Metabolic Effects Of Catecholamines Research Articles

Glucose metabolism and catecholamines

Until now, catecholamines were the drugs of choice to treat hypotension during shock states. Catecholamines, however, also have marked metabolic effects, particularly on glucose metabolism, and the degree of this metabolic response is directly related to the beta2-adrenoceptor activity of the individual compound used. Under physiologic conditions, infusing catecholamine is associated with enhanced rates of aerobic glycolysis (resulting in adenosine triphosphate production), glucose release (both from glycogenolysis and gluconeogenesis), and inhibition of insulin-mediated glycogenesis. Consequently, hyperglycemia and hyperlactatemia are the hallmarks of this metabolic response. Under pathophysiologic conditions, the metabolic effects of catecholamines are less predictable because of changes in receptor affinity and density and in drug kinetics and the metabolic capacity of the major gluconeogenic organs, both resulting from the disease per se and the ongoing treatment. It is also well-established that shock states are characterized by a hypermetabolic condition with insulin resistance and increased oxygen demands, which coincide with both compromised tissue microcirculatory perfusion and mitochondrial dysfunction. This, in turn, causes impaired glucose utilization and may lead to inadequate glucose supply and, ultimately, metabolic failure. Based on the landmark studies on intensive insulin use, a crucial role is currently attributed to glucose homeostasis. This article reviews the effects of the various catecholamines on glucose utilization, both under physiologic conditions, as well as during shock states. Because, to date (to our knowledge), no patient data are available, results from relevant animal experiments are discussed. In addition, potential strategies are outlined to influence the catecholamine-induced effects on glucose homeostasis.

Phosphoribosyl-pyrophosphate binding to aspartate transcarbamylase of pseudomonas aeruginosa

In this chapter various components of cardiac adenine nucleotide metabolism have been analyzed and then integrated into the discussion of two clinically relevant pathophysiological conditions, ischemia and catecholamine actions. The most common form of cell injury in the heart is ischemia. The most likely causes for injury, such as depletion of adenine nucleotides, accumulation of glycolytic products, calcium overload, and oxygen free radicals have been described. These distinct mechanisms have been used to characterize and possibly explain three newly recognized features of myocardial ischemia: stunning, ischemic preconditioning, and hibernation.Apart from the well-known functional and metabolic effects of catecholamines, in particular of norepinephrine, on the heart, several new molecular biological findings have been observed such as the increased expression of proto-oncogenes. Another new aspect is the stimulation of the oxidative pentose phosphate pathway. Both the mRNA and activity of G-6-PD, the rate-limiting enzyme of this pathway, are enhanced by norepinephrine in the entire rat heart and in isolated cardiac myocytes. Stimulation of this pathway leads to more reducing equivalents in the form of NADPH and to more ribose-5-phosphate which is the immediate precursor of PRPP. This is important for both the de novo purine synthesis and the salvage pathways. A new homeostatic mechanism has been formulated in that catecholamines reduce the possible metabolic damage they inflict on the heart by action on the oxidative pentose phosphate pathway.On the basis of adenine nucleotide metabolism, several therapeutic interventions have been developed and partially applied in patients. Among these, adenosine, inosine, and ribose have been described in more detail. Adenosine and inosine have pronounced hemodynamic effects which may not be desired in some patients. In contrast, ribose is entirely neutral in functional terms and can be combined with conventional cardiac therapy without interfering with it. It may therefore be an appropriate adjunct in treating cardiac diseases.

Induction of in vivo resistance against gemcitabine (GEM, 2′,2′-difluorodeoxy-cytidine)

In this chapter various components of cardiac adenine nucleotide metabolism have been analyzed and then integrated into the discussion of two clinically relevant pathophysiological conditions, ischemia and catecholamine actions. The most common form of cell injury in the heart is ischemia. The most likely causes for injury, such as depletion of adenine nucleotides, accumulation of glycolytic products, calcium overload, and oxygen free radicals have been described. These distinct mechanisms have been used to characterize and possibly explain three newly recognized features of myocardial ischemia: stunning, ischemic preconditioning, and hibernation.Apart from the well-known functional and metabolic effects of catecholamines, in particular of norepinephrine, on the heart, several new molecular biological findings have been observed such as the increased expression of proto-oncogenes. Another new aspect is the stimulation of the oxidative pentose phosphate pathway. Both the mRNA and activity of G-6-PD, the rate-limiting enzyme of this pathway, are enhanced by norepinephrine in the entire rat heart and in isolated cardiac myocytes. Stimulation of this pathway leads to more reducing equivalents in the form of NADPH and to more ribose-5-phosphate which is the immediate precursor of PRPP. This is important for both the de novo purine synthesis and the salvage pathways. A new homeostatic mechanism has been formulated in that catecholamines reduce the possible metabolic damage they inflict on the heart by action on the oxidative pentose phosphate pathway.On the basis of adenine nucleotide metabolism, several therapeutic interventions have been developed and partially applied in patients. Among these, adenosine, inosine, and ribose have been described in more detail. Adenosine and inosine have pronounced hemodynamic effects which may not be desired in some patients. In contrast, ribose is entirely neutral in functional terms and can be combined with conventional cardiac therapy without interfering with it. It may therefore be an appropriate adjunct in treating cardiac diseases.

