Cyclic AMP Response to Epinephrine and Shock A.

Hope McArdle, PhD; Chu-Jeng Chiu, MD; E. John Hinchey, MD

Hormonal regulation is fundamental to homeostasis, and the reponse in tissues is mediated by adenosine 3\m='\:5\m='\ = cyclic phosphate (cyclic AMP). Since circulating levels of catecholamines are elevated during hemorrhagic shock, experiments were carried out to study the effects of epinephrine and of shock on cyclic AMP levels of plasma and of the intestine, a particularly vulnerable organ in canine hemorrhagic shock. Epinephrine was given to normotensive dogs as a constant infusion (group 1) or as a single pulse (group 2). Sequential blood samples showed a marked increase in circulating cyclic AMP, especially in portal and hepatic venous blood. Little change was noted in the tissues. Hemorrhagic shock (group 3) induced a marked increase in plasma cyclic AMP, with a depletion of mucosal cyclic AMP and adenosine triphosphate (ATP). Pretreatment before shock with \g=a\ x=req-\ blockade (group 4) abolished the decrease in mucosal cyclic AMP and ATP, and reduced the increase in plasma cyclic AMP.

AMP.4 The second messenger system of the intestinal mucosal epithelium has been studied, particularly in rela¬ tion to cholera toxin, and the level of cellular cyclic AMP has been related to the absorption-secretion pattern of the mucosal epithelial cells.7' The circulating level of catecholamines increases markedly during prolonged shock, and the excessive vaso¬ constriction of the mesenteric bed due to sympathetic hyperactivity decreases blood flow, producing ischemie dam¬ age to the intestinal mucosal cells." Since the response of the cell to catecholamines is mediated through formation of the second messenger, cyclic AMP, the present series of experiments was designed to study the changes in cyclic AMP in the canine intestine in response to both epineph¬ rine and to hemorrhagic shock. MATERIALS AND METHODS

circulating plasma adenosine 3':5' cyclic phosphate (cyclic AMP) appears to be the normal re¬ sponse to catecholamines, whether infused exogenously or as the initial endogenous response to hypovolemia. If in¬ testinal ischemia is prolonged, the tissue becomes inca¬ pable of further response to these hormones and levels of cyclic AMP drop precipitously, perhaps because of the con¬ comitant depression of its substrate, adenosine triphosphate (ATP). Support for this suggestion is seen with -blockade, where improved blood flow to the intestine during hypovolemia permits target organ response. The morphologic and metabolic alterations of the canine



intestine that result from a reduction in blood flow are well documented. The susceptibility of this organ to hy¬ povolemia and ischemia is a major contributing factor to irreversibility in shock, as shown by the work of Lillehei,1 Bounous et al,2 and others, who have demonstrated that protection of the intestine during shock markedly im¬ proves survival. Hormones and the autonomie nervous system provide the homeostatic mechanisms that maintain the "milieu in¬ térieur" described by Claude Bernard3 in a living orga¬ nism. It is now clear that at the cellular level much of the hormonal and neural influence is transmitted intracellularly by the second messenger to the hormones, cyclic Accepted

for From McGill

publication Oct 1, 1974. University Surgical Clinic, Montreal General Hospital. Reprint requests to University Surgical Clinic, Montreal General Hospital, Montreal, Canada H3G 1A4 (Dr. McArdle).

Mongrel dogs of either sex, weighing from 14 to 18 kg, were anesthetized with 30 mg/kg intravenously administered pentobarbital sodium. The animals were allowed to lie on the operating table for two hours before the experimental procedures began, in order to offset the effects of the induction of anesthesia. The dogs were divided into four groups.



Four dogs received epinephrine at a constant infusion rate of 0.03 mg/min for three hours. Before infusion, a cannula was placed in the femoral artery for the removal of blood samples for cyclic AMP determination. A laparotomy was also performed, and a sample of intestine was removed as a control. During the infu¬ sion period, blood samples and intestinal biopsy samples were taken at 30-minute intervals for three hours.

Group 2 Four dogs received a single pulse injection of 1.0 mg epineph¬ rine intravenously. Before injection, sampling cannulas were placed in the femoral artery, femoral vein, and portal vein. Blood

samples were obtained before injection and at one, three, five, ten, and 15 minutes following epinephrine injection. Samples were also taken by direct puncture of the hepatic vein at the same time in¬ tervals.

Group 3 A laparotomy was carried out on five dogs, and samples of small intestine, liver, and arterial blood were taken as controls. The ani¬ mals were then bled using a modified Wiggers procedure to a mean arterial blood pressure of 35 mm Hg that was maintained for three hours. Samples of blood and of intestine were removed

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Cyclic AMP response to epinephrine and shock.

Cyclic AMP Response to Epinephrine and Shock A. Hope McArdle, PhD; Chu-Jeng Chiu, MD; E. John Hinchey, MD Hormonal regulation is fundamental to home...
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