Inhibition of catecholamine Uptake2 by steroids in the isolated rat heart
TL;DR: Various steroids (1 7‐fl‐oestradiol, cortico‐sterone, deoxycorticosterone, progesterone, testosterone and androsterone) produced a dose‐dependent inhibition of the uptake of 3H‐noradrenaline by the Uptake2 mechanism in the isolated perfused heart.
Abstract: Various steroids (17-β-oestradiol, corticosterone, deoxycorticosterone, progesterone, testosterone and androsterone) produced a dose-dependent inhibition of the uptake of 3H-noradrenaline by the Uptake2 mechanism in the isolated perfused heart. It is suggested that these results may explain the potentiating effects of such steroids on the responses of vascular smooth muscle to catecholamines.
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754 citations
TL;DR: Standard therapy for the latter patients consists of the administration of high doses of corticosteroids during any severe illness and perioperatively, and replacement doses or high doses in patients with severe illness, especially those with multiorgan-system diseases.
Abstract: Severe illnesses, trauma, anesthesia, and surgery are accompanied by activation of the hypothalamic–pituitary–adrenal axis, as demonstrated by increased serum corticotropin and cortisol concentrations.1–7 This activation is an essential component of the general adaptation to stress and contributes to the maintenance of homeostasis.8 The efficacy of replacement doses or high doses of corticosteroids in patients with severe illness, especially those with multiorgan-system diseases, is uncertain.9–12 The uncertainty is even greater in patients who are already taking corticosteroids. Standard therapy for the latter patients consists of the administration of high doses of corticosteroids during any severe illness and perioperatively. We . . .
454 citations
TL;DR: Experiments with variation of extracellular calcium concentration and with neuronal uptake (uptakei) blocking agents suggest that different mechanisms of catecholamine release are acting during the course of ischemia, suggesting a calcium-independent carrier-mediated efflux of noradrenaline from the nerve terminals is of major importance.
Abstract: 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.
380 citations
Cites background from "Inhibition of catecholamine Uptake2..."
...Blockade of the extraneuronal uptake with corticosterone (Iversen and Salt, 1970) increases the ischemia-induced noradrenaline overflow from the heart by approximately 20 pmol/g (Fig....
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TL;DR: The transport characteristics and steroid sensitivity provide strong evidence for the molecular identity of OCT3 as uptake2, and regional distribution studies with in situ hybridization show that OCT3 is expressed widely in different brain regions, especially in the hippocampus, cerebellum, and cerebral cortex.
376 citations
TL;DR: Through their reward-related effects, glucocorticoids may play a key role in tuning adaptation to stress and in determining reward- related behavioral pathologies.
366 citations
References
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TL;DR: Measurement of the initial rates of noradrenaline uptake during perfusion with various concentrations of nonradioactive (+)- and (-)-noradrenalin showed that the uptake process exhibited stereochemical specificity, which suggested that diffusion did not play any significant role in the entry of nor adrenaline into the tissue.
Abstract: The uptake of noradrenaline by the isolated perfused rat heart was studied after perfusion with a medium containing various concentrations of (+/-)-[(3)H]-noradrenaline. Simultaneous measurement of the uptake of [(3)H]-noradrenaline and of the net increase in the noradrenaline content of the heart showed that [(3)H]-noradrenaline entering the heart both increased the tissue content and exchanged with endogenous noradrenaline. A large part (about 75%) of the endogenous noradrenaline pool, however, exchanged very slowly if at all with exogenous noradrenaline. The initial rates of noradrenaline uptake satisfied Michaelis-Menten kinetics with a Km for (+/-)-noradrenaline of 6.64x10(-7) M. Further analysis of the uptake process indicated that noradrenaline entered into at least two intracellular pools at different rates. Measurement of the initial rates of noradrenaline uptake during perfusion with various concentrations of nonradioactive (+)- and (-)-noradrenaline showed that the uptake process exhibited stereochemical specificity. The Km values for (+)- and (-)-noradrenaline were 13.9x10(-7) and 2.66x10(-7) M respectively. Cocaine acted as a potent competitive inhibitor of noradrenaline uptake. This finding suggested that diffusion did not play any significant role in the entry of noradrenaline into the tissue.
