which the bleeding volume reached its maximum (tMBV in.) was shortened considerably and spontaneous uptake of shed blood started earlier than in the controls. At 20 micrograms/kg/min 24 hr mortality was 63% and tMBV in. was shortened. At 5 micrograms/kg/min and lower 24 hr mortality was negligible, but at 5 micrograms/kg/min tMBV in. was still shortened. At all doses used the maximum bleeding volume was essentially the same. At 20 micrograms/kg/min and lower no significant effect on the severity of kidney lesions was observed. The absence of a favourable effect of dopamine may largely be explained by the high sympathetic tone present during the period of hypotension.

The effect of ATP on survival in intestinal ischemia shock, hemorrhagic shock, and endotoxin shock in rats.

Mg-ATP 72 mumole/kg was injected into anesthetized rats subjected to intestinal ischemia shock (SAO), hemorrhagic shock (HS), and endotoxin shock (ES), shock models in which all untreated animals died. Administration of Mg-ATP in no instance improved survival rate. In SAO, Mg-ATP given intra-arterially (IA) or intraperitoneally (IP) before the period of ischemia significantly reduced the survival time, and when given IA after the period of ischemia caused no significant change in survival time. In HS survival time was not significantly altered if Mg-ATP was given IA before or after the period of hypotension, but if given IP before bleeding survival time was significantly prolonged. Marked hemodynamic effects of Mg-ATP were observed resulting in reduction of the maximum bleeding volume and in an earlier spontaneous reuptake of the shed blood. In ES survival time was not affected if the Mg-ATP was given before the endotoxin, but survival time was significantly decreased if Mg-ATP was given before as well as after the endotoxin. It is concluded that any beneficial effect of ATP is probably small, whereas the occurrence of adverse effects cannot be neglected.

Disturbances in the glucose metabolism in intestinal ischemia shock.

Intestinal ischemia shock is obtained in fasted rats by 40-minute splanchnic arterial occlusion (SAO) or by 35-minute portal vein occlusion (PVO). Survival is prolonged by plasma treatment; further prolongation is obtained by additional administration of glucose. After SAO early hyperglycemia is marked. Plasma adrenaline rises steeply after opening of the arteries and remains high, while plasma insulin remains unaltered. The hyperglycemia is abolished by adrenalectomy and section of the major splanchnic nerves (MSN) proximal to the adrenals but not by section of the MSN distal from the adrenals or by vagotomy. It is concluded that the sympathetic nervous system is stimulated by a substance, possibly related to VIP, released from the intestines. After PVO hyperglycemia is less marked. Plasma adrenaline as well as insulin are increased. During late and fatal hypoglycemia after PVO plus plasma treatment, the liver still appears to be functionally intact. It is assumed that gluconeogenesis is reversibly inhibited by as yet unknown factors. The hypoglycemia cannot be abolished by injection of common substrates of gluconeogenesis but the combination fructose plus glucagon plus NAD is highly effective.

The possible role of catecholamines in the protective effect of general anesthetics against kidney lesions in rats subjected to hemorrhagic hypotension.

Dibenamine, 15 mg/kg, injected i.p. in rats anesthetized with ketamine, 60 min before bleeding for 60 min against 40 mm Hg, significantly reduced the severity of kidney lesions. The maximum bleeding volume was reduced by 14%. Adrenalectomy also reduced the bleeding volume but all animals died within 24 hr. In unanesthetized rats bled against 40 mm Hg, plasma adrenaline and nor-adrenaline rose approximately tenfold as compared with unbled animals. Comparable marked increases in plasma adrenaline and somewhat smaller increases in plasma nor-adrenaline were observed after bleeding rats anesthetized with ketamine and ethylurethane, anesthetics which protect only slightly against the occurrence of kidney lesions. The rise in plasma adrenaline and nor-adrenaline was significantly lower after bleeding rats anesthetized with the highly protective anesthetics Na-pentobarbital, halothane and methoxyflurane. If, however, rats anesthetized with Na-pentobartical were bled for 40 min against 25 mm Hg, a situation in which the occurrence of kidney lesions is not prevented, the plasma concentration of both catecholamines was as high as in unanesthetized rats bled against 40 mm Hg. It is concluded that vasoconstriction due to the release of catecholamines is an important factor in the generation of kidney lesions during hypotension in rats and that the protective effect of a number of general anesthetics largely depends on their ability to suppress the release of catecholamines.

Effect of pentobarbital and urethane on the oxygen tension in the kidney of hypotensive rats.

The effect of bleeding against a predetermined pressure on the relative oxygen tension in the kidney was studied in rats anesthetized with either pentobarbital-Na or ethylurethane. In rats bled either for 30 min against 40 mm Hg or for 60 min against 50 mm Hg, the fall in the relative oxygen tension was significantly less during anesthesia with pentobarbital-Na, a highly potent protector against the occurrence of kidney lesions, than during anesthesia with ethylurethane, which possesses only slight protective potency. When rats anesthetized with ethylurethane were allowed to breathe oxygen the relative oxygen tension in the kidney was increased only for 15 to 20 min and accordingly the severity of the kidney lesions was decreased only when the animals were bled for 30 min at 40 mm Hg. When a number of different bleeding schedules were applied, a correlation was found between the average relative oxygen tension during bleeding and the incidence and degree of kidney lesions observed, irrespective of either the bleeding schedule or the anesthetic used. It is concluded that hypoxia may be a major factor in determining the occurrence of kidney lesions after bleeding and that the protective effect of anesthetics depends on their ability to diminish the fall in oxygen tension in the kidney during bleeding.