Tu-Pos390 MODULATION OF K+ CHANNEL ACTIVITY OF STRIATED FIBERS OF HYPOKALEMIC RATS UNDERLIES THE THERAPEUTICAL EFFICACY OF MINOXIDIL AND ACETAZOLAMIDE. ((D. Tricaiico, M. Barbieri, R. Mallamaci , R. Capriulo* and D. Conte Camerino)) Dept. of Pharnacobiology, Faculty of Pharmacy and *Clinic of Aniestesiology and Intensive Care, Faculty of Medicine, University of Bari, ITALY. K' depleted rats (hypoK rats) resemble humans affected by hypokalemic periodic paralysis for the serum K+ levels lower than 3.2meq/L, the muscle fiber depolarization and the attacks of paralysis induced by acute injection of insulsn (4U/IOOgr) and/or glucose (0.5gr) (Lehmann- Hom et al., Myology: 1303-1310,1994). Moreover, skeletal muscle fibers of hypoK rats have an abnormally lower activity of ATP sensitive K' channels (KATp) (Tricarico et al., Biophys.J. 72/2:A249, 1997). We observed by patch clamp recordings, that in vitro application of minoxidil sulphate increased KATP activity of normokalemic rat striated fibers (ED55=465±4pM) and significantly restored KATP currents of hypoK rats fibers (ED50=11±2gM). Accordingly, minoxidil sulphate (1-100lM) repolarized hypoK rats fibers, effect antagonized by glybenclamide (60-lO0nM). To evaluate the potential benefit of in vivo administration of minoxsdil to hypoK rats, 8 depleted animals were treated for 10 days with 18jg/kg/die minoxidil. The effects were compared with those of 2.8mg/kg/die acetazolamide (4 hypoK rats), a drug currently used in the therapy of human hypokalemic periodic paralysis. Acetazolamide restored normal serum K' levels, whereas minoxidil did not. However, 50% of the rats treated with either minoxidil or acetazolamide were not paralyzed after the acute injection of insulin and glucose. In vitro recordings on muscle fibers from no-paralyzed treated rats showed normal values of resting potential and further hyperpolarization in low K' solution. This effect was antagonized by glybenclamide in minoxidil treated and by charybdotoxin in the acetazolamide treated rat fibers. Furthermore, patch clamp recordings showed that the treatment with minoxidil restored the KATP channel activity whereas acetazolamide increased Ca2+activated K+ channel activity. These results suggest that KATP channel openers could be beneficial in the therapy of hypokalemic periodic paralysis and increase our understanding on the mechanism of action of acetazolamide. (Telethon Italy project n°579).
Modulation of K+ channel activity of striated fibers of hypokalemic rats underlies the therapeutical efficacy of minoxidil and acetazolamide.
MALLAMACI, Rosanna;
1998-01-01
Abstract
Tu-Pos390 MODULATION OF K+ CHANNEL ACTIVITY OF STRIATED FIBERS OF HYPOKALEMIC RATS UNDERLIES THE THERAPEUTICAL EFFICACY OF MINOXIDIL AND ACETAZOLAMIDE. ((D. Tricaiico, M. Barbieri, R. Mallamaci , R. Capriulo* and D. Conte Camerino)) Dept. of Pharnacobiology, Faculty of Pharmacy and *Clinic of Aniestesiology and Intensive Care, Faculty of Medicine, University of Bari, ITALY. K' depleted rats (hypoK rats) resemble humans affected by hypokalemic periodic paralysis for the serum K+ levels lower than 3.2meq/L, the muscle fiber depolarization and the attacks of paralysis induced by acute injection of insulsn (4U/IOOgr) and/or glucose (0.5gr) (Lehmann- Hom et al., Myology: 1303-1310,1994). Moreover, skeletal muscle fibers of hypoK rats have an abnormally lower activity of ATP sensitive K' channels (KATp) (Tricarico et al., Biophys.J. 72/2:A249, 1997). We observed by patch clamp recordings, that in vitro application of minoxidil sulphate increased KATP activity of normokalemic rat striated fibers (ED55=465±4pM) and significantly restored KATP currents of hypoK rats fibers (ED50=11±2gM). Accordingly, minoxidil sulphate (1-100lM) repolarized hypoK rats fibers, effect antagonized by glybenclamide (60-lO0nM). To evaluate the potential benefit of in vivo administration of minoxsdil to hypoK rats, 8 depleted animals were treated for 10 days with 18jg/kg/die minoxidil. The effects were compared with those of 2.8mg/kg/die acetazolamide (4 hypoK rats), a drug currently used in the therapy of human hypokalemic periodic paralysis. Acetazolamide restored normal serum K' levels, whereas minoxidil did not. However, 50% of the rats treated with either minoxidil or acetazolamide were not paralyzed after the acute injection of insulin and glucose. In vitro recordings on muscle fibers from no-paralyzed treated rats showed normal values of resting potential and further hyperpolarization in low K' solution. This effect was antagonized by glybenclamide in minoxidil treated and by charybdotoxin in the acetazolamide treated rat fibers. Furthermore, patch clamp recordings showed that the treatment with minoxidil restored the KATP channel activity whereas acetazolamide increased Ca2+activated K+ channel activity. These results suggest that KATP channel openers could be beneficial in the therapy of hypokalemic periodic paralysis and increase our understanding on the mechanism of action of acetazolamide. (Telethon Italy project n°579).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
