Open state block by fendiline of L-type Ca++ channels in ventricular myocytes from rat heart.
The effects of fendiline on L-type Ca++ currents [ICa(L)] were investigated in rat ventricular cardiomyocytes using the patch-clamp technique both in the whole-cell disrupted-patch and in the cell-attached configuration. For comparison, the effects of verapamil were also investigated. Both compounds depressed the magnitude of whole cell ICa(L), verapamil being about 15 times more potent than fendiline. Verapamil did not change the time course of the current, whereas fendiline accelerated its decay when either Ca++ or Ba++ ions were used as charge carriers. In the presence of the Ca++ agonist BayK8644 (10 microM), the potency ratio of fendiline/verapamil was inverted. BayK8644 (10 microM) also reversed the potency ratio of verapamil/fendiline in smooth muscle, with respect to changes in tension induced by K+ (48 mM). In single channel recordings at 0.1 Hz, in the presence of BayK8644 (1 microM) and using Ba++ ions as the charge carrier, fendiline (1 microM) reduced mean open time by 34% and channel availability by 8%; the ensemble average current of Ca++ channels was reduced by 43%. In the same experimental conditions, verapamil (1 microM) was ineffective. These results can be explained by the assumption that fendiline blocks Ca++ channels preferentially in the open state, in contrast to verapamil which blocks preferentially inactivated Ca++ channels.
Nawrath
H
H
Pharmakologisches Institut der Universität Mainz, Germany.
Klein
G
G
Rupp
J
J
Wegener
J W
JW
Shainberg
A
A
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D020746:Calcium Channels, L-Type; D005260:Female; D005275:Fendiline / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D005275:Fendiline