K_ATP channel therapeutics at the bedside

Abstract

The family of potassium channel openers regroups drugs that share the property of activating adenosine triphosphate-sensitive potassium (K_ATP) channels, metabolic sensors responsible for adjusting membrane potential-dependent functions to match cellular energetic demands. K_ATP channels, widely represented in metabolically-active tissue, are heteromultimers composed of an inwardly rectifying potassium channel pore and a regulatory sulfonylurea receptor subunit, the site of action of potassium channel opening drugs that promote channel activity by antagonizing ATP-induced pore inhibition. The activity of K_ATP channels is critical in the cardiovascular adaptive response to stress, maintenance of neuronal electrical stability, and hormonal homeostasis. Thereby, K_ATP channel openers have a unique therapeutic spectrum, ranging from applications in myopreservation and vasodilatation in patients with heart or vascular disease to potential clinical use as bronchodilators, bladder relaxants, islet cell protector, antiepileptics and promoters of hair growth. While the current experience in practice with potassium channel openers remains limited, multitude of ongoing investigations aims at defining the benefit of this emerging family of therapeutics in diverse disease conditions associated with metabolic distress.

1. Introduction

Therapeutic agents, collectively termed potassium channel opening drugs, have been developed to target adenosine triphosphate-sensitive potassium (K_ATP) channels with the recognition that these metabolism-sensing channels play a vital role in matching membrane electrical excitability with changes in energetic state. In this way, K_ATP channels serve as endogenous homeostatic transducers balancing cellular resources in response to altered demand [1–13]. Indeed, in the heart, K_ATP channels protect against the metabolic insult of ischemia, and contribute as molecular mediators in the adaptive response to distress. Moreover, K_ATP channels regulate vascular tone, and thereby the delivery of metabolic resources to match demand [4–6,11]. Furthermore, these channels are central in setting blood glucose levels by regulating insulin secretion in pancreatic β-cells and insulin-dependent glucose uptake in skeletal muscle [5,6]. In the brain, K_ATP channel activation also serves a protective role against metabolic challenge [9]. Thus, K_ATP channels, integrated with cellular and systemic metabolism, act at various levels to ensure metabolic well being under the challenge of stress [13]. By promoting K_ATP channel activity, potassium channel openers stabilize membrane excitability and preserve metabolic expenditure [9,13] making this class of therapeutics highly desirable as cytoprotective agents under diverse conditions of excessive demand [1–6,14]. In particular, potassium channel openers have shown promise in myocardial protection, as antihypertensive vasodilators, bronchodilators, bladder relaxants, islet cell protectors, antiepileptics, and promoters of hair growth (Fig. 1).

Fig. 1.

ATP-sensitive potassium channel subunits (A) and potential clinical use of potassium channel openers. The KATP channel complex consists of the pore-forming Kir6.x (Kir6.2 or Kir6.1) subunit and the regulatory sulfonylurea receptor (SUR1, SUR2A or SUR2B) subunit, which serves as a metabolic sensor and target of drug action. The SUR subunit has 17 transmembrane segments (TMs) arranged in three domains, TMD0 (5 TMs), TMD1 (6 TMs) and TMD2 (6 TMs). Two critical sites for KCO binding exists in TMD2 at position Tyr1059 to Leu1087 (KCO I) and Arg1218 to Asn1320 (KCO II). Nucleotide binding folds (NBD-1 and NBD-2) with Walker A and B consensus motif are present on two large intracellular loops and implicated in channel regulation by ATP and MgADP. N and C represent respective amino and carboxy terminus of constitutive channel subunits and are intracellularly located. B). Clinical conditions in which potassium channel openers have therapeutic promise.

Potassium channel openers are chemically diverse [1,2], and belong to a number of structural classes (Fig. 2). These include benzopyrans (levcromakalim, bimakalim), benzothiadiazines (diazoxide), cyanoguanidines (pinacidil), cyclobutenediones (WAY-151616), nicotinamides (nicorandil), pyrimidines (minoxidil), tertiary carbonoles (ZD-6169), thioformamides (aprikalim), and dihydropyridine-like structures (ZM-244085) [1–4].

Fig. 2.

Classification of potassium channel openers based on chemical structure.

