2,5‐Di(<i>tert</i>‐butyl)‐1,4‐benzohydroquinone — a novel inhibitor of liver microsomal Ca<sup>2+</sup> sequestration

Moore, Gregory A.; McConkey, David J.; Kass, Georges; O’Brien, Peter J.; Orrenius, Sten

doi:10.1016/0014-5793(87)80479-9

Cited by 205 publications

(96 citation statements)

References 30 publications

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“…BHQ was first characterised as an inhibitor of the Ca" pump in the hepatic endoplasmic reticulum (Moore et al 1987). Subsequently, BHQ was found to inhibit also the Caz+ pump in sarcoplasmic reticulum vesicles isolated from skeletal muscle (Wictome et al 1992;Nakamura et al 1992) Furthermore, BHQ is a potent, specific and reversible inhibitor of the sarcoplasmic reticulum Ca'+ pump in intact mouse skeletal muscle (Westerblad & Allen 1994) and completely blocks Ca2+ uptake with half maximum concentration of 1.6 pM in a rat heart muscle homogenate (Ravens et a1 unpublished results).…”

Section: Effects Of Drugsmentioning

confidence: 99%

Mechanical Restitution in Atrial Muscle from Human and Rat Hearts: Effects of Agents that Modify Sarcoplasmic Reticulum Function

Ravens¹,

Gath²,

Hussaini³

et al. 1997

Pharmacology & Toxicology

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Abstract; Force of contraction (F,) of isolated human and rat atrial myocardium shows characteristic patterns of mechanical restitution when single test intervals are interposed in regular stimulation. With several pharmacological agents that modify the function of the sarcoplasmic reticulum we have investigated the role of the sarcoplasmic reticulum in mechanical restitution in these two species. Caffeine, thapsigargin and 2,5-di-(terr-butyl)-l ,4-benzohydroquinone (BHQ) were used to reduce Ca'+ uptake, ryanodine to open Ca2+ release channels, and forskolin to stimulate Ca'+ uptake. Under control conditions, F, recovered rapidly with test intervals shorter than steady-state. and was potentiated with longer than steadystate intervals. In human atrial tissue the maximum potentiation factor was 1.2620.03 after a mean test interval of 9.70% 1.55 s (n=43) as compared to 3.07%0.45 after 30 sec. in rat atria (n=48). Caffeine (3 mM) did not significantly affect steady-state F, but abolished post-rest potentiation in human and rat preparations. Forskolin ( I pM) enhanced and accentuated the mechanical restitution curve in particular for short test intervals. In the presence of thapsigargin (10 pM), steady-state F, and mechanical restitution could not be distinguished from time-matched controls exposed to solvent only.indicating that this agent is ineffective in human and rat atrial tissue. In contrast, the putative Ca2+ uptake inhibitor BHQ (100 pM) strongly reduced steady-state F, and decreased potentiation at all intervals in human muscle, but shifted the mechanical restitution curve in parallel to lower values in rat atria. Ryanodine (10 nM) induced post-rest decay in human and depressed both steady-state F, and post-rest potentiation in rat atrial muscle. From these results it is concluded that human and rat atrial muscle differ in the Ca2+ handling by the sarcoplasmic reticulum during mechanical restitution.In heart muscle, Ca2+ entry via L-type Ca2+ channels triggers the release of further Ca2+ from the sarcoplasmic reticulum. The increase in cytosolic C2+concentration activates contractile proteins for force production. During relaxation, Ca*+ is taken up again into the sarcoplasmic reticulum by the ATP-dependent Ca2+ pump and an amount equivalent to the systolic Ca" entry is transported out of the cell mainly via the Na+/Ca'+ exchanger. When regular pacing is disturbed by a single test pulse of variable interval, force of contraction (F,) changes in a characteristic pattern. The relationship between force of an interposed contraction and the preceding test interval is referred to as mechanical restitution. It consists of three phases (Schouten 1990): The initial one is a short and rapid phase of recovery for intervals shorter than steady-state. The second phase during which F, is potentiated with longer than regular intervals is followed by a third phase of force decline (post-rest decay).The adaptive changes in F, during mechanical restitution are considered to represent a physiological correlate of cellular Ca...

