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Recent advances in the pathogenesis and drug action in periodic paralyses and related channelopathies.

Tricarico D, Camerino DC - Front Pharmacol (2011)

Bottom Line: The periodic paralysis (PP) are rare autosomal-dominant disorders associated to mutations in the skeletal muscle sodium, calcium, and potassium channel genes characterized by muscle fiber depolarization with un-excitability, episodes of weakness with variations in serum potassium concentrations.One pharmacological strategy is based on blocking the I(gp) without affecting normal channel gating.It remains safe and effective the proposal of targeting the K(ATP), Kir channels, or BK channels by drugs capable to specifically open at nanomolar concentrations the skeletal muscle subtypes with less side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacobiology, Faculty of Pharmacy, University of Bari Italy.

ABSTRACT
The periodic paralysis (PP) are rare autosomal-dominant disorders associated to mutations in the skeletal muscle sodium, calcium, and potassium channel genes characterized by muscle fiber depolarization with un-excitability, episodes of weakness with variations in serum potassium concentrations. Recent advances in thyrotoxic PP and hypokalemic PP (hypoPP) confirm the involvement of the muscle potassium channels in the pathogenesis of the diseases and their role as target of action for drugs of therapeutic interest. The novelty in the gating pore currents theory help to explain the disease symptoms, and open the possibility to more specifically target the disease. It is now known that the fiber depolarization in the hypoPP is due to an unbalance between the novel identified depolarizing gating pore currents (I(gp)) carried by protons or Na(+) ions flowing through aberrant alternative pathways of the mutant subunits and repolarizing inwardly rectifying potassium channel (Kir) currents which also includes the ATP-sensitive subtype. Abnormal activation of the I(gp) or deficiency in the Kir channels predispose to fiber depolarization. One pharmacological strategy is based on blocking the I(gp) without affecting normal channel gating. It remains safe and effective the proposal of targeting the K(ATP), Kir channels, or BK channels by drugs capable to specifically open at nanomolar concentrations the skeletal muscle subtypes with less side effects.

No MeSH data available.


Related in: MedlinePlus

Targets of drug actions of potential interest in the hypokalemic periodic paralysis (modified from Matthews and Hanna, 2010). Acetazolamide or dichlorphenamide are capable to activate the calcium-activated K+ channels (BK) at submicromolar concentrations with fiber repolarization. Acetazolamide is also capable to inhibit the monocarboxylate transporter (MCT) reducing the efflux of lactate thereby preventing vacuolar myopathy. This drug also inhibits the membrane bound carbonic anhydrase (CA) enzymes with effects on the extra-/intracellular proton exchange mechanisms. KATP openers activate the ATP-sensitive K+channels (KATP) at submicromolar concentrations. Other pumps and co-transports such as the natrium-bicarbonate co-transport (NBC), natrium hydrogen exchanger (NHE), or sodium–potassium ATPase may have a role in hypoPP pathogenesis are however not directly affected by drug actions. Drugs targeting inwardly rectifying K+channels (Kir) can be effective in preventing fiber depolarization but are not currently available. Even the novel small synthetic guanidinium analogs appear to block at millimolar concentrations the R-H or the R-not H mutant subunits of the voltage-dependent Na+ channels but are however far from the clinical development.
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Figure 3: Targets of drug actions of potential interest in the hypokalemic periodic paralysis (modified from Matthews and Hanna, 2010). Acetazolamide or dichlorphenamide are capable to activate the calcium-activated K+ channels (BK) at submicromolar concentrations with fiber repolarization. Acetazolamide is also capable to inhibit the monocarboxylate transporter (MCT) reducing the efflux of lactate thereby preventing vacuolar myopathy. This drug also inhibits the membrane bound carbonic anhydrase (CA) enzymes with effects on the extra-/intracellular proton exchange mechanisms. KATP openers activate the ATP-sensitive K+channels (KATP) at submicromolar concentrations. Other pumps and co-transports such as the natrium-bicarbonate co-transport (NBC), natrium hydrogen exchanger (NHE), or sodium–potassium ATPase may have a role in hypoPP pathogenesis are however not directly affected by drug actions. Drugs targeting inwardly rectifying K+channels (Kir) can be effective in preventing fiber depolarization but are not currently available. Even the novel small synthetic guanidinium analogs appear to block at millimolar concentrations the R-H or the R-not H mutant subunits of the voltage-dependent Na+ channels but are however far from the clinical development.

