G. Perez

Studies on the Mechanism Underlying the Influence of Alanine Infusion on Glucose Dynamics in the Dog

These experiments have been designed to study the influence of alanine infusion on glucose dynamics in the dog and to further elucidate the role of pancreatic hormones in the interaction of alanine with glucose homeostasis. The primed constant infusion of glucose-2-t was used in order to quanti ta te the rates of glucose production by the liver (Ra) and glucose utilization (Rd). In a first group of experiments, the intravenous infusion of alanine at the rate of 2 mg./kg./min. produced a moderate enhancement of plasma insulin (IRI), while pancreatic glucagon (IRG) increased more consistently. This different pattern of IRI and IRG response caused the insulin/glucagon molar ratio to decline progressively throughout the experiment. Both rates of glucose turnover increased significantly during alanine infusion. Since Ra rose more rapidly than Rd did initially, hyperglycemia developed. Later, glucose production slowly decreased and, in spite of the sustained hyperglucagonemia, reached levels very close to the baseline in the second part of the experiment. A significant direct correlation between Ra and IRG was found, while the changes in Ra correlated inversely with those in I/G molar ratio. In a second group of experiments, alanine was infused at the same dose together with 0.4 /mg./kg./min. of cyclic somatostatin. In the First part of the infusion, IRG fell more than IRI did, so that I/G ratio increased. Later, IRI levels maintained at low values while IRG returned slowly to the baseline and consequently I/G ratio significantly decreased. Glucose production fell rapidly soon after the beginning of the infusion, and therefore hypoglycemia developed. Later, Ra increased progressively to levels above baseline and plasma glucose returned to the preinfusion levels. As in the first group of experiments, a significant direct correlation between Ra and IRG and an inverse correlation between the changes in Ra and I/G ratio were observed. These experiments demonstrate that alanine infusion produces an acceleration of glucose turnover and that a clear interrelationship between the release of glucose by the liver and the mobilization of pancreatic hormones exists. Finally, the experiments with somatostatin indicate that hyperglucagonemia is one of the mechanisms underlying the stimulatory effect of alanine on glucose production.

Effects of Theophylline on Glucose Kinetics in Normal and Sympathectomized Rats

The influence of intraperitoneal administration of aminophylline on the rate of hepatic glucose production and peripheral uptake (Ra and Rd) was studied in normal and in adrenodemedullated and reserpinized rats by using the primed constant infusion of Glucose-2-3H. In normal rats, the dose of 100 mg. per kilogram of aminophylline produced a marked increase of Ra and Rd. Since Ra rose more rapidly than Rd did initially, hyperglycemia developed. Thereafter, glucose production and uptake increased to nearly the same extent, and a new steady state was reached at plasma glucose levels almost twice those of the baseline. Smaller and transient modifications were observed after the administration of 20 mg. per kilogram of aminophylline. With the higher dose, insulin levels markedly rose (reaching a tenfold peak above the basal value) while minor increments were observed with the lower dose. In a group of normal rats which were given glucose (10 mg. per kilogram per minute) in order to achieve a degree of hyperglycemia comparable to that brought about by the higher dose of aminophylline an almost identical enhancement of glucose uptake was recorded. However, insulin levels were much higher in aminophylline-treated rats as compared to normal rats. From these findings it was concluded that aminophylline induces resistance to insulin effect. When aminophylline was injected into demedullated rats pretreated with reserpine, at the dose of 100 mg. per kilogram, a marked enhancement of Ra, and consequently of glycemia, was recorded initially; later, severe hypoglycemia developed depending on both a progressive exhaustion of hepatic glucose production and a marked increase of glucose utilization. Insulin levels dramatically increased in these experiments. These results suggest that aminophylline directly increases glucose production by the liver and insulin secretion. The simultaneous activation of the sympathetic system blunts the insulin response and counteracts the restraining effect of insulin on the liver and the stimulatory effect of insulin on overall glucose uptake as well.

