Inhibitory action of 4-aminopyridine on Ca(2+)-ATPase of the mammalian sarcoplasmic reticulum

Abstract

In the isolated guinea pig diaphragm muscle, 4-aminopyridine (4-AP) elicited a marked potentiation of twitch contraction evoked by direct electrical stimuli. Although tetraethylammonium (TEA) and charybdotoxin only slightly potentiated twitch contraction, 4-AP, but not TEA, also augmented a contractile response to caffeine. These effects of 4-AP on muscle contraction could not be interpreted by a simple inhibition of potassium channels on the plasma membrane. In the fragmented sarcoplasmic reticulum (SR) prepared from the guinea pig psoas muscle, 4-AP inhibited the ATP-driven Ca2+ uptake from the extravesicular medium. Furthermore, 4-AP at concentrations less than 10 mM elicited a selective inhibition of Ca(2+)-activated SR ATPase in a competitive manner against the Ca2+ concentration of the medium and 10 mM 4-AP showed the unsurmountable inhibition. 4-AP at 30 mM apparently inhibited activities of other ATPases such as Na+,K+- and myosin ATPases. In contrast, other potassium channel blockers such as TEA, apamin, charybdotoxin, and glibenclamide did not inhibit the SR function. These results suggest that, although the specific concentration range is rather small, 4-AP elicits an inhibition of SR Ca(2+)-pumping activity, leading to the marked potentiation of muscle contractile responses to electrical stimuli and caffeine.