267 citations
TL;DR: The results of these experiments led to the conclusion that a second type of uptake operates at high perfusion concentrations, and the properties of this second process are sufficiently different from those described previously to justify a clear-cut distinction between the two processes.
Abstract: In previous studies of the uptake of catechol amines in the rat isolated heart it was shown that adrenaline and noradrenaline were accumulated by a common mechanism (Iversen, 1963, 1965). In these experiments the uptake saturated at an external amine concentration of approximately 0.2 μg/ml. noradrenaline or 0.5 μg/ml. adrenaline. However, in subsequent experiments in which hearts were perfused with (±)-adrenaline at a concentration of 5.0 μg/ml. an unexpectedly large uptake of adrenaline was observed. This fortuitous observation led to an examination of the uptake of adrenaline and noradrenaline during perfusions at higher concentrations of each amine than had previously been studied.
The results of these experiments led to the conclusion that a second type of uptake operates at high perfusion concentrations. The properties of this second process are sufficiently different from those described previously to justify a clear-cut distinction between the two processes.
255 citations
TL;DR: It is concluded that hydrocortisone enhances the responses of vascular smooth muscle to epinephrine and norepinephrine by inhibiting a major enzymatic pathway for the inactivation of these amines.
Abstract: Hydrocortisone potentiated responses of rabbit aortic strips to catecholamines (epinephrine, norepinephrine, nordefrin, isoproterenol) but not to amines lacking the catechol nucleus (phenylephrine, synephrine, methoxamine). Contractions in response to epinephrine were increased much more than those to norepinephrine. Neither the presence of cocaine nor pretreatment of the rabbits with reserpine impaired the potentiating action of hydrocortisone. Experiments with the oil immersion technique (to prevent loss of amine by diffusion from the tissue) demonstrated that hydrocortisone reduced the rate at which aortic strips inactivated epinephrine, apparently by inhibiting catechol-O-methyl transferase (COMT). Known inhibitors of COMT (U-0521, tropolone, pyrogallol) potentiated responses of aortic strips to epinephrine much more than to norepinephrine and also enhanced responses to isoproterenol and nordefrin to the same extent as did hydrocortisone. Known inhibitors of COMT consistently abolished the enhancing effects of hydrocortisone without materially interfering with potentiation produced by cocaine which is mediated through an independent mechanism unrelated to amine inactivation. Hydrocortisone also abolished the enhancing effects of known COMT inhibitors. It is concluded that hydrocortisone enhances the responses of vascular smooth muscle to epinephrine and norepinephrine by inhibiting a major enzymatic pathway for the inactivation of these amines.
209 citations
TL;DR: Direct observation of the functional behavior of the capillary bed in tissues such as the mesentery under various experimental conditions has made it possible to relate the observed phenomena to specific structural components of the terminal vascular bed.
Abstract: Many investigators have shown that a central feature of adrenal insufficiency is the profound collapse of the circulation, which develops progressively. Swingle’ was greatly impressed with the increased capacity of the peripheral vascular tree in such cases and attributed it to a deficiency of adrenocortical secretions essential for the maintenance of “vascular tone.” Used in its broadest sense, the term encompasses many facets of vascular activity and is in no way specific. Unfortunately, the experimental data thus far available do not permit a more precise evaluation of the particular homeostatic pathways through which the adrenal cortex influences the behavior of the peripheral blood vessels. The mechanism of action of adrenal corticosteroids on the vascular system should be considered with three possible categories in view. First, does the gland produce hormones that act as blood-borne principles with a direct effect on the vascular system? Secondly, are the vascular effects referable to the basic function of the adrenal corticosteroids in the electrolyte metabolism of the smooth muscle cell? Thirdly, does the adrenal cortex influence vascular behavior indirectly through effects on other organ systems, such as the kidney? One of the most fruitful approaches to this problem is that of direct observation of the functional behavior of the capillary bed in tissues such as the mesentery under various experimental conditions.2. This approach has made it possible to relate the observed phenomena to specific structural components of the terminal vascular bed. With this as a frame of reference, one encounters less difficulty in orienting the complex behavior of the capillary circulation in its proper perspective with reference to the regulatory influence of the adrenal cortex.
186 citations