In-vitro Untersuchungen zur Amphotericin B-induzierten Hypokaliämischen Periodischen Paralyse
Auch gedruckt in der BibliothekZ: J-H 14.271; W: W-H 12.723
Ressourcen- / MedientypDissertation, Text
Datum der Freischaltung2011-12-05
Familial hypokalemic periodic paralysis is a rare inherited muscle disease characterised by episodic attacks of flaccid muscle paralysis. These episodes go along with an increased shift of K+ ions into muscle, what results in hypokalemia. There is also a depolarization of muscle fibers to membrane potentials at which voltage-gated channels are inactivated. In the end, this results in inexcitability and the characteristic paralysis. It is caused by mutations in the voltage-sensing domain of voltage-gated sodium or calcium channels of skeletal muscle. It is supposed that these mutations create a cation leak, which might be the primary pathogenetic cause of the disease. Acetazolamide (AZ), a carboanhydrase-inhibitor, seems to be an effective therapy. In reference to this guess, we conducted an in-vitro study on rat skeletal muscle preparations that we made leaky for cations by Amphothericin B (AMB) and measured the membrane potential with glass microelectrodes. AMB is an ionophore clinically used as an antifungal drug and is well known for its serious side effects. The study showed that there are two populations of fibers with regard to the resting membrane potential. One is polarized close to the Nernst potential of K+, the other is depolarized to about - 60 mV. In low [K+], the fraction of depolarized fibers is larger. The leak induced by AMB leads to the result that there are more depolarized fibers at intermediate [K+] compared to control. Studies with AZ showed that in low [K+] the fraction of polarized fibers is increased about thirty percent. The conclusion is that a depolarizing leak might shift the region of bistability of resting membrane potentials to near physiologic [K+]. Our study shows that AMB increases the fraction of depolarized muscle fibers at physiologic and reduced [K+]. Thus, AMB might be a suitable pharmacological model for hypokalemic periodic paralysis and AZ a stabilizer for the membrane potential.
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