New synthetic ligands for L-type voltage-gated calcium channels

Rampe, David; Triggle, David J.

doi:10.1007/978-3-0348-7147-1_7

Cited by 5 publications

(3 citation statements)

References 160 publications

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“…Indeed, the firstgeneration Ca 21 channel blockers were essentially "accidental" discoveries (although it is clear, however, that these drugs have proved subsequently to be invaluable molecular tools with which to dissect and analyze channel function). 1,5,14,15,169,171,172,179 Second, the drugs were discovered in biological assay systems with a direct and readily observable relationship between the measured response in vitro and in vivo-vascular smooth muscle tension and blood pressure-and the desired therapeutic goal of antianginal and antihypertensive activity. Third, the cardiovascular system is dominated by the activity of the Ca V l class of channel; hence, differential functional contributions by other classes of channel are relatively unimportant, and fine-tuning of drug action occurs essentially within one channel class.…”

Section: Discussionmentioning

confidence: 99%

“…Ca 21 channel activators, particularly, but not exclusively, of the 1,4-dihydropyridine class, are known, but only as molecular tools. [169][170][171][172] These activators serve as vasoconstrictors, positive inotropic agents, secretagogues, and stimulants of neurotransmitter release and induce complex behavioral syndromes consistent with actions in the central nervous system. 173 Some 1,4-dihydropyridine activators have been examined for their potentially selective actions as positive inotropic species, [174][175] but this has yet to translate to therapeutic utility.…”

Section: Ca 21 Channel Activatorsmentioning

confidence: 98%

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Drug Targets in the Voltage-Gated Calcium Channel Family: Why Some Are and Some Are Not

Triggle

2003

ASSAY and Drug Development Technologies

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The L-type calcium channel antagonists have been, and continue to be, a very successful group of therapeutic agents targeted at cardiovascular disorders, notably angina and hypertension. The discovery that the voltage-gated calcium channels are a large and widely distributed family with important roles in both the peripheral and central nervous systems has initiated a major search for drugs active at other calcium channel types directed at disorders of the central nervous system, including pain, epilepsy, and stroke. These efforts have not been therapeutically successful thus far, and small molecule equivalents of the L-type blockers nifedipine, diltiazem, and verapamil directed at non-L-type channels have not been found. The underlying reasons for this are discussed together with suggestions for new directions, including fertility control, oxygen-sensitive channels, and calcium channel activators.

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Section: Discussionmentioning

confidence: 99%

Section: Ca 21 Channel Activatorsmentioning

confidence: 98%

Drug Targets in the Voltage-Gated Calcium Channel Family: Why Some Are and Some Are Not

Triggle

2003

ASSAY and Drug Development Technologies

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“…This CaN-dependent signal is sensitive to the inhibition of calcium channel blockers, such as verapamil, or CaN inhibitors, such as cyclosporine A (CSA) and tacrolimus (FK-506) ( 52 – 54 ). L-type Ca 2+ channels are widely distributed in the heart, smooth and skeletal muscles ( 55 , 56 ). In the heart and smooth muscle cells, the L-type Ca 2+ channels are responsible for the inward movement of Ca 2+ , thereby causing contraction.…”

Section: Discussionmentioning

confidence: 99%

Calcium inhibitor inhibits high glucose‑induced hypertrophy of H9C2 cells

Ruan

Tian

et al. 2020

Mol Med Rep

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The aim of the present study was to explore whether the hypertrophy of H9C2 cardiomyocytes was induced by high glucose, to investigate whether the calcium channel inhibitor (Norvasc) could inhibit this process and to clarify the possible signaling pathways. The morphology of H9C2 cells was observed under an optical microscope, and the cell surface area was measured by Image Pro Plus 6.1 software. Furthermore, fluorescence spectrophotometry was used to detect intracellular calcium concentration ([Ca 2+ ]i). ELISA was performed to detect calcineurin (CaN) activity; reverse transcription-quantitative PCR and western blotting were performed to detect the mRNA and protein expression levels of CaN Aβ subunit (CnAβ), nuclear factor of activated T cells 3 (NFAT3) and β type myosin heavy chain (β-MHC). Cell size was increased with the increase in glucose concentration of culture medium at 48 and 72 h, respectively, and decreased with the addition of Norvasc compared with those without Norvasc (P<0.05). There was no significant difference in cell size with the addition of Norvasc compared with cells cultured with 5 mM glucose (P>0.05). The average [Ca 2+ ]i activity of single cells in the 48- and 72-h culture groups treated with 50 mM glucose was significantly higher than cells treated with 5 mM glucose (P<0.05); and the fluorescent value of average [Ca 2+ ]i activity of single cells was lower, following the addition of Norvasc than that without Norvasc (P<0.05). CaN activity in the 48- and 72-h culture group treated with 50 mM glucose was markedly higher than that treated with 5 mM glucose, and the activity of CaN notably decreased with the addition of Norvasc compared with those without Norvasc. The mRNA and protein expression levels of CnAβ, NFAT3 and β-MHC in the 48- and 72-h culture groups treated with 50 mM glucose were all significantly higher than those treated with 5 mM glucose (P<0.05). The mRNA and protein expression of CnAβ, NFAT3 and β-MHC cultured with 50 mM glucose were significantly decreased following the addition of Norvasc (P<0.05). Thus, the calcium channel inhibitor Norvasc may inhibit high glucose-induced hypertrophy of H9C2 cardiomyocytes by inhibiting the Ca 2+ -CaN-NFAT3 signaling pathway.

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Calciseptine, a Ca 2+ Channel Blocker, Has Agonist Actions on L-type Ca 2+ Currents of Frog and Mammalian Skeletal Muscle

García

Hernández-Gallegos

Escamilla

et al. 2001

Journal of Membrane Biology

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Calciseptine is a natural peptide consisting of 60 amino acids with four disulfide bonds. The peptide is a natural L-type Ca2+-channel blocker in heart and other systems, but its actions in skeletal muscle have not been previously described. The aim of this study is to characterize the effects of calciseptine on L-type Ca2+ channels of skeletal muscle and on contraction. Whole-cell, patch-clamp experiments were performed to record Ca2+ currents (I(Ca)) from mouse myotubes, whereas Vaseline-gap voltage-clamp experiments were carried out to record I(Ca) from frog skeletal muscle fibers. We found that calciseptine acts as a channel agonist in skeletal muscle, increasing peak I(Ca) by 37% and 49% in these two preparations. Likewise, the peptide increased intramembrane charge movement, though it had little effect on contraction. The molecular analysis of the peptide indicated the presence of a local, electrostatic potential that resembles that of the 1,4-dihydropyridine agonist Bay K 8644. These observations suggest that calciseptine shares the properties of 1,4-dihydropyridine derivatives in modulating the permeation of divalent cations through L-type channels.

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New synthetic ligands for L-type voltage-gated calcium channels

Cited by 5 publications

References 160 publications

Drug Targets in the Voltage-Gated Calcium Channel Family: Why Some Are and Some Are Not

Drug Targets in the Voltage-Gated Calcium Channel Family: Why Some Are and Some Are Not

Calcium inhibitor inhibits high glucose‑induced hypertrophy of H9C2 cells

Calciseptine, a Ca 2+ Channel Blocker, Has Agonist Actions on L-type Ca 2+ Currents of Frog and Mammalian Skeletal Muscle

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