The primary target for potassium channel opener action is through the regulatory subunit of the K_ATP channel, known as the sulfonylurea receptor or SUR, an ATP-binding cassette protein [5,6,15–17]. This subunit contains nucleotide binding domains, implicated in decoding and processing of metabolic signals. Through physical association with the pore-forming Kir6.x inwardly rectifying potassium channel, the SUR subunit forms a heteromultimeric K_ATP channel complex (Fig. 1A [5,6,15]). While the precise molecular mechanism of action remains only partially understood, activation of K_ATP channels has been ascribed to the ability of potassium channel openers to reduce the ATP-induced pore inhibition [8]. This can be achieved by promoting stabilization of the MgADP-bound state at the nucleotide binding domain 2 of the SUR subunit associated with positive channel gating and pore opening [8]. Progress has been made in identifying the residues, which determine potassium channel opener action [18–24]. These includes amino acids located within the last transmembrane domain TMD2 of SUR (Fig. 1A [18]), the cytoplasmic loop connecting TM helices 13 and 14, a region encompassing TM helices 16 and 17 and a short segment of the nucleotide binding domain NBD2, [23] along with two residues within TM helix 17 (L1249 and T1253 in the SUR2A, T1286 and M1290 in the SUR1 isoform) [18]. These recent findings have provided information on the tissue-specificity and selectivity of the pharmacological response to potassium channel openers [18–25]. Indeed, the SUR2A isoform, predominantly expressed in cardiac and skeletal muscles and its splice variant SUR2B in smooth muscle, are activated by a broad range of potassium channel openers [16,17,23–27], whereas the isoform SUR1, expressed in neuronal and pancreatic β-cells, is activated by a limited number of openers [5,6,26]. The distribution of SUR isoforms with differential responsiveness to potassium channel openers thus provides unique targets for the development of tissue-specific therapeutics.

2. Potassium channel openers in ischemic heart disease

Potassium channel openers have proven useful in limiting myocardial dysfunction under conditions of ischemia–reperfusion and heart failure through direct actions on the myocardium [27–32]. This protective action exploits the essential role of K_ATP channels in cardiac stress adaptation, ranging from preservation of contractile performance under imposed load to myocardial salvage following ischemic challenge [13]. Overexpression of K_ATP channel genes enhances cytoprotection, while knockout of channel subunits has been associated with predisposition to myocardial damage and survival disadvantage under stress [13,31], along with loss of the cardioprotective response to ischemic preconditioning [10,27–33]. Disease-induced K_ATP channel dysregulation compromises cardiac stress adaptation [30], and mutations in the regulatory SUR subunit increases susceptibility for inherited cardiomyopathy [34]. The benefit of potassium channel openers apparently stems from prevention of intracellular Ca²⁺ overload, as opening of plasma membrane K_ATP channels shortens the action potential duration (APD) limiting cellular injury by preserving cellular energetics and ultimately cell survival (Fig. 3 upper panel) [27–31]. Additional, subcellular sites of potassium channel opener action have been identified, including the inner membrane of the mitochondria where a protective outcome has been linked to prevention of mitochondrial Ca²⁺ overload [27,35–38], modulation of reactive oxygen species generation [35,39], and preservation of energetics and nucleotide pools [35–45].

Fig. 3.

Potassium channel openers (KCO) effect on (A) cardiac and (B) vascular smooth muscle. A). KCO decreases intracellular Ca²⁺ influx through the voltage-gated Ca²⁺ channels by activating cardiac sarcolemmal K_ATP channel and shortening of APD. Opening of K_ATP channels is promoted in ischemia and hypoxia through adenine nucleotide-dependent channel gating, increase in intracellular protons (H⁺) or lactate, and release of adenosine (Ado). KCO also modulate mitochondrial membrane potential, prevent mitochondrial Ca²⁺ overload and free radical production. ATP, adenosine triphosphate, ADP, adenosine diphosphate. B). KCO promote vascular smooth muscle relaxation and vasodilatation by membrane hyperpolarization and decrease in intracellular Ca²⁺. Nicorandil may also vasodilate through a nitric oxide (NO)-dependent activation of guanylate cyclase (GC) and cyclic guanosine monophosphate (cGMP).