Studies on the Nature of the Vasodilator Fibers Running in the Lumbar Sympathetic Chain of the Dog

These experiments were performed to further elucidate the nature of the vasodilator fibers running in the sympathetic chain in the dog. The electrostimulation of the lumbar sympathetic trunk caused vasoconstriction in the perfused hind limb which inverted to vasodilatation after guanethidine was administered. This vasodilator response is mediated by cholinergic fibers since it was completely abolished by atropine. The observation, furthermore, that hexamethonium completely nullified both vasodilator and vasoconstrictor responses to the electrostimulation of the sympathetic chain indicates that both vasoconstrictor and vasodilator fibers, which are activated during the stimulation of the sympathetic chain, are preganglionic in nature.

Studies on the hemodynamic changes in the perfused hindlimb induced by the electrostimulation of the sinus nerve in the dog

Abstract The effects of intravenous administration of guanethidine and guanethidine plus atropine on the reflex vasodilatation induced in the perfused hindlimb by the electrostimulation of the sinus nerve were studied in dogs. Guanethidine induced a marked decrease in the reflex response of the perfused hindlimb. Moreover, the following administration of atropine completely abolished the hemodynamic response to the sinus nerve stimulation. These findings suggest that the cholinergic system is involved, along with the sympathetic and the histaminegic system, in the genesis of the reflex vasodilatation produced by the electrostimulation of the sinus nerve.

Studies on the Hemodynamic Changes Induced by Electrical Stimulation of the Vagosympathetic Trunks in the Dog

The effects of electrostimulation of the cephalic endings of the vago-sympathetic trunks on the systemic and perfusion pressure of the hind limb of the dog depend upon frequency, intensity and duration of the stimulus. The electrostimulation performed with stimuli of high frequency, low intensity and moderately long duration (rectangular waves of 1.5 V, 0.7 msec, 100 Hz) consistently elicited systemic hypertension and vasoconstriction. This response was completely abolished by pretreatment with guanethidine or hexamethonium. On the other hand, electrostimulation with stimuli of low frequency, high intensity and long duration (5 V, 1 msec, 10 Hz) produced systemic hypotension and vasodilatation in the perfused hind limb. These effects were completely blocked by atropine or hexamethonium, while guanethidine was unable to induce any modification. These findings suggest that electrostimulation of vagosympathetic trunks can evoke different hemodynamic responses depending upon the characteristics of the stimulus. The occurrence of a vasodilatation specifically blocked by atropine demonstrates that a purely cholinergic mechanism underlies such a reflex response.

Some peculiarities of the glucoregulatory response to glucose infusion in the rat.

SummaryThe glucoregulatory response to the i.v. infusion of different doses of glucose and glucose plus insulin was studied in anesthetized rats by using the primed constant infusion of glucose-2-3H. Infusion of glucose at the rate of 10 mg/kg/min induced a rise of about 100% in blood glucose, while the hepatic release of glucose showed only a small and transient decrease. A proportional increase of glycemia and glucose utilization (Rd) was observed without any appreciable change in the metabolic clearance rate (MCR) of glucose; a two-fold increase in plasma insulin was recorded at all times. In the group of rats receiving 20 mg/kg/min of glucose, changes in the above parameters were slightly greater; MCR showed a moderate increment in spite of the six-fold rise of plasma insulin. Finally, the infusion of large doses of insulin together with 20 mg/kg/min of glucose resulted in complete cessation of glucose release by the liver and in a remarkable increase of Rd and MCR. These results suggest a poor adaptability of the glucoregulatory system of the rat in response to glucose infusion as compared to other mammalian species.

Effects of Hypotensive Doses of Prostaglandin A1 on Plasma Glucose, Free Fatty Acids and Insulin in Reserpinized Dogs

Intravenous infusion of prostaglandin A1 at hypotensive dosage into reserpinized dogs increased plasma glucose and FFA levels and lowered the rate of glucose disappearance following glucose