This article provides an update about catecholamine metabolism, with emphasis on correcting common misconceptions relevant to catecholamine systems in health and disease. Importantly, most metabolism of catecholamines takes place within the same cells where the amines are synthesized. This mainly occurs secondary to leakage of catecholamines from vesicular stores into the cytoplasm. These stores exist in a highly dynamic equilibrium, with passive outward leakage counterbalanced by inward active transport controlled by vesicular monoamine transporters. In catecholaminergic neurons, the presence of monoamine oxidase leads to formation of reactive catecholaldehydes. Production of these toxic aldehydes depends on the dynamics of vesicular-axoplasmic monoamine exchange and enzyme-catalyzed conversion to nontoxic acids or alcohols. In sympathetic nerves, the aldehyde produced from norepinephrine is converted to 3,4-dihydroxyphenylglycol, not 3,4-dihydroxymandelic acid. Subsequent extraneuronal O-methylation consequently leads to production of 3-methoxy-4-hydroxyphenylglycol, not vanillylmandelic acid. Vanillylmandelic acid is instead formed in the liver by oxidation of 3-methoxy-4-hydroxyphenylglycol catalyzed by alcohol and aldehyde dehydrogenases. Compared to intraneuronal deamination, extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism. The single largest source of metanephrines is the adrenal medulla. Similarly, pheochromocytoma tumor cells produce large amounts of metanephrines from catecholamines leaking from stores. Thus, these metabolites are particularly useful for detecting pheochromocytomas. The large contribution of intraneuronal deamination to catecholamine turnover, and dependence of this on the vesicular-axoplasmic monoamine exchange process, helps explain how synthesis, release, metabolism, turnover, and stores of catecholamines are regulated in a coordinated fashion during stress and in disease states.

Catecholamine Metabolism: A Contemporary View with Implications for Physiology and Medicine

Drug response triggered by receptor activation arises from a chain of events that are regulated by many factors. Molecular changes associated with drug sensitization or tolerance are currently being elucidated on the molecular level, e.g. for adenylate cyclase coupled systems. Despite the complexity of the drug-response mechanism, simple empirical pharmaco-dynamic models on the basis of the law of mass action are widely applicable to describe drug-effect relationships. In combination with a pharmacokinetic model and suitable delay functions, such models are capable of simulating the complete time course of drug action in vivo. The predictive potential of the pharmacokinetic-pharmacodynamic models should prove useful in evaluating pharmaceutical formulations with controlled drug delivery.

Directed Drug Delivery

Determination of antibiotics in different water compartments via liquid chromatography-electrospray tandem mass spectrometry.

. Objectives. The acute effect of smoking and snuffing on insulin sensitivity was studied in a group of healthy habitual smokers.

Design The euglycaemic clamp technique was combined with the subcutaneous injection of a bolus (0.1 U kg−1) of fast-acting insulin (Actrapid®). Randomized subjects smoked either one cigarette per hour for 6 h, took one bag-packed snuff per hour for 6 h or refrained from nicotine for 48 h before as well as during the clamp.

Subjects. Seven healthy smokers, four females and three males, of normal weight (BMI, mean ± SKM. 21 ± 0.7 kg m−2 with a range of 18.6–23.9), aged 31 ± 2 years (range 24–35 years), who had consumed at least 20 cigarettes per day for at least 5 years were studied. They were recruited through an advertisement in a newspaper. Results. The steady-state plasma nicotine levels were similar during smoking and snuffing. The insulin and glucose levels were also similar during all three clamps. Smoking, but not snuffing, impaired insulin action (P < 0.05) mainly due to a lower peripheral glucose uptake. The mean growth hormone levels during the 6-h study were more than doubled during smoking (P < 0.01) while no significant differences were seen in the other counter-regulatory hormones.

Conclusion. Smoking (also in habitual smokers) acutely impairs insulin action and leads to insulin resistance. Thus, smoking can be of importance for the development of the insulin resistance syndrome associated with risk for cardiovascular disease.

Smoking induces insulin resistance--a potential link with the insulin resistance syndrome.

The accumulation of endogenous catecholamines within the extracellular space of the ischemic myocardium has been studied in the isolated perfused (Langendorff) heart of the rat subjected to various periods of complete ischemia, with subsequent collection of the reperfusate. Catecholamines and deaminated metabolites were measured by radioenzymatic methods, or high pressure liquid chromatography. Ischemic periods of less than 10 minutes are not associated with an increased overflow of catecholamines or metabolites. Longer periods of ischemia are accompanied by the overflow of noradrenaline and its deaminated metabolite 3,4-dihydroxyphenylglycol. This overflow increases with lengthening of the preceding ischemic period (10 minutes: 2.5 +/- 0.6, 20 minutes: 209.8 +/- 17.2, 60 minutes: 1270.5 +/- 148.1 pmol noradrenaline/g heart). Noradrenaline concentration is highest during the first minute of reperfusion, suggesting that the noradrenaline detected during reperfusion is released into the extracellular space of the myocardium during ischemia and is subsequently eluted. Experiments with variation of extracellular calcium concentration and with neuronal uptake (uptake1) blocking agents suggest that different mechanisms of catecholamine release are acting during the course of ischemia. A calcium-independent carrier-mediated efflux of noradrenaline from the nerve terminals is of major importance, using the same carrier as is normally responsible for transporting noradrenaline from the synaptic clefts into the neuronal varicosities. Thus, various uptake1-blocking agents diminish the noradrenaline overflow following ischemic periods of between 10 and 40 minutes. The noradrenaline overflow following longer periods of ischemia is unaffected by uptake1-blocking agents, and additional noradrenaline release at this time is probably consequent upon dissolution of cell membranes. Overflow of adrenaline and dopamine occurs to a minor degree (less than 5% of the corresponding noradrenaline overflow), and only after ischemic periods of more than 15 minutes.

Release of endogenous catecholamines in the ischemic myocardium of the rat. Part A: Locally mediated release.

Determination of catecholamines in rat heart tissue and plasma samples by liquid chromatography with electrochemical detection

Liquid chromatographic determination of the macrolide antibiotics roxithromycin and clarithromycin in plasma by automated solid-phase extraction and electrochemical detection

Britt-Marie Eriksson

Papers

Determination of catecholamines in rat heart tissue and plasma samples by liquid chromatography with electrochemical detection

Liquid chromatographic determination of the macrolide antibiotics roxithromycin and clarithromycin in plasma by automated solid-phase extraction and electrochemical detection

Multiple peak formation in reversed-phase liquid chromatography of ramipril and ramiprilate

Determination of catecholamines in urine by ion-exchange liquid chromatography with electrochemical detection

Determination of fluvastatin enantiomers and the racemate in human blood plasma by liquid chromatography and fluorometric detection