In addition to direct effects on heart muscle per se, potassium channel openers through regulation of vascular smooth muscle (Fig. 3 lower panel) are also potent vasodilators [11]. This is due to K_ATP channel-dependent membrane hyperpolarization, reduction in Ca²⁺ influx through the voltage-gated Ca²⁺ channels and regulation of intracellular Ca²⁺ mobilization in smooth muscle cells [46,47]. Knockout of K_ATP channel subunits promotes vasospasm [12], and hypertension. Potassium channel openers primarily vasodilate arterioles and arteries [46–48]. Venodilation does not occur with most potassium channel openers, although nicorandil and KRN by means of a nitrate moiety also dilate venous capacitance vessels and thereby reduce cardiac preload [49].

Due to combined cardioprotective and vasodilatory properties, potassium channel openers are considered for therapy in a number of cardiac conditions. These include protecting the myocardium under cardiopulmonary bypass [45,50], preserving donor transplant heart [51,52], treating ischemic heart disease [49,53], hypertension [48], peripheral vascular disease [54], and arrhythmia related to abnormal repolarization [55–60].

In cardiac surgery, openers of K_ATP channels may serve as adjuncts or main components in cardioplegic solutions. In several experimental models of surgical ischemia and cardiopulmonary bypass, potassium channel openers, including nicorandil, aprikalim and pinacidil, provide greater cardio-protection than conventional cardioplegia [50–52]. In patients undergoing coronary artery graft surgery, the time required to achieve cardiac arrest, ST-segment changes on the electrocardiogram after aortic unclamping, plasma levels of peak creatine kinase-MB, malondialdehyde and human-heart fatty acid-binding protein and dosage of inotropic agents required were all lower in the group treated with nicorandil compared to controls on conventional therapy [61]. Potassium channel openers are also considered for preservation of donor heart for transplantation, and when used before storage provides superior preservation of cardiac function following prolonged hypothermic storage [51].

In ischemic heart disease, the value of potassium channel openers in protecting the myocardium is clinically best documented with nicorandil [49]. In patients, nicorandil has been shown to be useful in the management of both stable and unstable angina with minimum adverse effects [49]. In placebo-controlled, single- and double-blind studies of patients with stable angina pectoris, nicorandil attenuated rest and effort angina, prolonged the duration of exercise and the time to onset of angina or ischemic ST-T changes [62]. In a multicenter trial enrolling more than 5000 subjects with stable angina pectoris, long-term use of nicorandil was associated with reduction in cardiovascular events and the combined endpoints of death, myocardial infarction and hospitalization due to chest pain [63].

In patients with unstable angina, nicorandil, when added to aggressive anti-anginal treatment, reduces transient myocardial ischemia, and arrhythmias when compared to placebo [64]. Nicorandil improves ischemia-induced regional wall motion abnormalities, and perfusion in infarct-related areas [65–67]. In patients undergoing angioplasty, nicorandil preconditions the heart, improves coronary hemodynamics, dilates stenotic and non-stenotic segments, and ameliorates the “no-reflow” phenomenon [44,51,53,65–68]. Intravenous nicorandil, in conjunction with coronary angioplasty, preserves microvascular integrity and myocardial viability in patients with acute myocardial infarction [49,63,65]. Nicorandil also reduces preload and afterload, enhances cardiac endothelial nitric oxide synthase expression and has antiplatelet, fibrinolytic and antioxidant properties [49,69]. Unlike nitroglycerin, no development of tolerance to the anti-anginal effect of nicorandil has been reported [49]. Nicorandil is an effective anti-anginal agent at a dose of 10 to 40 mg twice a day, controlling stable chronic angina in 70 to 80 percent of patients [49]. The response to nicorandil is maintained for 12 h, with an efficacy that compares favorably with that of nitrates [70], β-adrenoceptor [71] and Ca²⁺-channel blockers [72]. Main side-effects include headache, gastrointestinal disturbances and dizziness [3,49]. Recently, nicorandil use has been associated with mucosal ulceration, including stomatitis and mouth and anal ulcerations [49]. No evidence of proarrhythmia, conduction disturbance, exacerbation of myocardial ischemia, infarction, abrupt withdrawal syndrome, symptomatic decrease in blood pressure or change in heart rate has been observed [49,63]. Also, no adverse interaction has been reported in patients on oral anticoagulants or hypoglycemic agents. The pharmacokinetics of nicorandil is unaltered in the elderly or patients with renal or hepatic insufficiency [49].

