What is the clinical evidence from this study?

Study design: Observational. Population: Hypokalemic periodic paralysis (HOPP) (n=5). Intervention: R528H mutation of the dihydropyridine receptor (HOPP) vs. Healthy subjects. Primary outcome: Sarcolemma KATP current density and channel subconductance states.

March 1, 1999Journal of Clinical Investigation109 citationsOpen Access

Impairment of skeletal muscle adenosine triphosphate–sensitive K+ channels in patients with hypokalemic periodic paralysis

DTDomenico TricaricoUniversity of Bari Aldo Moro SSSerenella ServideiUniversità Cattolica del Sacro Cuore PTP. TonaliUniversità Cattolica del Sacro Cuore

Key Result

Muscle biopsies from patients with hypokalemic periodic paralysis carrying the R528H mutation showed a severely reduced sarcolemma KATP current with abnormal subconductance states that was not stimulated by MgADP, unlike healthy controls.

Study Design

Type

Observational (n=5)

Structured PICO

Population

5 subjects (3 patients with hypokalemic periodic paralysis carrying the R528H mutation and 2 healthy controls) whose muscle biopsies were analyzed for KATP channel activity.

Exposure

In vitro patch clamp recordings of sarcolemma KATP currents with exposure to MgADP, MgATP, cromakalim, and low-K+ solutions.

Comparator

Muscle biopsies from healthy subjects and rat muscles incubated in normokalemic solution.

Outcome

Sarcolemma KATP current amplitude and single-channel subconductance states.surrogate

HOPP patients carrying the R528H mutation exhibit impaired skeletal muscle KATP channels with abnormal subconductance states, providing a mechanistic explanation for disease symptoms such as hypokalemia and depolarization.

Limitations

Very small sample size (3 patients and 2 healthy controls)
In vitro experimental conditions in excised patches may not fully replicate in vivo metabolic influences

Abstract

The adenosine triphosphate (ATP)-sensitive K+ (KATP) channel is the most abundant K+ channel active in the skeletal muscle fibers of humans and animals. In the present work, we demonstrate the involvement of the muscular KATP channel in a skeletal muscle disorder known as hypokalemic periodic paralysis (HOPP), which is caused by mutations of the dihydropyridine receptor of the Ca2+ channel. Muscle biopsies excised from three patients with HOPP carrying the R528H mutation of the dihydropyridine receptor showed a reduced sarcolemma KATP current that was not stimulated by magnesium adenosine diphosphate (MgADP; 50-100 microM) and was partially restored by cromakalim. In contrast, large KATP currents stimulated by MgADP were recorded in the healthy subjects. At channel level, an abnormal KATP channel showing several subconductance states was detected in the patients with HOPP. None of these were surveyed in the healthy subjects. Transitions of the KATP channel between subconductance states were also observed after in vitro incubation of the rat muscle with low-K+ solution. The lack of the sarcolemma KATP current observed in these patients explains the symptoms of the disease, i.e., hypokalemia, depolarization of the fibers, and possibly the paralysis following insulin administration.

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