Long‐lasting in vivo inotropic effects of the K⁺ channel blocker 3,4‐diaminopyridine during fatigue‐inducing stimulation

Blocking K(+) channels with aminopyridines enhances muscle contractile performance in vitro, but the improvements are relatively short-lasting during fatigue-inducing stimulation. We hypothesized that in vivo inotropic actions persist over long periods of fatigue-inducing stimulation. The effects of 3,4-diaminopyridine (DAP) were evaluated for rat extensor digitorum longus (EDL) muscle. DAP increased twitch force by 105%. There was a significant leftward shift in the force-frequency relationship, with force values being increased at frequencies up to and including 20 HZ. During repetitive fatigue-inducing 20-HZ stimulation, DAP-induced force increases were large and persisted significantly for at least 30 minutes. Thus, DAP substantially improves contractile performance of EDL muscle in vivo for much longer periods during fatigue-inducing contractions than in vitro. These data provide support for a potential role for aminopyridines as inotropic agents in applications such as functional electrical stimulation, in which low to medium stimulation frequencies are typically utilized.