Adrenaline and Noradrenaline: Partners and Actors in the Same Play (original) (raw)
Catecholamines: Knowledge and understanding in the 1960s, now, and in the future
Brain and Neuroscience Advances, 2019
The late 1960s was a heyday for catecholamine research. Technological developments made it feasible to study the regulation of sympathetic neuronal transmission and to map the distribution of noradrenaline and dopamine in the brain. At last, it was possible to explain the mechanism of action of some important drugs that had been used in the clinic for more than a decade (e.g. the first generation of antidepressants) and to contemplate the rational development of new treatments (e.g. l-dihydroxyphenylalanine therapy, to compensate for the dopaminergic neuropathy in Parkinson’s disease, and β1-adrenoceptor antagonists as antihypertensives). The fact that drug targeting noradrenergic and/or dopaminergic transmission are still the first-line treatments for many psychiatric disorders (e.g. depression, schizophrenia, and attention deficit hyperactivity disorder) is a testament to the importance of these neurotransmitters and the research that has helped us to understand the regulation of ...
The Release of Catecholamines from the Adrenal Medulla Peptides
British Journal of Pharmacology and Chemotherapy, 1967
In the cat, angiotensin and bradykinin release catecholamines from the adrenal medulla (Feldberg & Lewis, 1964, 1965), but eledoisin does not (Staszewska-Barczak & Vane, 1965; Lewis & Reit, 1966). The present experiments extend the observations on the releasing actions of these peptides and compare their effects in cat and dog. Some of the results were communicated to the Physiological Society (Staszewska- Barczak & Vane, 1964). Cats of either sex weighing 2-5 kg were anaesthetized with ethylchloride and ether; anaesthesia was then maintained with chloralose (80 mg/kg intravenously). Dogs of either sex weighing 6-15 kg were anaesthetized with ether and anaesthesia was then maintained with chloralose (100 mg/kg intravenously). A carotid or brachial artery was cannulated with polyethylene tubing to supply blood to an extra- corporeal circulation for the blood-bathed organ technique (Vane, 1964) and to record the blood pressure on a mercury manometer. To detect the release of catecholamines a continuous stream of arterial blood was superfused over the rat isolated stomach strip (Vane, 1957) and the chick isolated rectum (Mann & West, 1950); the blood was then returned to the animal through a cannula in a jugular vein. With these organs superfused in series, it was possible to distinguish between the release of adrenaline which relaxed both rat stomach and chick rectum and noradrenaline which only relaxed the rat stomach (Armitage & Vane, 1964; Staszewska-Barczak & Vane, 1965). In some experiments the series also included a rat colon which contracted to angiotensin (Regoli & Vane, 1964). Heparin (" Pularin," Evans; 1,000 i.u./kg intravenously) was injected into the animal before the external circulation of blood was started. Artificial ventilation was maintained with a pump. To make intra-arterial injections to the adrenal glands a fine polyethylene catheter was introduced into the aorta through a femoral artery, so that the tip of the catheter lay upstream to the origins of the adrenal arteries. Thus, an " intra-arterial " injection mixes with that portion of the cardiac output which flows down the aorta below the diaphragm but only a small aliquot of the injected substance reaches the adrenal glands. Intra-arterial injections made in this way have the advantages, first, that they by-pass the lungs and, secondly, that the blood taken for assay from a carotid artery contains only that portion of the injected substance which recirculates. The position of the catheter was checked at the end of the experiment. The amounts of catecholamines released by intra-arterial or intravenous infusions or injections of peptides were determined by comparing the effects of the released catecholamines on the blood-bathed organs with the effects of intravenous injections or infusions of adrenaline and noradrenaline. The
Historical Landmarks in the Discovery of Adrenal Hormones
World Journal of Endocrine Surgery
urinary excretion of the sodium-24 isotope in adrenalectomized rats. He approached separately to two specialists in the field of bioassay and radioisotope-Sylvia Agnes Sophia Tait and James Francis Tait (Fig. 3). 5 Later, they succeeded in developing a bioassay by measuring the effect of adrenal steroids on urinary excretion of radioisotopes of sodium-24 and potassium-42 in adrenalectomized rats. 6 This method paved the way for further discoveries of adrenal gland products. They also discussed the methods of isolation, biochemistry, and physiology of electrocortin. In 1952, they partnered with a Swiss Chemist, Professor Tadeus Reichstein, and were able to demonstrate the structure of electrocortin. 6 Later, Reichstein demonstrated the steroid nature of the electrocortin, and renamed the compound "aldosterone." 7 Glucocorticoids In January 1931, Dr Leonard G Rowntree of the Mayo Clinic demonstrated the efficacy of adrenal cortex extract in reducing the symptoms of Addison's disease in a patient. After knowing Edward Calvin Kendall's (Fig.