In vasospastic angina, nicorandil, with potent vasospasmolytic activity, relieves both ergonovine-evoked and spontaneous coronary spasm, attenuates episodes of variant angina, suppresses ST-segment changes and improves perfusion defects [73,74]. Levcromakalim, aprikalim and KRN4884 relax conduit arteries (internal mammary and gastroepiploic arteries) used as coronary artery bypass grafts and could be useful in preventing spasm of bypass grafts in patients undergoing surgery for atherosclerotic heart disease [75,76].

3. Potassium channel openers in rhythm disturbances

Potassium channel openers by shortening the cardiac action potential may prevent arrhythmias related to triggered activity resulting from abnormal repolarization and early or delayed after depolarization [58,77–82]. In models of prolonged QT syndrome and drug-induced ventricular arrhythmias, pinacidil and nicorandil are effective in suppressing abnormal automaticity, triggered activity and Torsade de pointe [81]. In fact, genetic deletion of the K_ATP channel pre-disposes to catecholamine-induced ventricular dysrhythmia [82]. In patients with congenital long QT syndrome and history of syncope, nicorandil improved repolarization abnormalities, abolishes early after depolarization and prevents recurrence of syncope [59,83]. Potassium channel openers are therefore an attractive therapeutic consideration in conditions with congenital or acquired prolongation of repolarization. Because of their heterogeneous effect on shortening of refractoriness in the epicardium versus endocardium and ischemic versus non-ischemic areas, concerns have been raised that potassium channel openers may further increase dispersion of refractoriness and therefore facilitate reentrant arrhythmias by increasing electrical inhomogeneity [84,85]. However, in clinical trials aggravation of arrhythmia or induction of life-threatening arrhythmias has not been documented for any of the potassium channel openers tested [49,63,86]. In fact, a recent study in patients with acute myocardial infarction treated with intravenous nicorandil at the time of coronary angioplasty showed a reduction in both dispersion of repolarization and incidence of malignant ventricular arrhythmias [79].

4. Potassium channel openers in peripheral vascular disease

Potassium channel openers may be advantageous for symptomatic control of peripheral ischemia. Drugs such as calcium channel blockers or direct vasodilators are typically not beneficial in peripheral vascular disease, and could worsen ischemia due to reduction in perfusion pressure in the affected area with diversion of blood to vasodialted non-ischemic regions [54]. Potassium channel openers do not promote such “steal phenomenon”. Accordingly, potassium channel openers improve blood flow and oxygen availability to the chronically ischemic muscle. This restores the high-energy phosphate content and improves muscle performance during acute ischemia in models of occlusive arterial disease [54,87].

5. Potassium channel openers in systemic and pulmonary hypertension

Potassium channel openers control blood pressure in 70–85% of patients with systemic hypertension [88]. Their efficacy in reducing high blood pressure is similar to other conventional antihypertensive medications in most individuals [88] but in those with resistant hypertension where therapy has failed with multi-drug regimens they are especially effective [88,89]. Diazoxide and minoxidil are currently recommended for the management of hypertensive emergencies and severe resistant hypertension, especially in patients with advanced renal disease [89] (Table 1). Tachyphylaxis to the antihypertensive effect of potassium channel openers and rebound hypertension on abrupt withdrawal has not been reported. Their routine use as antihypertensive agents is limited because of a reflex increase in heart rate due to the stimulation of the sympathetic nervous system in response to arterial vasodilatation causing flushing, headache and/or sodium and water retention [88]. Therefore, potassium channel openers should be administered in conjunction with a diuretic and β-adrenergic blocker to control reflex increase in heart rate [89]. An increase in plasma renin activity (largely due to activation of the sympathetic nervous system) and aldosterone level may also occur. Hyperglycemic effects of diazoxide and possible hypertrichosis with minoxidil also limit their long-term use, particularly in women [89]. Although potassium channel openers are effective in reducing blood pressure, the accompanying neurohumoral and hemodynamic changes may partially attenuate or offset the antihypertensive effect and preclude their routine use, especially when other antihypertensive with lesser side-effects are available. However, cardioprotective and antiischemic properties of potassium channel openers, beneficial effects on glycation and plasma lipids or bronchial smooth muscle relaxation still makes potassium channel openers an attractive antihypertensive class in patients with ischemic heart disease, diabetes mellitus and bronchospastic disease [90].