Mentions: The treatment of the hyperkalemia and hypokalemia in hyperPP or hypoPP is achieved with some success by the administration of the benzothiazide diuretics as hydrochlorothiazide and of K+ sparing diuretics, respectively. But the most effective medications for the prevention of attacks in both disorders remain the CA inhibitors, particularly acetazolamide and dichlorphenamide. These drugs ameliorate paralysis reducing the frequency of the attacks. One of the main mechanism responsible for the therapeutic effects of these drugs is related to their capability to open the muscular calcium-activated potassium channels (Tricarico et al., 2000, 2004). These drugs activate BK channels in excised patch experiments from normal and depleted rat fibers at micromolar concentrations indicating that the observed actions are due to a direct interaction of the molecules with the channel subunits in the isolated membrane (Figure 3). The actions of acetazolamide and dichlorphenamide are structure-related; indeed, these molecules share the same pharmacophoric characteristics of benzimidazolone class of compounds which are well known small synthetic BK channel openers (Tricarico et al., 2004). Acetazolamide and dichlorphenamide repolarize skeletal muscle fibers and prevent muscle paralysis and weakness in K-depleted rats induced by insulin/glucose injection by openings the BK channels (Tricarico et al., 2006). Acetazolamide at 100 × 10−4 M is also capable to repolarize muscle fibers from human hypoPP patients even in the presence of low ext. K+ ions (Jurkat-Rott et al., 2009). The effects of acetazolamide and dichlorphenamide on human BK channel have been also recently investigated, and we found that these two drugs are effective against the hslo channel subunit expressed in HEK293 cell at submicromolar concentrations being 10 times more potent against human channel vs. rat channel. These effects were observed at −60 mV (Vm) justifying their use in the attack prevention rather than during the attack of PP (unpublished observations). Currently no direct interaction of these drugs with Kir including KATP channels have been observed in native fibers or recombinant clones expressed in cell lines indicating that acetazolamide by targeting BK channel increase the KDR current component thereby shifting the control of the resting potential under a voltage-dependent current component (Figure 1A).


Recent advances in the pathogenesis and drug action in periodic paralyses and related channelopathies.

Tricarico D, Camerino DC - Front Pharmacol (2011)

Targets of drug actions of potential interest in the hypokalemic periodic paralysis (modified from Matthews and Hanna, 2010). Acetazolamide or dichlorphenamide are capable to activate the calcium-activated K+ channels (BK) at submicromolar concentrations with fiber repolarization. Acetazolamide is also capable to inhibit the monocarboxylate transporter (MCT) reducing the efflux of lactate thereby preventing vacuolar myopathy. This drug also inhibits the membrane bound carbonic anhydrase (CA) enzymes with effects on the extra-/intracellular proton exchange mechanisms. KATP openers activate the ATP-sensitive K+channels (KATP) at submicromolar concentrations. Other pumps and co-transports such as the natrium-bicarbonate co-transport (NBC), natrium hydrogen exchanger (NHE), or sodium–potassium ATPase may have a role in hypoPP pathogenesis are however not directly affected by drug actions. Drugs targeting inwardly rectifying K+channels (Kir) can be effective in preventing fiber depolarization but are not currently available. Even the novel small synthetic guanidinium analogs appear to block at millimolar concentrations the R-H or the R-not H mutant subunits of the voltage-dependent Na+ channels but are however far from the clinical development.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108473&req=5