Biochemical Pharmacology, 1970
The exocytosis hypothesis for neurotransmitter release from sympathetic nerves was experimentally tested by studying the effect of nerve stimulation on the outflow of adenine nucleotide material from the cat spleen, and by comparing the adenine nucleotide content of stimulated and control portions of the splenic capsule. The adrenal medulla was used as a reference organ, assumed to secrete by exocytosis. The method used involved labelling the adenine nucleotides of the catecholamine storage particles in sympathetic nerves and adrenal medulla by daily injections of radioactive orthophosphate (32p) for one week. Results obtained by sucrose density gradient centrifugation and analysis by anion exchange column chromatography indicated that the technique used had resulted in significant labelling of the adenine nucleotides of the adrenal medullary amine storage particles, which have previously proved to be highly resistant to labelling with 32p. Induction of secretion in the perfused adrenal by carbachol consistently resulted in a largely parallel increase in cateeholamines and a2P-labelled material in the effluent from the gland. Chromatographic analysis showed that the labelled material consisted mainly of inorganic phosphate, with only small amounts of AMP and no ADP or ATP. In the splenic peffusion experiments contraction of the organ, whether induced by injection of angiotensin or by nerve stimulation, resulted in increased outflow of 32P-labelled material, exclusively as inorganic phosphate. However, when contraction was blocked by phenoxybenzamine, nerve stimulation caused a large rise in noradrenaline outflow, but had no effect on the level of saP-labelled material in the effluent. Moreover, prolonged nerve stimulation, known to cause release of about one half of the noradrenaline in the spleen, did not in any way affect the content of labelled adenine nucleotides of the splenic capsule. The present findings appear to be compatible with the exocytosis hypothesis for hormone secretion from the adrenal medulla, but they do not support the same hypothesis for neurotransmitter release from sympathetic nerves.
Pharmacology of Adrenaline, Noradrenaline, and Their Receptors
2020
Adrenaline and noradrenaline are important catecholamines of the biological system, responsible for the regulation of major functions of the body via their action on the brain. This noradrenaline is the chief neurotransmitter of the sympathetic nervous system, whereas adrenaline is an important metabolic hormone, known to play a vital role in the cardiovascular system and a mediator of the fight-or-flight response. These catecholamines act in the system through the membrane-bound GPCRs, adrenergic receptors (ARs). Two major classes of ARs, α-ARs and β-ARs, facilitate a number of functions at central and peripheral sites. There are two subtypes of α-ARs (α1-AR and α2-AR), whereas three different subtypes of β-ARs have been identified-β1-AR, β2-AR, and β3-AR. Based on their role, different AR modulators have been introduced clinically for their therapeutic application. In this chapter, we focus on the pharmacology of the two catecholamines through their action on different ARs within the biosystem
Long-term application of some catecholamines elevates levels of other catecholamines in rats
Experimental pathology, 1985
Male Sprague-Dawley rats were treated during 20 h with subcutaneously implanted tablets (controlled release systems) containing either adrenaline (A), noradrenaline (NA), isoprenaline (ISO) or just placebos. Levels of the exogenously administered catecholamines (CA) in plasma and liver homogenate were significantly higher than in controls throughout the test time. During NA application endogeneous A and dopamine (DA) plasma values rose considerably, while ISO application enhanced endogenous NA and A levels. Adrenaline application increased NA and DA plasma levels. Several possibilities for this phenomenon are discussed, and it is concluded that previous papers dealing with observations of long term action of CA's should be reevaluated unless the influence of the artificially given CA on the elevation of endogenous CA's has been already taken into consideration.
