Mechanisms of action of membrane calcium channel blockers and intracellular calcium antagonists

Rahwan, Ralf G.

doi:10.1002/med.2610030103

Cited by 39 publications

(14 citation statements)

References 95 publications

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“…At higher concentration, ve rapamil (10_6A/) and nifedipine (10~7A/) significantly affected both the magnitude of contraction as well as ED50. This indicates that effects of IBI depends on the calciumsensitive mechanism [Fleckenstein, 1982;Rahwan, 1983]. The calcium-sensitive site or source which contributes to the response of IBI, however, provides an interesting new challenge.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical Effects of Isothiocyanate Analog of Tolazoline on Rat Aorta and Human Platelets

Venkataraman

Hamada²,

Shams³

et al. 1989

J Vasc Res

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The isothiocyanate analog (IBI) of tolazoline produced contraction of the rat aortic strip, with an ED₅₀ value of 1.63 × 10^–5 M. The maximum contraction of the analog was nearly equal to that of tolazoline or phenylephrine. At 27 °C the tissue reactivity of phenylephrine and IBI was similar. When compared at equiactive concentrations, the total duration of contraction of IBI was three times longer than that of tolazoline. Thus, the longer duration of action of IBI may be attributed to the S=C=N group substitution of the molecule. IBI at 10^-6 M shifted the dose-response curve of phenylephrine to the right with reduction in maxima. Phentolamine and other α₁or α₂ adrenoceptor blockers failed to block the responses of IBI in aorta, whereas verapamil or nifedipine blocked the response significantly. It appears that IBI is acting through calcium-channel-sensitive or calcium-receptor-related mechanism(s). In aspirin-treated platelets from human plasma, a distinct phase of aggregation induced by epinephrine can be blocked by IBI with KB of 2 × 10^–5 M. This indicates a small but selective α₂ related action of IBI. The aggregation induced by ADP or second component of aggregation induced by epinephrine were also blocked by IBI at concentrations comparable to that of the 012-adrenoceptor-mediated response. This indicates a lack of specificity of IBI in differentiating various phases of aggregation. Therefore, as compared to tolazoline, IBI presents an interesting paradox in its interaction with various receptors or mechanisms in the vascular tissue and platelets.

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Section: Discussionmentioning

confidence: 99%

Paradoxical Effects of Isothiocyanate Analog of Tolazoline on Rat Aorta and Human Platelets

Venkataraman

Hamada²,

Shams³

et al. 1989

J Vasc Res

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“…The inhibitory effect of this drug was probably reduced by the elevated Ca 2+ (Janis and Triggle, 1991) present in the nutrient solution. Trifluoperazine (and other phenothiazine drugs) can affect the two principal ways by which the Ca mechanism can be interrupted: first by the blockade of the Ca 2+ channels of the cell membrane, thereby limiting entry of Ca 2+ into cells; and second, through blockade of intracellular receptors such as calmodulin (Popov, 1974;Rahwan, 1983). Calmodulin levels are typically elevated in actively growing regions of plants (Hauber et al, 1984;Muto and Miyachi, 1977;Zielinski, 1987;Ling and Assmann, 1992) and it is more probable that the latter mechanism is effectively inhibited by TFP.…”

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confidence: 99%

Effect of trifluoperazine and verapamil on herbicide stimulated growth of cotton

Allender¹

1997

Journal of Plant Nutrition

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Pretreatment of hydroponically-grown cotton with trifluoperazine (TFP) and verapamil (VPL), respectively, inhibited 2,4-dichlorophenoxyacetic acid (2,4-D) and metribuzin [4-amino-6-tert-butyl-3-methylthiol,2,4-triazin-5(4H)-one (MTZ)]-induced hormetic growth as measured by total leaf areas and dry weights. Trifluoperazine, an anti-calmodulin drug, proved to be a more effective inhibitor of hormetic growth than VPL, a calcium (Ca 2+ )-channel antagonist. It is suggested that Ca 2+ influx is involved in the growth increase observed in hormesis.

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“…Since aging results in decreased plasma membrane fluidity with concomitant conformational changes [22,23], it was deemed less than ideal to only utilize as pharmacological tools the membrane calcium channel blockers (e.g., nifedipine) whose action is primarily exerted at the level of the cell membrane [24], This is because any observed agerelated changes in sensitivity to these agents might reflect altered binding kinetics to their membrane binding sites in a conformationally altered membrane rather than changes in muscle sensitivity to their actual pharma cological effect. Hence, another calcium an tagonist selected for this study was propylmethylenedioxyindene (pr-MDI) [for re views, see ref.…”

Section: Introductionmentioning

confidence: 99%

Age-Related Changes in Responsiveness of the Rat Aorta to Depolarizing and Receptor-Mediated Contractile Stimuli and to Calcium Antagonism1

Olah

Rahwan²

1987

Pharmacology

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This study was undertaken to determine the relative age-dependent responsiveness of the rat aorta to depolarizing (potassium) and receptor-activating (norepinephrine) contractile stimulants, and to the calcium antagonists propyl-methylenedioxyindene (pr-MDI) and nifedipine. Pr-MDI exhibits intracellular calcium antagonistic and calcium channel blocking properties in this tissue, while nifedipine acts principally as a calcium channel blocker. Thoracic strips from young (4–6 months old) and senescent (22–23 months old) Fischer F344 rats were contracted with KCl (10–60 mmol/l) or norepinephrine (10^–9–5 × 10^–6 mol/l). Aortae from old rats were significantly more sensitive to norepinephrine than aortae from young rats, while the reverse was observed for KCl. Pr-MDI (10^–5–10^–4 mol/l) significantly relaxed the aortic contractions induced by norepinephrine (10–7 mol/l, a nondepolarizing concentration producing 88% of maximum response in young and old aortae) and by KCl (50 mmol/l, a depolarizing concentration producing 96 % of maximum response in young and old aortae). However, there were no age-related differences in sensitivity to the relaxant effects of pr-MDI against either stimulant. Pr-MDI was more effective in relaxing KCl-induced contractions than those induced by norepinephrine. Similar results were obtained with nifedipine (10^–10–10^–6 mol/l). These results indicate that senescence of the rat aorta is accompanied by an enhanced responsiveness of adrenergic α-receptor-mediated contraction, a reduced responsiveness to depolarizing stimuli, and no change in sensitivity to calcium antagonism.

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Mechanisms of action of membrane calcium channel blockers and intracellular calcium antagonists

Cited by 39 publications

References 95 publications

Paradoxical Effects of Isothiocyanate Analog of Tolazoline on Rat Aorta and Human Platelets

Paradoxical Effects of Isothiocyanate Analog of Tolazoline on Rat Aorta and Human Platelets

Effect of trifluoperazine and verapamil on herbicide stimulated growth of cotton

Age-Related Changes in Responsiveness of the Rat Aorta to Depolarizing and Receptor-Mediated Contractile Stimuli and to Calcium Antagonism1

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