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Section: Effects Of Drugsmentioning

confidence: 99%

Mechanical Restitution in Atrial Muscle from Human and Rat Hearts: Effects of Agents that Modify Sarcoplasmic Reticulum Function

Ravens¹,

Gath²,

Hussaini³

et al. 1997

Pharmacology & Toxicology

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“…Recently, using permeabilised chromaffin cells, it has been possible to establish that these two stores are in fact distinct [ 141; and also to provide further evidence that the stores contain distinct Ca*+ ATPase-like proteins, using the Ca*'-ATPase inhibitor thapsigargin [14-161. In this present study we used another Ca*'-ATPase inhibitor 2,5-di-(tert-butyl)-1,4-benzohydroquinone (tuI3HQ) to further characterise the internal stores in chromaffin cells, this compound having previously been used to study Ca"-ATPase and Ca'+ release in rat liver microsomes [17,18] and permeabilised rat hepatocytes [ 191. …”

Section: Introductionmentioning

confidence: 99%

A distinct 2,5‐di‐(tert‐butyl)‐1,4‐benzohydroquinone‐sensitive calcium store in bovine adrenal chromaffin cells

Robinson

Burgoyne

1991

FEBS Letters

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The Ruorescent Ca" indicator Fura 2 was used to monitor Ca" release induced by the Ins( 1,4,5)P,-mobilizing agonist angiotensin II (Ag II) Stimulation of the cells with tuBHQ before either Ag II or caffeine, similarly had no effect on Ca*' released by these two agonists. It was concluded, therefore, that there is a third intracellular Ca" store in bovine adrenal chromaffin cells, distinct and non-overlapping, from those sensitive to caffeine or Ins(l,4,5)P,-mobilizing agonists.

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“…We have also confirmed in permeabilized cells results that they obtained in microsomes showing that unidirectional 45Ca2+ efflux from preloaded stores is unaffected by tBuBHQ (results not shown). The effect of tBuBHQ is therefore to inhibit Ca 2÷ sequestration by the stores and not to stimulate a Ca 2+ efflux pathway suggesting that the inhibitory effects of tBuBHQ on microsomal Ca2+-ATPase [12] probably underlie its effects on intracellular Ca 2+ stores.…”

Section: Resultsmentioning

confidence: 98%

2,5‐Di‐(tert‐butyl)‐1,4‐benzohydroquinone mobilizes inositol 1,4,5‐trisphosphate‐sensitive and ‐insensitive Ca²⁺ stores

1990

FEBS Letters

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In permeabilized rat hepatocytes a maximal concentration (25/tM) of 2, mobilized 70% of sequestered Ca 2+ and a half-maximal effect was produced by 1.7/iM tBuBHQ. Inositol 1,4,5-trisphosphate (Ins(l,4,5)P3) stimulated release of about 40% of the intracellular Ca 2+ stores. Combined applications of a range of tBuBHQ concentrations with a maximal concentration of Ins(1,4,5)P 3 demonstrated that tBuBHQ has slight selectivity for the Ca 2÷ transport process of the Ins(1,4,5)P3-sensitive stores. We conclude that the Ins( 1,4,5)P3-sensitive stores are a subset of those sensitive to tBuBHQ and that the latter is therefore unlikely to prove useful as a tool to discriminate Ins(1,4,5)P3-sensitive and -insensitive Ca 2÷ stores though it may provide opportunities to design more selective agents.Inositol 1,4,5-trisphosphate; Intracellular Ca 2÷ store; 2,

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2,5‐Di(tert‐butyl)‐1,4‐benzohydroquinone — a novel inhibitor of liver microsomal Ca²⁺ sequestration

Cited by 205 publications

References 30 publications

Mechanical Restitution in Atrial Muscle from Human and Rat Hearts: Effects of Agents that Modify Sarcoplasmic Reticulum Function

Mechanical Restitution in Atrial Muscle from Human and Rat Hearts: Effects of Agents that Modify Sarcoplasmic Reticulum Function

A distinct 2,5‐di‐(tert‐butyl)‐1,4‐benzohydroquinone‐sensitive calcium store in bovine adrenal chromaffin cells

2,5‐Di‐(tert‐butyl)‐1,4‐benzohydroquinone mobilizes inositol 1,4,5‐trisphosphate‐sensitive and ‐insensitive Ca²⁺ stores

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2,5‐Di(tert‐butyl)‐1,4‐benzohydroquinone — a novel inhibitor of liver microsomal Ca2+ sequestration

Cited by 205 publications

References 30 publications

Mechanical Restitution in Atrial Muscle from Human and Rat Hearts: Effects of Agents that Modify Sarcoplasmic Reticulum Function

Mechanical Restitution in Atrial Muscle from Human and Rat Hearts: Effects of Agents that Modify Sarcoplasmic Reticulum Function

A distinct 2,5‐di‐(tert‐butyl)‐1,4‐benzohydroquinone‐sensitive calcium store in bovine adrenal chromaffin cells

2,5‐Di‐(tert‐butyl)‐1,4‐benzohydroquinone mobilizes inositol 1,4,5‐trisphosphate‐sensitive and ‐insensitive Ca2+ stores

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2,5‐Di(tert‐butyl)‐1,4‐benzohydroquinone — a novel inhibitor of liver microsomal Ca²⁺ sequestration

2,5‐Di‐(tert‐butyl)‐1,4‐benzohydroquinone mobilizes inositol 1,4,5‐trisphosphate‐sensitive and ‐insensitive Ca²⁺ stores