The inhibition in vivo of norepinephrine synthesis by adrenalone
Biochemical Pharmacology, 1962
THE BIOGENESIS of norepinephrine involves the oxidation of phenylalanine to tyrosine followed by hydroxylation to 3,4_dihydroxyphenylalanine, decarboxylation to dopamine (3,4_dihydroxyphenylethylamine) and ,%hydroxylation of dopamine to norepinephrine. The rate-limiting step in this reaction sequence may be the conversion of dopamine to norepinephrine, and the inhibition of dopamine-&hydroxylation may produce lower levels of norepinephrine and consequently higher levels of dopamine. The enzyme that catalyses the conversion of dopamine to norepinephrine was isolated from bovine adrenal medulla1 and it was shown not to be specific for dopamine. In view of this finding the enzyme was named phenylamine-ghydroxylase. a Many compounds were tested as possible inhibitors of the conversion of dopamine to norepinephrine by the hydroxylating enzyme.* Among the compounds thus far tested, adrenalone was the most effective in vitro." At a concentration of the substrate, dopamine, of 2 ~moles/ml, the formation of norpinephrine in a standard incubation mixture at pH 6-4 is i~ibited approxi~tely 50 per cent by adrenalone in a concentration of @2 pmoles/ ml. At lower pHs, the inhibition by adrenalone decreases sharply. A Lineweaver-Burk plot revealed that the inhibition by adrenalone is not of a competitive nature. The effective inhibition in vitro of norepinephrine synthesis by adrenalone at physiological pHs suggests that this compound may also be active in vivo. The inhibition in viva was investigated by a comparison of the content of norepinephrine-H3 formed from dopamine-Ii3 in several organs of rabbits treated and untreated with adrenalone. Each rabbit was treated with 100 mg iproniazid/kg 16 hr before the infusion of dopamine-HS. The adrenalone-treated rabbits received 4 mg adrenalone/kg i.p. both 12 hr and 1 hr before the infusion and, in addition, 2 mg/kg i.v. during the infusion of dopamine-H3; 0.2 mg of dopamine-a-H*, with the specific activity 10s cpm/mg, in a 20-ml solution was infused during a period of 20 min into the rabbit's ear vein. The rabbits were killed one hr after the infusion, The liver, heart, and spleen were removed and homogenized, and the homogenate was deproteinized with 5% trichloracetic acid. After centrifugation the acid metabolites of dopamine and the excess of trichloracetic acid were removed by extraction three times with an equal volume of ethylacetate. The aqueous phase was adjusted to pH4 and the amines were acetyiated as previously described.* The acetylated amines were chromatographed in the "c" solvent system of Bush, and the dry chromatograms were scanned for radioactive zones. The radiochromatograms obtained from the spleen of the rabbits treated and untreated with adrenalone are presented in Fig. 1. It is evident that in the spleen of the adrenalone-treated rabbit the content of no~inephrine-H3 is decreased and the content of dopamine-HB is increased, as compared with the control. The radi~hromato~~s obtained from the hearts and livers of adrenalonetreated rabbits also show a decrease in the norepinephrine-Ha and an increase in the dopamine-Hs content, as compared with the controls. Upon elution of the corresponding radioactive peaks, the amounts of norepinephrine-Ha and dopamine-II" in each organ were determined in a Packard liquid scintillation spectrometer. Table 1 shows that the content of norepinephrine-H3 is decreased approximately 50 per cent in the heart and spleen of adrenalone-treated animals. The content of dopamineHs is increased almost to the same extent in these organs. The inhibition of norep~ep~~e synthesis by adrenalone in the liver is less effective. The results given in Table 1 are averages of three experiments.
