Ethaverine, a derivative of papaverine, inhibits cardiac L-type calcium channels.
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.
Wang
Y
Y
Department of Pharmacology, University of North Carolina, Chapel Hill 27599.
Rosenberg
R L
RL
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008051:Lipid Bilayers / Q000378:metabolism; D009568:Nitrendipine / Q000378:metabolism; D010208:Papaverine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011336:Probability; D012508:Sarcolemma / Q000378:metabolism; D013552:Swine; D014700:Verapamil / Q000494:pharmacology
D015220:Calcium Channels; D008051:Lipid Bilayers; D010276:Parasympatholytics; D010726:Phosphodiesterase Inhibitors; C007639:ethaverine; D009568:Nitrendipine; D014700:Verapamil; D010208:Papaverine