Effects of verapamil on metabolism and function of hearts from normaland hyperthyroid rats

That thyroid hormones sensitize the heart and other organs to the metabolic effects of catecholamines is generally accepted. A possible important factor in mediating this hypersensitivety is the intracellular concentration of calcium ions. Hartley and McNeill (1) studied the effect of calcium on cardiac metabolism and myocardial contraction in isolated, perfused hearts from hyperthyroid rats a decade ago. They reported that pretreatment of rats with triiodothyronine did not enhance the elevation in cardiac phosphorylase a activity produced by progressively increasing doses of calcium ions in the fluid perfusing the isolated rat hearts.

Acute increase of noradrenaline on vascular resistance in the corpus luteum of the pseudopregnant rat.

Noradrenaline infusion for 2 min (0.4 microgram/min) in anaesthetized rats increased the vascular resistance in 6-day-old corpora lutea, but had no significant effect on the vascular resistance in young (2-day-old) or old corpora lutea (11 days old). The luteal blood flow of the control rats was higher in 6-day-old corpora lutea than in those of 2 and 11 days. The luteal blood flow apparently lacks autoregulation, since a linear relationship between blood flow and arterial blood pressure was registered. The present study shows that, besides the well known metabolic effects of catecholamines on corpus luteum function, catecholamines can exert acute vascular effects, but only on the corpus luteum of pseudopregnancy in the middle of its life span.

Adenosine as inhibitor of myocardial effects of catecholamines

Infusion of adenosine into the coronary arteries of isolated guinea pig hearts produced a dose-dependent inhibition of dP/dtmax caused by bolus injections of isoproterenol (4 X 10(-11) moles). Threshold concentration of adenosine was 10(-7) M and maximal inhibition (90%) occurred at 10(-5) M. Coronary dilation induced by papaverine did not influence the contractile response to catecholamines. In addition to its influence on cardiac performance, adenosine (10(-5) M) effectively inhibited the isoproterenol (10(-7)M) induced initial rise in myocardial levels of cyclic 3'5'-AMP, glucose-1-phosphate and glucose-6-phosphate. Adenosine also antagonized the effect of isoproterenol on adenylate cyclase activity in a crude membrane preparation from guinea pig ventricles; it was without effect on the activity of the membrane phosphodiesterase. Theophylline inhibited the actions of adenosine both on adenylate cyclase activity and on contractile force development. Upon infusion of isoproterenol (3 X 10(-7)M) into the coronary arteries of the isolated heart (perfusion at constant pressure), the adenosine concentration in the effluent perfusate increased within 45 s from 10(-8) M to about 10(-6) M. It thus appears conceivable that in ventricular myocardium endogenously formed adenosine may serve 2 functions: dilation of the coronary arteries and limitation of the inotropic and metabolic effects of catecholamines.

The influence of kinins on the metabolic effects of chosen drugs

The influence of bradykinin and kallikrein on some metabolic effects of catecholamines and theophylline were studied. The activity of phosphorylase a in heart muscle, the level of free fatty acids in the serum and epididymis, and the lactic acid content in the blood, striated muscle and intestine of the rat were studied after the administration of all drugs in vivo. Furthermore, the content of free fatty acids in the epididymal adipose tissue was estimated after incubation with the drugs in vitro. It was found that neither bradykinin nor kallikrein administered alone altered the studied parameters. However, kinins significantly diminished the effects of norepinephrine, epinephrine, isoprenaline and theophylline on the metabolic indicators. The authors suggest that kinins could act as modulators of the activity of adrenergic receptors and this modulating action could depend on their effect on cyclic 3′,5′AMP.

Metabolic effects of epinephrine and norepinephrine in the eel Anguilla anguilla L

Studies have been conducted on the metabolic effects of catecholamines on the eel ( Anguilla anguilla L.). The fishes were injected intraperitoneally with epinephrine and during 24 hr alterations in the following parameters were measured: hematocrit, hemoglobin, blood glucose, blood lactate, plasma contents of free fatty acids (FFA), cholesterol, triglycerides, sodium, potassium, chloride, and inorganic phosphate. In addition, the effects of intraperitoneally injected norepinephrine on blood glucose, blood lactate, and plasma FFA were studied. Epinephrine in low doses (0.5 mg/kg) produced a delayed hyperglycemia and a slight and trasient hyperlactemia. High doses of epinephrine (5.0 mg/kg) had stronger hyperglycemic and hyperlactemic effects. In addition, the higher dose of epinephrine induced a rapid and prolonged rise in plasma FFA, and a delayed increase in plasma cholesterol. Treatment with the higher dose also caused a marked polycythemia and significant increases in plasma electrolytes. Norepinephrine injections (5.0 mg/kg) resulted in slight and short-lasting hyperglycemic and hyperlactemic responses, but had no effect on the plasma FFA level. In general it appears that epinephrine in eels induces metabolic effects which are more sluggish and durable, but qualitatively similar to those in warm-blooded animals. Among the two hormones, epinephrine seems to be more potent than norepinephrine both in its hyperglycemic and its lipolytic action on the eel.

Metabolic effects of catecholamines in sheep.

Intravenous infusion of 1� 5 mg adrenaline over 30 min into adult Merino wethers (50 kg body weight), increased glucose, lactate, and free fatty acid (FFA) concentrations in plasma much more than did a single rapid intravenous injection of the same amount. There was no increase in plasma insulin concentration during adrenaline infusion or after adrenaline injection.