Inhibition of adenosine accumulation into guinea pig ventricle by benzodiazepines

Barker, Philip H.; Clanachan, Alexander S.

doi:10.1016/0014-2999(82)90244-8

Cited by 19 publications

(4 citation statements)

References 6 publications

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“…Existence of the peripheral Bz receptor in vascular smooth muscle has been shown (Cox et al, 1991). Although the precise function of this receptor is not fully understood (Casellas et al, 2002), previous in vivo and in vitro studies showed that Bz agonists can directly cause peripheral vasodilatation in animals (Barker and Clanachan, 1982;Clark and Lipton, 1981;Erne et al, 1989;Seubert et al, 2000). HR after DZP administration can inform us indirectly about this issue.…”

Section: Commentmentioning

confidence: 99%

Heat Loss, Sleepiness, and Impaired Performance after Diazepam Administration in Humans

Echizenya

Mishima

Satoh

et al. 2003

Neuropsychopharmacol

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In spite of the accumulation of knowledge regarding the neuropharmacological action of benzodiazepines (Bz), the physiological process by which their sedative/hypnotic effects are induced remains poorly understood. We conducted a single-blind, crossover trial to evaluate the role of the thermoregulatory process in sleepiness and impaired psychomotor performance induced by a standard Bz, diazepam (DZP). Each of the eight healthy young male volunteers (mean age, 19.75 years; range, 18-23 years) was given a single oral dose of either 5 or 10 mg of DZP or placebo 12 h after his average sleep onset time. Changes in plasma DZP concentration, proximal body temperature (p-BT), distal body temperature (d-BT), subjective sleepiness measured by the Visual Analog Scale and Stanford Sleepiness Scale, and psychomotor performance measured by Choice Reaction Time were monitored under a modified constant routine condition in which various factors affecting thermoregulation, alertness, and psychomotor performances were strictly controlled. Orally administered DZP induced a significant transient decrease in p-BT and psychomotor performance as well as an increase in d-BT and subjective sleepiness. DistalÀp-BT gradient (DPG; difference between d-BT and p-BT), which is an indicator of blood flow in distal skin regions, showed a strong positive correlation with the plasma DZP concentration, indicating that DZP in clinical doses promotes heat loss in a dose-dependent manner. The DPG also correlated positively with the magnitude of subjective sleepiness and impaired psychomotor performance. These findings indicate that the sedative/hypnotic effects of Bz could be due, at least in part, to changes in thermoregulation, especially in the process of heat loss, in humans.

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Section: Commentmentioning

confidence: 99%

Heat Loss, Sleepiness, and Impaired Performance after Diazepam Administration in Humans

Echizenya

Mishima

Satoh

et al. 2003

Neuropsychopharmacol

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“…Although the peripheral-type sites are found widely distributed in many tissues and cells (3)(4)(5)(6)(7)(8)(9)(10), and the structural requirements for binding have been defined (11), the role of these sites in vivo is unknown. However, a number of in vitro studies have demonstrated that the BZDs have diverse noncentral biological effects (12)(13)(14)(15)(16)(17)(18). In particular, Matthew et al (19) found that certain BZDs accelerated the onset of spontaneous melanogenesis in mouse B16/C3 melanoma cells, and Clarke and Ryan (20) observed that some BZDs blocked mnitogenesis in Swiss 3T3 cells and induced the differentiation of Friend erythroleukemia (FEL) cells.…”

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confidence: 99%

Differentiation of Friend erythroleukemia cells induced by benzodiazepines.

Wang¹,

Morgan²,

Spector³

1984

Proc. Natl. Acad. Sci. U.S.A.

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Many benzodiazepines of the type whose receptors are found in peripheral tissues cause the differentiation of cultured Friend erythroleukemia cells. The maximal level of induction of hemoglobin synthesis is 10-80% of the cells, depending on the compound tested. The Induction is concentration and time dependent, requiring micromolar amounts of the drugs and about 5 days of treatment for full expression. The time course is very similar to that observed for a well-studied inducer, dimethyl sulfbxide. The affinities of the agents for the peripheral-type benzodiazepine binding site are not correlated with their capacity to induce differentiation. Also, the biological effect is stereospecific since the (3S) btereoisomer Roll-6896 is at least an order of magnitude more potent than its (3R) enantiomer, Rol1-6893. The benzodiazepine effect exhibits definite structure-activity relationships. A 1-methyl group is an absolute requirement, although this is not sufficient in itself Hydroxyl and methoxyl groups at the 4' position enhance the biological activity, but 4'-chloro decreases it. Substitutions at the 2', 6', and 4 positions also decrease the biological activity, as does the lack of a 2-carbonyl group. These data suggest that the benzodiazepines act in a specific manner to induce the differentiation of Friend erythroleukemia cells.The binding sites for the benzodiazepines (BZDs) are divided into two major groups-"central-type" and "peripheraltype"-on the basis of their tissue localization (1). The central-type receptors, found only in brain, are thought to be involved in the therapeutic actions of these compounds and have been intensively studied (for review see ref.2). Although the peripheral-type sites are found widely distributed in many tissues and cells (3-10), and the structural requirements for binding have been defined (11) (Fig. 1). The rhaximal number of cells induced varied in a compound-specific fashion. The six most active agents induced 60-80% of the cells, while other less active ones induced no more than 20-40%, and tie least active compounds could induce only 10-15% of the cells. At supramaximal concentrations these less active BZDs did not cause further increase in the percent of benzidine-positive cells; instead they inhibited cell proliferation and eventually became Abbreviations: BZD, benzodiazepine; FEL, Friend erythroleukemia; Me2SO, dimethyl sulfoxide.

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“…Indeed, diazepam and adenosine share a similar physico-chemical structure (Bruns et al, 1983). Inhibition of adenosine uptake by BZDs, including diazepam, lorazepam, and flurazepam, has been demonstrated in different experimental preparations, including rat brain synaptosomes (Phillis et al, 1980) and guinea pig ventricle (Barker and Clanachan, 1982). A study showing that BZDs prevent NBTI binding revealed ENT1 as a specific target of these drugs (Hammond et al, 1981).…”

Section: Benzodiazepines and Adenosine Signalingmentioning

confidence: 99%