Biophysical changes of skeletal muscle K-ATP channels in K+ depleted rats and pharmacological interventions.

W-Pos2 BIOPHYSICAL CHANGES OF SKELETAL MUSCLE KATP CHANNELS IN Kl DEPLETED RATS AND PHAIRMAOLOGICAL INTERVENTION'S ((D. Tricarico. R. Mallamaci. V. Tortorella* and D. Conte Camerino)) Dept. of Pharmacobiology, and Dept. of Medicinal Chlsmisqn*. Faculty of Pharmacy. Universitv of Bari, Bari, ITALY. Recently, mutations in the gene encoding the al-subunit of the skeletal muscle Ca2'channel have been found in patients affected by hypokalemic periodic paralysis (HOPP) (Sipos et al.. J.Phvsiol. 483.2-299, 1995). However, the link between the fiber depolarization, the paralysis and the Ca2+ channel mutation is still obscure. The administration of ATP sensitive K' channels (KATp) openers, pinacidil and cromakalim, to HOPP patients prevents the muscle paralysis. In the present work we investigated the properties of KATP channels of skeletal muscle fibers of K' depleted rats (Hypo K'), the animal model of HOPP. In these rats, we tested cromakalim, and vanadate and me.xiletine, drugs that have been shown to open KATP channels of cardiac cells. A treatment of male Wistar rats with K' free diet for 38-45 days led to a drop of serum K' level from 5.0+0.1 meq/L in the normokalemic rats (normo K-) to 2.6+0.2 meq/L in the Hypo K' rats. In these animals, the resting potential of the extensor digitorum longus (EDL) muscle fibers of the Hypo K+ rats, recorded by the two microelectrode technique. was drastically reduced. Further depolarization occurred after "in vivo" and "in vitro" administration of insulin. Similar phenomenas occurs in HOPP patients. Patch clamp recordings, showed that the mean current of KATP channel was reduced in the Hypo K' rats. Two types of KATP channels have been found in the Hypo K+ rats. The first type, had a low single channel conductance (y) of 29+4 pS. Whereas, y was 71+1 pS in the normo K' rats. The second type had a KATP channel with normal y but an altered selectivity to K' ion. Both types of channels partially lost the sensitivity to both MgATP and MgADP. Cromakalim (10- 100 FM), vanadate (500 FLM) and mexiletine (100-500 ,uM) restored the KATP conductance and prevented the fiber depolarization induced by insulin in Hypo K+ rats. Our data indicate that closure of KATP channels contributes to the fiber depolarization in the Hypo K+ rats. and that this animal model is suitable to search for therapeutic strategies in HOPP. (Telethon-Italy. project n° 579).