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    • The study by Lo http www

    2022-11-07

    The study by Lowry et al. (2001) pointed toward functionally uncharacterized DA- and 5-HT-accumulating neurons within the DMH as a potential target for rapid nongenomic effects of CORT. Similar DA- and 5-HT-accumulating systems are distributed throughout the central and peripheral nervous systems, suggesting that the proposed effects of CORT on these cells play an important role in stress-related physiology and behavior. Furthermore, in rat and vole brains, the highest concentrations of CORT Miglitol in synaptosomal membrane fractions are found in the hypothalamus (Orchinik et al., 1997; Towle and Sze, 1983). Thus, the hypothalamus may be an important site for rapid, nongenomic effects of CORT in both nonmammalian and mammalian brain.
    Physiologists working in the mid-twentieth century observed that glucocorticoids, either injected or topically applied, in both in vivo and ex vivo preparations, rapidly potentiated the actions of catecholamines in peripheral tissues. These effects occurred within minutes of either injection or topical application of the steroid, and were observed in nictitating membranes, conjunctival vessels, and aortic smooth muscle preparations (Fowler and Chou, 1961; LeComte et al., 1959; Reis, 1960). Such observations led Richard Schayer to state that the potentiation of catecholamine action on microcirculatory smooth muscle is “the most rapid known effect of injected glucocorticoids”, occurring within 2–3 min after intravenous injection (Schayer, 1963). These interactions are likely the earliest reports of rapid physiological responses to glucocorticoids, and stimulated a large number of studies to elucidate the mechanisms and sites of glucocorticoid action. Evidence for a direct action of glucocorticoids at the smooth muscle was demonstrated by studies of conjunctival microvessels. Direct subconjunctival application of corticosteroid suspensions rapidly (within 15 min) decreased, by 3- to 10-fold, the threshold concentration of norepinephrine required to induce spasm of the precapillary sphincters and metarterioles in both rabbits (Lepri and Cristiani, 1964) and human subjects (Reis, 1960; Lepri and Cristiani, 1964). Similar rapid potentiating effects of a variety of corticosteroids were observed using ex vivo preparations of spirally cut aortic smooth muscle to which steroids and catecholamines were directly applied (Besse and Bass, 1966; Fowler and Chou, 1961). In both studies, the potentiating actions of the corticosteroid were observed within 0–2 min. Corticosterone, aldosterone, androsterone and dehydroepiandrosterone (DHEA) all produced immediate and reversible potentiation of norepinephrine-induced muscle contraction, with corticosterone exerting effects at the lowest concentration (Fowler and Chou, 1961). Hydrocortisone rapidly potentiated both alpha- and beta-adrenergic responses, and potentiation was maintained in aortic strips pretreated with reserpine to deplete catecholamines stored in sympathetic terminals (Besse and Bass, 1966), indicating that the steroid was not acting to release endogenous transmitter, but was somehow increasing the potency of applied catecholamines at the receptor. These studies further demonstrated that, while cocaine-induced blockade of uptake also potentiated norepinephrine-induced contractions, the effects of hydrocortisone were greater than those of cocaine, and effects were additive to those of cocaine. Thus, the mechanism of corticosteroid-induced potentiation was distinct from that of cocaine, suggesting at the time that the steroid was not interfering with norepinephrine clearance. However, studies were published at about this time indicating the existence of a second, cocaine-insensitive, catecholamine uptake system that was inhibited by corticosteroids. Studies of the transport and metabolism of catecholamines in heart tissue revealed the presence of two distinct uptake processes for epinephrine and norepinephrine. Uptake1, a high-affinity (Kd = 0.27 μM), low-capacity (Vmax = 1.22 nmol/min/g tissue) system; and uptake2, a low-affinity (Kd = 252 μM), high-capacity (Vmax = 100 nmol/min/g) system (Iversen, 1965). Uptake1, termed “neuronal uptake”, was inhibited by cocaine and desipramine, while uptake2, or “extraneuronal uptake”, insensitive to cocaine and desipramine, was inhibited by normetanephrine. Based on its low affinity, uptake2 was originally thought to operate only at very high concentrations of substrate. However, subsequent studies demonstrated that this transport process operates at all substrate concentrations (Lightman and Iversen, 1969). Importantly, later studies identified additional substrates of uptake2, including the β-adrenergic receptor antagonist isoproterenol, the α2-adrenergic receptor agonist clonidine, the monoamines DA, 5-HT, histamine, and the trace amine tyramine (Grohmann and Trendelenburg, 1984). Russ et al. later demonstrated that the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) is an excellent uptake2 substrate (Russ et al., 1992). Because it is not subject to metabolic breakdown or oxidation, MPP+ is commonly used as a substrate to measure monoamine transporter activity.