Table 1.

Potassium channel openers in clinical use

	Therapeutic uses	Dosage	FDA labeled uses	Contraindications and pecautions	Adverse effects
Diazoxidea,b (Hyperstat® Proglycem®)	HTN (malignant, pregnancy)	HTN (13 mg/kg IVbolus Q 5–15 min)	Hypertension	Hypersensitivity to diazoxide	Hypotension
	Pulmonary hypertension	Hypoglycemia (3–8 mg/kg PO QD in Q8–12 h)	Hypoglycemia	Functional hypoglycemia	Reflex tachycardia
	Hypoglycemia	Hypoglycemia infants (8–15 mg/kg PO QD in Q8–12 h)		Recent myocardial infarction	Aggravation of angina
	Uterine hyperactivity				Gastric disturbances
					Hyperglycemia
MinoxidiLa,b (Loniten®, Rogaine®)	Alopecia (drug induced)	Hypertension	Alopecia androgenica	Hypersensitivity to minoxidil	Hypertrichosis
	Alopecia androgenica	2.5–80 mg PO (QD–BID (with β-blocker &/or diuretic)	Hypertension (refractory/resistant)		Pleural/pericardial effusion
	Alopecia areata	Alopecia: topically			Reflex tachycardia
	Malignant/refractory HTN	2% (1 ml BID)			Fluid retention
	Impotence
Nicorandilb (SG-75® Adancor®, Dancor®, Ikorel®, Sigmart®)	Angina pectoris	Angina	N/A	Hypersensitivity	Headache
	Arrhythmia	10–40 mg PO BID		Symptomatic hypotension	Postural hypotension
	CHF	Angina, CHF		Cardiac conduction defects	Gastric disturbances
	Hypertension	2–6 mg/h IV		Recent myocardial infarction	Flushing
					Rash
					Mouth ulceration
Pinacidilb (Pindac®)	Hypertension	Hypertension	N/A	Hypersensitivity	Headache, Fluid retention
		12.5 mg BID (in combination with diuretic)		Acutely after myocardial infarction or cerebral vascular accidents	Dizziness, Flushing
					Postural hypotension
					Reflex tachycardia
					Hypertrichosis,

PO = by mouth; IV = intravenous; HTN = hypertension; BID = twice daily; QD = once daily; QID = four times daily.

^aApproved in USA.

^bApproved outside USA.

In pulmonary hypertension, potassium channel openers have been useful by inhibiting hypoxic pulmonary vasoconstriction [91,92]. Potassium channel openers also decrease mean pulmonary artery pressure and pulmonary resistance in models of pulmonary hypertension, which are otherwise resistant to conventional pharmacotherapy [93,94]. Also, a beneficial effect on decreasing pulmonary vascular resistance and limitation of reperfusion injury after lung allotransplantation has been reported [95].

