Bumetanide prevents transient decreases in muscle force in murine hypokalemic periodic paralysis

Abstract

The Na-K-2Cl inhibitor bumetanide was highly effective in preventing attacks of weakness in the NaV1.4-R669H mouse model of HypoPP and should be considered for management of patients with HypoPP due to sodium channel mutations. Dehydration may aggravate HypoPP by stimulating the Na-K-2Cl transporter.

Channelopathies of Skeletal Muscle Excitability

“…The Cl − gradient is an important modifier for susceptibility to depolarization of HypoPP fibers in low K + (87, 277). This effect is a consequence of the high Cl − conductance of resting muscle.…”

“…This model predicts that reduction of internal Cl − should be protective against attacks HypoPP whereas increased internal Cl − would increase the likelihood of an attack (87). Indeed, inhibition of the NKCC transporter with bumetanide prevents the loss of force from a low K + challenge in the knock-in mouse model of Na V 1.4-HypoPP (Figure 11C) (277). Conversely, stimulation of NKCC by hypertonic challenge can trigger an attack.…”

“…The same strategy could improve strength in HyperPP, however, this approach is limited by vasodilation with hypotension and hyperpolarization of pancreatic beta cells which reduces insulin secretion. In the knock-in mouse model of Na V 1.4 HypoPP, the NKCC inhibitor bumetanide protects against low K + induced weakness and can even restore muscle force during an attack (Figure 11C) (277). As expected, this inhibitor of Cl − influx does not protect against HyperPP which is not sensitive to the Cl − gradient.…”

“…Progress in understanding the pathomechanisms for the channelopathies of skeletal muscle has been rapid in comparison to the pace of discovery for other heritable disorders, which often involves a novel gene product, because the functional properties of the mutant gene product – a voltage-gated ion channel – has been extensively well characterized over the past 60 years (35, 102), the roles of various voltage-gated ion channels in the regulation of muscle fiber excitability are well known (111), and the requirements of sarcolemma excitability to achieve effective excitation-contraction coupling are known. These concepts are now being tested with knock-in mutant mouse models that have advanced our understanding for the basis of muscle excitability (275, 278) and demonstrated proof-of-principle for therapeutic approaches to alleviate symptoms (277). …”

Dichlorphenamide efficacy in the primary periodic paralyses

“…Bumetanide is a diuretic that inhibits this cotransporter. Based on the hypothesis that inhibiting intramuscular chloride accumulation would reduce or prevent muscle membrane depolarisation and muscle paralysis in hypoPP two studies examined the in vitro and in vivo effects of bumetanide using a murine model 19,20 . In both scenarios bumetanide was effective in aborting an episode of muscle weakness in the presence of hypokalaemia and in preventing muscle weakness from occurring if given prior to the induction of hypokalaemia.…”