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Tetrandrine is not a selective calcium channel blocker in vascular smooth muscle
1Department of Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Abstract:
The effects of tetrandrine (Tet) on the contractile properties of rat aortic ring preparations were studied to test the hypothesis that Tet is a Ca2+ antagonist acting on voltage-operated Ca2+ channels (VOC). The tests were performed on contractions induced by depolarizing concentrations of KCl and by alpha 1-adrenoceptor agonist, phenylephrine (Phe). These vascular effects of Tet were compared to those of nifedipine (Nif). We found that Tet behaved qualitatively similar to, but less potent than, Nif in that it inhibited KCl-induced contraction in a concentration-dependent fashion and its inhibitory effect was long-lasting. However, the effects on Phe-induced contraction of Tet was different from those of Nif in that the extracellular Ca(2+)-dependent contraction was inhibited by Tet, but not by Nif. Tet (60 mumol.L-1) completely inhibited the 45Ca2+ uptake induced by KCl and Phe in rat aortic muscle strips. When the aortic muscle contractile response was induced by addition of Ca2+ following depletion of intracellular stores by Phe in the presence of sarcoplasmic reticulum Ca(2+)-pump inhibitor, cyclopiazonic acid, Tet (60 mumol.L-1) was more effective than Nif 1 mumol.L-1 in inhibiting such a response to extracellularly added Ca2+. Furthermore, Tet, but not Nif, also significantly inhibited the contraction to Phe in Ca(2+)-free medium. Collectively, these results led us to conclude that Tet does not behave as a selective VOC blocker like Nif.
Insights
Tetrandrine (Tet) inhibits KCl-induced contractions similarly to nifedipine but affects phenylephrine-induced contractions differently, suggesting it is not a selective voltage-operated calcium channel blocker.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Calcium Channel Blockade
Background:
- Tetrandrine (Tet) is investigated for its effects on vascular smooth muscle.
- Calcium channels play a crucial role in regulating vascular contractility.
- Understanding Tet's mechanism is important for its potential therapeutic applications.
Purpose of the Study:
- To test the hypothesis that Tetrandrine (Tet) acts as a calcium (Ca2+) antagonist on voltage-operated calcium channels (VOC).
- To compare the vascular effects of Tetrandrine with nifedipine (Nif).
- To elucidate the specific mechanisms by which Tetrandrine modulates vascular smooth muscle contraction.
Main Methods:
- Rat aortic ring preparations were used to study contractile properties.
- Contractions were induced using potassium chloride (KCl) and phenylephrine (Phe).
- 45Ca2+ uptake and responses to extracellular Ca2+ were measured.
Main Results:
- Tetrandrine inhibited KCl-induced contractions concentration-dependently, similar to nifedipine but less potent.
- Tetrandrine inhibited extracellular Ca2+-dependent contractions induced by phenylephrine, unlike nifedipine.
- Tetrandrine significantly inhibited 45Ca2+ uptake induced by both KCl and Phe.
- Tetrandrine was more effective than nifedipine in inhibiting contractions induced by extracellular Ca2+ after store depletion.
Conclusions:
- Tetrandrine does not act as a selective voltage-operated calcium channel blocker.
- Tetrandrine exhibits complex inhibitory effects on vascular smooth muscle contraction.
- Its mechanism of action differs from that of nifedipine, involving more than just VOC blockade.