6. Potassium channel openers and pulmonary disease

Bronchial hyperreactivity, the hallmark of asthma, occurs due to an increased excitability of the bronchial smooth muscle, airway microvascular leakage or increased mucus secretion in response to allergens and irritants. Currently available therapies for bronchial asthma provide symptomatic relief but are unable to normalize the exaggerated airways response to bronchospasmogens [96,97] raising the need for novel therapies to reverse or prevent airway hyperreactivity [97,98]. Potassium channel openers with their capacity to induce hyperpolarization of smooth muscle, neurons and secretory cells can reduce bronchial hyperresponsiveness both by a direct effect on smooth muscle relaxation and through an indirect inhibition of excitatory cholinergic and non-adrenergic/non-cholinergic neurotransmission (Fig. 4A [97–102]). Both experimental and clinical studies with potassium channel openers demonstrate bronchorelaxation, prevention of bronchoconstriction, reduction in microvascular leakage and goblet cell secretion, thereby provide the foundation for the therapeutic use of these agents in bronchial asthma and chronic obstructive pulmonary disease (Fig. 4A). Dyspnea, evoked by inflammatory mediators and airway hyperresponsiveness induced by a variety of stimuli, is suppressed by potassium channel openers through smooth muscle and neuroinhibitory effects [96–99]. In contrast to the conventional therapy with beta-adrenoceptor agonists [96], potassium channel openers do not cause hyperreactivity or development of tolerance to the smooth muscle relaxation with long-term use [101]. It has been suggested that the use of potassium channel openers may decrease the requirement for higher doses of glucocorticosteroids, thereby limiting their potential side effects. Several clinical trials have demonstrated the potential therapeutic efficacy of potassium channel openers for bronchospastic disease [99,102,103]. Moreover, certain but not all potassium channel openers have been shown to protect against histamine-induced bronchoconstriction [98] and controlled bronchospasm in patients with nocturnal asthma, by prevention of the early morning fall in forced expiratory volume [103,104].

Fig. 4.

Potassium channel openers (KCO) reduce (A) bronchial hyperactivity and bronchoconstriction, (B) excessive glutamate neurotransmission and (C) insulin release from pancreatic β-cell. A). KCO promote membrane hyperpolarization of bronchial smooth muscle and neuronal membrane, reducing Ca²⁺ influx through voltage-dependent Ca²⁺ channels causing bronchodilation and reduction of cholinergic and non-adrenergic, non-cholinergic (NANC) neurotransmission. ACh, acetylcholine. B). KCO by activating K_ATP channels, prevent anoxia-induced membrane depolarization, excessive glutamate release, thus preventing postsynaptic neuronal cation channel activation, Ca²⁺ overload and neuronal damage. C). Diazoxide-induced opening of K_ATP channels hyperpolarizes the β-cell membrane and prevents insulin release.

Despite the potent effect of potassium channel openers on airway hyperreactivity, the clinical potential of such compounds has been compromised mainly by the lack of selectivity for bronchial smooth muscle, and cardiovascular and cerebrovascular side-effects causing hypotension and headaches [98,99]. Development of bronchoselective potassium channel openers with greater efficacy and inhaled drug preparations with advantageous pharmacokinetics (poor absorption from airways and rapid systemic clearance) to limit adverse effects may be necessary before these drugs can be considered for clinical use [105].

7. Potassium channel openers use in urology

Urinary incontinence caused by detrusor muscle hyperreactivity and involuntary contraction of the bladder is common particularly in the elderly impacting quality of life. No effective or well-tolerated therapeutic regimen is available [106]. Detrusor muscle hyperactivity is mainly due to super-sensitivity to neurogenic and/or myogenic stimuli causing depolarization and increased membrane excitability [106]. Hyperpolarization of the membrane through opening of K⁺ channels provides an approach to suppress bladder hyperreactivity [100,107]. This has been shown to be the case in normal and hypertrophic bladder including models of bladder outflow obstruction [106–109], where potassium channel openers inhibit abnormal spontaneous increase in detrusor pressure without impairing the ability to respond to intrinsic nerve stimulation and to void urine [110,106]. Potassium channel openers are of interest to eliminate unwanted bladder contractions during the filling phase without affecting normal micturition [106]. In clinical pilot studies in patients with detrusor muscle overactivity, cromakalim improved symptoms of urinary frequency and increased the mean voided volume but the benefit was limited by cardiovascular side-effects with hypotension and tachycardia [108]. Uroselective potassium channel openers, which can target urinary bladder smooth muscle without adverse cardiovascular effects are currently being developed [111].

