Ethaverine, a derivative of papaverine, inhibits cardiac L-type calcium channels.

Abstract

Ethaverine is a derivative of papaverine used in the treatment of peripheral vascular disease and is thought to cause vasodilation by reducing intracellular Ca2+ concentrations in vascular smooth muscle cells. We tested its effects on single, dihydropyridine-sensitive, L-type calcium channels from porcine cardiac muscle, incorporated into planar lipid bilayers. L-type calcium channels were activated by step depolarizations from a holding potential of -60 mV to a test potential of 0 mV, and unitary currents carried by 100 mM BaCl2 were recorded. Channel activity was enhanced by the presence of the dihydropyridine agonist (+)-202-791 (0.5 microM) and the activated alpha subunit of the stimulatory GTP-binding protein, Gs. We found that 0.3-30 microM ethaverine on either side of the channel caused a reduction in the channel open probability (EC50 approximately 1 microM), with the higher concentrations inhibiting channel activity almost completely. In addition, the ethaverine caused a small reduction in the unitary current amplitude of single open channels (approximately 20%). To test whether the effect of ethaverine on open probability was due to a displacement of the dihydropyridine agonist, we studied the effect of ethaverine on the binding of [3H]nitrendipine to cardiac sarcolemma and found that ethaverine inhibited [3H]nitrendipine binding with a Ki of approximately 8.5 microM. Ethaverine also inhibited the binding of [3H]diltiazem and [3H]verapamil, with Ki values of 1-2 microM. Because ethaverine is structurally related to verapamil, it is likely that ethaverine acts by binding to the verapamil binding sites on the L-type calcium channels to inhibit channel activation and dihydropyridine binding.

• Authors: Y Wang, R L Rosenberg
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 40 Issue 5 Pg. 750-5 (Nov 1991) ISSN: 0026-895X [Print] United States
• PMID: 1658607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Calcium Channels
• Lipid Bilayers
• Parasympatholytics
• Phosphodiesterase Inhibitors
• ethaverine
• Nitrendipine
• Verapamil
• Papaverine

Topics

• Animals
• Calcium Channels (drug effects, physiology)
• Heart (drug effects)
• In Vitro Techniques
• Lipid Bilayers (metabolism)
• Nitrendipine (metabolism)
• Papaverine (analogs & derivatives, pharmacology)
• Parasympatholytics (pharmacology)
• Phosphodiesterase Inhibitors (pharmacology)
• Probability
• Sarcolemma (metabolism)
• Swine
• Verapamil (pharmacology)