European Journal of Pharmacology, 184 (1990) 151-161 151 Elsewer EJP 51423 Voltage-dependent action of valproate on potassium channels in frog node of Ranvier Mannus G. Van Erp 1, Antomus M.J Van Dongen and Rutgens J Van den Berg Departmentof Physwlogyand Physwlogwal Physics, Unwerstty of Letden, The Netherlands Recewed 12 February 1990, rexased MS received 17 April 1990, accepted 8 May 1990 The influence of the antl-epdeptlc drug, valproate, on K conductance (gK) was lnvesagated m voltage-clamped Ranwer nodes of Xenopus laews A double pulse method was used m order to ehnunate the effect of accumulatmn of potassium ions m the pennodal space, thus enabhng the determmatmn of the 'true' magmtude of gg Valproate (2 4 raM) had a voltage-dependent action on the magmtude of gg With small step depolanzattons more negative than about -50 mV, valproate mcreased gK (20 ms after the step) to approxamately 12% of the maxamal gK, an increase wluch d~sappeared due to a relatavely rap~d ( < 200 ms) reactivation process However, with step depolanzatmns more positive than about -50 mV, valproate markedly reduced gK (20 ms after the step) at greater depolanzataons, with a maxtmum of about 40% of the maxtmal gg Moreover, at these voltages gK was mactwated completely (~< 10 s), whereas under control condlttons the mactlvatmn was only partml Both the temporary mcrease and the steady state decrease of gK could contribute to an antl-epdeptlc effect by increasing the actmn potential threshold and by preventing excesswe depolarizations of the nerve dunng epdeptlc seizures, respectively Antl-epdeptlc drugs, Valproate, K + conductance, Voltage clamp, Node of Ranwer, (Voltage-dependent mlubltlon) 1.~edu~on Dunng the last decade valproate (valprolc acid, dl-propylaceuc acid) has become an important antl-epdeptlc drug because it shows strong antt- convulsant properUes without reducing serious side effects Its mechanism of actmn is not known, however, it has been postulated that valproate operates by increasing GABA-ergdc mtubltmn in the brain (Chapman et al, 1982, Prelsendorfer et al, 1987, Gram et al, 1988) An alternative hy- pothesis put forward by Johnston (1984) proposed that valproate acted on the voltage-regulated mn I Department of Chmcal Nenrophysmlogy,Umverslty Hospt- tal, P O Box 9600, 2300 RC Leiden, The Netherlands Correspondence to R J Van den Berg, Laboratory of Physi- ology, Wassenaarseweg 62, P O Box 9604, 2300 RC Leiden, The Netherlands channels of the nerve membrane Evidence for such an action has been found m isolated nerves of the sqmd axon (Fohlmelster et al, 1984), the frog node of Ranwer (Van Erp and Van Dongen, 1984, 1987, Van Dongen et al, 1986) and m cultured mouse neurons (McLean and Mac- Donald, 1986) Using the frog node of Ranvaer, we have dem- onstrated that valproate increases the threshold for spike generation, decreases the peak of the action potential, and reduces the maxamum forced finng frequency In agreement with these observa- uons, we have observed that voltage-dependent sodium and potassium currents, measured under voltage clamp conchtlons, are also reduced More- over, m the presence of valproate, the potassmm current Is more reduced at more posmve mem- brane potentials (Van Dongen et al, 1986) Since the accumulataon of K runs in the node dunng 0014-2999/90/$03 50 © 1990 Elsewer Soence Pubhshers B V (BiomedicalDlwslon)