In patients with erectile dysfunction, vasorelaxants are injected intracorporeally to achieve penile erection, but such treatment produces priapism, local fibrosis and pain [112]. By activating K_ATP channels [113], potassium channel openers hyperpolarize and relax corpus cavernosum smooth muscle tone to produce penile tumescence and erection, which could be of therapeutic benefit in patients with impotence [114,115]. In a prospective, double-blind trial in patients with neurogenic impotence, minoxidil applied as a lubricating gel on the glans penis was more effective than placebo or nitroglycerin in facilitating erection with fewer side-effects [116]. In a placebo-controlled clinical trial involving men with erectile dysfunction of vascular etiology encouraging results with a potassium channel opener with no cardiovascular side-effects or penile pain were reported [112]. Nicorandil-like compounds, with potassium channel opening properties and additional vasodilatory effect due to nitric oxide release and guanylate cyclase stimulation, seem particularly attractive in patients with cardiovascular disease. Further clinical investigation is needed to demonstrate the efficacy of topical and/or oral potassium channel openers, alone or in combination with other vasoactive agents, in the treatment of erectile dysfunction.

8. Potassium channel openers use in muscular diseases

K_ATP channels were demonstrated to secure optimal performance of skeletal muscle, particularly in the elderly [117], and to play a role in muscle disorders related to hypokalemia [118]. In muscle biopsies from patients with hypokalemic periodic paralysis due to mutation of dihydropyridine receptor, abnormal K_ATP channel with subconductance states was demonstrated with lack of sensitivity to ADP and insulin stimulation, suggesting a possible role of K_ATP channel in determining the phenotype of hypokalemic periodic paralysis [119]. A reduction in overall sarcolemma K_ATP current was present, which was partially restored by cromakalim [119]. In skeletal muscle from other patients with hypokalemic periodic paralysis, cromakalim and pinacidil, decreased the membrane potential and increased the force of muscle contraction [120]. Similarly, in skeletal muscle bundles from patients with hyperkalemic paralysis [121], cromakalim restored the membrane potential of depolarized fibers and in patients with myotonia congenita and myotonic dystrophy, cromakalim and bimakalim suppress myotonic activity, after-contractions and spontaneous twitches [122]. Potassium channel openers, thus by restoration of the membrane potential of abnormally depolarized myopathic fibers could be of therapeutic use in muscular diseases related to abnormal membrane depolarization [121,123]. In addition, potassium channel openers by promoting pharmacological preconditioning could also be of therapeutic benefit in protecting skeletal muscle against ischemia–reperfusion injury in patients with vascular disease with peripheral ischemia [124,125].

9. Potassium channel openers use in neurological disorders

In cerebral vasospasm, several potassium channel openers, including nicorandil, cromakalim and aprikalim have been shown to relax basilar artery preventing and reversing the vasospasm after subarachnoid hemorrhage, without adversely affecting systemic hemodynamics [126–128]. Potassium channel openers have also been shown to exert strong neuroprotective effects when injected prior to severe ischemic or epileptic insult [129–131]. Activation of potassium channels and associated hyperpolarization inhibit release of excitatory amino acids, glutamate and aspartate, which are released during hypoxia with neuronal depolarization [129–131]. Thus, the neurotransmitter-induced postsynaptic depolarization and Ca²⁺ loading is inhibited by potassium channel openers, decreasing excitability and preventing neuronal injury (Fig. 4B). Moreover, potassium channel openers have been shown to inhibit apoptosis induced by oxidative stress in cerebellar granule neurons [132] and to protect neuronal and vascular endothelial cells from beta-amyloid toxicity, which contributes to cerebrovascular amyloidosis, a major neuropathological feature of Alzheimer’s disease and senescence [133,134]. Although, these promising observations indicate a role for potassium channel openers in neuroprotection [135], selective openers which can readily cross the blood–brain barrier while avoiding effects on peripheral hemodynamics needs to be developed.

Impaired repolarization contributes to generation of convulsion and movement disorders [136]. Potassium channel openers by hyperpolarizing the membrane decrease neuronal excitability and epileptiform discharges [137] preventing seizures [131,138]. Potassium channel openers also have an anti-nociceptive effect [139,140], mediated through the release of endorphins and enkephalins and activation of opioid receptors [139]. Pinacidil and cromakalim both have been shown to augment the analgesic effect of opioids [140,141] and cromakalim and diazoxide prevent signs of morphine withdrawal precipitated by naloxone [142]. These studies suggest a role for potassium channel openers as analgesics in the treatment of chronic pain syndromes and in the management of narcotic withdrawal in addicted patients. Indeed, potassium channel openers may serve as a substitute for morphine by attenuating the withdrawal syndrome in morphine-dependent patients, and may be useful in the management of chronic pain by augmenting the analgesic effects of, or substituting for, narcotics [139–142]. Potassium channel openers are therefore potential drug candidates for the treatment of diseases related to neuronal hyperexcitabilty such as epilepsy, neuropathic pain, and neurodegeneration.