Excretion of catecholamines in rats, mice and chicken
Journal of Comparative Physiology B, 2008
Stress assessment favours methods, which do not interfere with an animal's endocrine status. To develop such non-invasive methods, detailed knowledge about the excretion of hormone metabolites in the faeces and urine is necessary. Our study was therefore designed to generate basic information about catecholamine excretion in rats, mice and chickens. After administration of 3 H-epinephrine or 3 H-norepinephrine to male and female rats, mice and chickens, all voided excreta were collected for 4 weeks, 3 weeks or for 10 days, respectively. Peak concentrations of radioactivity appeared in one of the Wrst urinary samples of mice and rats and in the Wrst droppings in chickens 0.2-7.2 h after injection. In rats, between 77.3 and 95.6% of the recovered catecholamine metabolites were found in the urine, while in mice, a mean of 76.3% were excreted in the urine. Peak concentrations in the faeces were found 7.4 h post injection in mice, and after about 16.4 h in rats (means). Our study provides valuable data about the route and the proWle of catecholamine excretion in three frequently used species of laboratory animals. This represents the Wrst step in the development of a reliable, non-invasive quantiWcation of epinephrine and norepinephrine to monitor sympatho-adrenomedullary activity, although promising results for the development of a non-invasive method were found only for the chicken.
Why Is the Adrenal Adrenergic?
Endocrine Pathology, 2003
The adrenal gland is the body's primary source for epinephrine production and release, and the chromaffin cells that comprise the adrenal medulla possess all of the catecholamine biosynthetic machinery, including phenylethanolamine N-methyltransferase (PNMT), the enzyme synthesizing epinephrine from norepinephrine. In most species, epinephrine, also known as adrenaline, is the predominant neurotransmitter/neurohormone expressed by chromaffin cells. Present knowledge about "what makes the adrenal adrenergic" is derived from studies of normal and neoplastic adrenal medullary tissue and cells, with the PNMT gene serving as a marker of adrenergic function. The preference for adrenergic expression occurs, in part, because of the juxtaposition of adrenal medulla and adrenal cortex, as the cortex provides high circulating levels of glucocorticoids to the medulla. However, although glucocorticoids and the activated glucocorticoid receptor clearly are critical elements, they are apparently not the sole components defining the adrenergic phenotype. Other factors may include several transcriptional activators of the PNMT gene: Egr-1, AP2, Sp1, and MAZ. The existence of transcription factors that silence PNMT expression in noradrenergic cells has also been postulated. Understanding the requirements for adrenergic expression may provide important insights and potential therapies for disorders in which adrenergic/catecholaminergic dysfunction leads to illnesses refractory to present treatment strategies.
Studies on the long term effects of SK&F 29661 upon adrenal catecholamines
Naunyn-Schmiedeberg's Archives of Pharmacology, 1982
SK&F29661 (1,2,3,4-tetrahydro-7-isoquinolinesulfonamide) is a potent and selective in vitro and in vivo inhibitor of adrenal phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28). Its Ki value for in vitro inhibition of rat adrenal PNMT was 133 nM. In vivo, the adrenal conversion of 3H-norepinephrine to 3H-epinephrine was maximally inhibited by a single oral dose of 100 mg/kg. In long term chronic studies in rats, adrenal epinephrine was reduced by SK&F29661 in a dose dependent fashion to greater than 90 %, without substantial increases in norepinephrine. Urinary excretion of epinephrine was significantly reduced by the drug both basally and following 2-deoxyq)glucose stimulation. No drug related changes were found in plasma corticosterone values and only small effects were observed on adrenal tyrosine hydroxylase and PNMT enzyme levels. The cardiac norepinephrine pool and its turnover time were both significantly reduced; its turnover rate, however, was only slightly increased. Our studies indicate that SK&F29661 is a highly effective, non-toxic and novel pharmacological tool which is useful in depleting adrenal epinephrine stores via inhibition of its biosynthesis.
The rat adrenal gland in the study of the control of catecholamine secretion
Seminars in Cell & Developmental Biology, 1997
Catecholamine secretion in the rat can be studied in freely moving and anaesthetized animals, in isolated-perfused adrenals, medullae slices and isolated cultured cells. In addition the rat offers the advantage over the more widely used bovine adrenal model that researchers can have access to animals of the same age, sex and feeding conditions. Catecholamine release is similar to other species although it gives robust secretion in response to stimuli such as muscarinic agonists, bradykinin or VIP. It also allows the study of neurotransmission at the splanchnic-adrenal synapse. The use of single-cell preparations (patch-clamp, microfluorimetry, amperometry or capacitance) has overcome the limitations of the number of cells obtained from a gland. It is possible to study secretion in animal models of hypertension, chronic stress or diabetes and rats can be genetically modified.