Figure 3: Targets of drug actions of potential interest in the hypokalemic periodic paralysis (modified from Matthews and Hanna, 2010). Acetazolamide or dichlorphenamide are capable to activate the calcium-activated K+ channels (BK) at submicromolar concentrations with fiber repolarization. Acetazolamide is also capable to inhibit the monocarboxylate transporter (MCT) reducing the efflux of lactate thereby preventing vacuolar myopathy. This drug also inhibits the membrane bound carbonic anhydrase (CA) enzymes with effects on the extra-/intracellular proton exchange mechanisms. KATP openers activate the ATP-sensitive K+channels (KATP) at submicromolar concentrations. Other pumps and co-transports such as the natrium-bicarbonate co-transport (NBC), natrium hydrogen exchanger (NHE), or sodium–potassium ATPase may have a role in hypoPP pathogenesis are however not directly affected by drug actions. Drugs targeting inwardly rectifying K+channels (Kir) can be effective in preventing fiber depolarization but are not currently available. Even the novel small synthetic guanidinium analogs appear to block at millimolar concentrations the R-H or the R-not H mutant subunits of the voltage-dependent Na+ channels but are however far from the clinical development.
Mentions: The treatment of the hyperkalemia and hypokalemia in hyperPP or hypoPP is achieved with some success by the administration of the benzothiazide diuretics as hydrochlorothiazide and of K+ sparing diuretics, respectively. But the most effective medications for the prevention of attacks in both disorders remain the CA inhibitors, particularly acetazolamide and dichlorphenamide. These drugs ameliorate paralysis reducing the frequency of the attacks. One of the main mechanism responsible for the therapeutic effects of these drugs is related to their capability to open the muscular calcium-activated potassium channels (Tricarico et al., 2000, 2004). These drugs activate BK channels in excised patch experiments from normal and depleted rat fibers at micromolar concentrations indicating that the observed actions are due to a direct interaction of the molecules with the channel subunits in the isolated membrane (Figure 3). The actions of acetazolamide and dichlorphenamide are structure-related; indeed, these molecules share the same pharmacophoric characteristics of benzimidazolone class of compounds which are well known small synthetic BK channel openers (Tricarico et al., 2004). Acetazolamide and dichlorphenamide repolarize skeletal muscle fibers and prevent muscle paralysis and weakness in K-depleted rats induced by insulin/glucose injection by openings the BK channels (Tricarico et al., 2006). Acetazolamide at 100 × 10−4 M is also capable to repolarize muscle fibers from human hypoPP patients even in the presence of low ext. K+ ions (Jurkat-Rott et al., 2009). The effects of acetazolamide and dichlorphenamide on human BK channel have been also recently investigated, and we found that these two drugs are effective against the hslo channel subunit expressed in HEK293 cell at submicromolar concentrations being 10 times more potent against human channel vs. rat channel. These effects were observed at −60 mV (Vm) justifying their use in the attack prevention rather than during the attack of PP (unpublished observations). Currently no direct interaction of these drugs with Kir including KATP channels have been observed in native fibers or recombinant clones expressed in cell lines indicating that acetazolamide by targeting BK channel increase the KDR current component thereby shifting the control of the resting potential under a voltage-dependent current component (Figure 1A).

Bottom Line: The periodic paralysis (PP) are rare autosomal-dominant disorders associated to mutations in the skeletal muscle sodium, calcium, and potassium channel genes characterized by muscle fiber depolarization with un-excitability, episodes of weakness with variations in serum potassium concentrations.One pharmacological strategy is based on blocking the I(gp) without affecting normal channel gating.It remains safe and effective the proposal of targeting the K(ATP), Kir channels, or BK channels by drugs capable to specifically open at nanomolar concentrations the skeletal muscle subtypes with less side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacobiology, Faculty of Pharmacy, University of Bari Italy.

ABSTRACT
The periodic paralysis (PP) are rare autosomal-dominant disorders associated to mutations in the skeletal muscle sodium, calcium, and potassium channel genes characterized by muscle fiber depolarization with un-excitability, episodes of weakness with variations in serum potassium concentrations. Recent advances in thyrotoxic PP and hypokalemic PP (hypoPP) confirm the involvement of the muscle potassium channels in the pathogenesis of the diseases and their role as target of action for drugs of therapeutic interest. The novelty in the gating pore currents theory help to explain the disease symptoms, and open the possibility to more specifically target the disease. It is now known that the fiber depolarization in the hypoPP is due to an unbalance between the novel identified depolarizing gating pore currents (I(gp)) carried by protons or Na(+) ions flowing through aberrant alternative pathways of the mutant subunits and repolarizing inwardly rectifying potassium channel (Kir) currents which also includes the ATP-sensitive subtype. Abnormal activation of the I(gp) or deficiency in the Kir channels predispose to fiber depolarization. One pharmacological strategy is based on blocking the I(gp) without affecting normal channel gating. It remains safe and effective the proposal of targeting the K(ATP), Kir channels, or BK channels by drugs capable to specifically open at nanomolar concentrations the skeletal muscle subtypes with less side effects.

No MeSH data available.


Related in: MedlinePlus