Modulation of the Ca(2+) release channel of sarcoplasmic reticulum by amiloride analogs.

Dichlorobenzamil, phenamil and other amiloride analogs (1-100 microM) elicit transient tension in rabbit skinned muscle fibers. Tension requires preloading of Ca(2+) into the sarcoplasmic reticulum, is facilitated by low-[Mg(2+)] solutions, abolished by ruthenium red or by functional disruption of the sarcoplasmic reticulum, and is followed by inhibition of the caffeine-evoked tension. Bilayer recording of Cs(+) currents through the sarcoplasmic reticulum Ca(2+) release channel reveals that phenamil (10-100 microM) increases the open channel probability, whereas dichlorobenzamil affects the channel activity in a complex concentration- and time-dependent manner: stimulation occurs throughout exposure to 10 microM, but is followed by channel blockade when 100 microM dichlorobenzamil is used. It is concluded that stimulation of the sarcoplasmic reticulum Ca(2+) release channel accounts for the dichlorobenzamil- or phenamil-induced tension in skinned fibers, whereas depletion of sarcoplasmic reticulum Ca(2+) stores and channel block (with dichlorobenzamil) explains the inhibition of the caffeine-evoked tension by amiloride analogs.