Modulation of the Ca2+ release channel of sarcoplasmic reticulum by amiloride analogs

Dichlorobenzamil, phenamil and other amiloride analogs (1-100 mu M) elicit transient tension in rabbit skinned muscle fibers. Tension requires preload ing of Ca2+ into the sarcoplasmic reticulum, is facilitated by low-[Mg2+] s olutions, abolished by ruthenium red or by functional disruption of the sar coplasmic reticulum, and is followed by inhibition of the caffeine-evoked t ension. Bilayer recording of Cs+ currents through the sarcoplasmic reticulu m Ca2+ release channel reveals that phenamil(10-100 mu M) increases the ope n channel probability, whereas dichlorobenzamil affects the channel activit y in a complex concentration- and time-dependent manner: stimulation occurs throughout exposure to 10 mu M, but is followed by channel blockade when 1 00 mu M dichlorobenzamil is used. It is concluded that stimulation of the s arcoplasmic reticulum Ca2+ release channel accounts for the dichlorobenzami l- or phenamil-induced tension in skinned fibers, whereas depletion of sarc oplasmic reticulum Ca2+ stores and channel block (with dichlorobenzamil) ex plains the inhibition of the caffeine-evoked tension by amiloride analogs. (C) 2000 Published by Elsevier Science B.V. All rights reserved.