10. Potassium channel openers use in endocrinology

K_ATP channels are essential in regulating insulin secretion in pancreatic β-cells (Fig. 4C) [5,6]. While sulfonylureas, which block pancreatic K_ATP channels, have been widely used as oral hypoglycemics in diabetic patients, potassium channel openers, in particular diazoxide, have been used in the management of hypoglycemia due to hyperinsulinism, associated with several conditions, such as inoperable islet cell adenoma/carcinoma, extra-pancreatic malignancy, leucine sensitivity, islet cell hyperplasia, and nesidioblastosis [143]. This includes familial persistent hyperinsulinemic hypoglycemia of infancy, in which impaired regulation of insulin secretion has been linked to mutations in K_ATP channel subunits [143–146].

Potassium channel openers, through pancreatic β-cell hyperpolarization, can also improve the insulin release pattern in type-2 diabetes [147], which is characterized by fasting hyperinsulinemia, insulin resistance and impaired insulin release. It is therefore proposed that in prediabetic conditions, characterized by impaired glucose tolerance and peripheral insulin resistance, potassium channel openers by inhibiting insulin release can reduce β-cell workload and long-term exhaustion preventing functional deterioration and failure, thus delaying onset of diabetes [148]. Chronic treatment with diazoxide [147] or NN414, a SUR1/Kir6.2-selective compound, has demonstrated an antidiabetic effect with improvement in first-phase insulin release and glucose tolerance [149]. Potassium channel openers reduced basal hyperglycemia, improved glucose tolerance, and reduced hyperinsulinemia during oral glucose tolerance test and improved insulin secretory responsiveness in a model of type-2 diabetes [149].

11. Potassium channel openers use in dermatology

Potassium channel openers promote hair growth by a direct effect on hair follicles, and by improving blood supply to follicles [150,151]. In particular minoxidil stimulates DNA synthesis in epidermal keratinocytes and whole-hair follicles enhancing proliferation and differentiation of the epithelial hair shaft and increase hair density by induction of anagen or an increase in anagen duration. [150,151]. Topical minoxidil maintain and stimulate new hair growth and helps stop the loss of hair in men with androgenic alopecia and women with female pattern hair loss [150–153]. The increase in hair growth, measured by hair counts or hair weight is evident within 6–8 weeks of starting treatment and generally peaks by 12–16 weeks [153]. Although no beneficial effect in the prevention of chemotherapy-induced alopecia in women has been demonstrated [154], minoxidil decreased the period of baldness from maximal hair loss to first regrowth after chemotherapy [155]. The role of these agents in promoting hair growth and stabilizing hair loss, especially in male-pattern baldness, is thus highly promising.

12. Conclusion

The clinical experience with potassium channel openers is summarized in Table 1. Modulation of K_ATP channels, a critical homeostatic metabolic sensor, is a novel pharmacological principle with significant clinical potential under conditions of metabolic challenge. Extensive experimental studies have identified a variety of potential indications, with limited clinical experience pointing toward the safety and efficacy of potassium channel openers in human use. This is illustrated in the recently completed IONA trial, a multicenter study enrolling more than 5000 subjects with stable angina pectoris treated with the prototypic nicorandil, that has further highlighted the promise of long-term use of potassium channel openers in clinical medicine [63]. With advances in our understanding of the molecular structure, organ-specific and integrative function, tissue-selective distribution and regulation of K_ATP channel subunit isoforms [16–26,156,157], a frame-work to develop new generations of potassium channel opening drugs with enhanced specificity is envisioned [2,25,26]. Moreover, with the further understanding of the pathogenesis of disease conditions associated with an alteration in expression or regulation of potassium channel-based channelopathies [4,158,159], a rational design of potassium channel openers may provide a unique opportunity to correct disease-associated deficiency.