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Pharmacology & Toxicology 1992,10, 244-254.

Clinical Pharmacology of Potassium Channel Openers Karl-Erik Anderson Department of Clinical Pharmacology, Lund University Hospital, S-22 1 85 Lund, Sweden (Received September 26, 1991; Accepted January 4, 1992) Abstract: Opening of K+ channels in cell membranes with resulting increase in K + conductance, shifts the membrane potential in a hyperpolarizing direction towards the K+ equilibrium potential. Hyperpolarization reduces the opening probability of ion channels involved in membrane depolarization and excitation is reduced. K+ channel openers are believed to hyperpolarize smooth muscle cells by a direct action on the cell membrane. The best known members of the group are cromakalim, nicorandil and pinacidil, but several new compounds are being evaluated. In addition, it has recently been shown that also clinically well-known drugs like, e.g. diazoxide and minoxidil exhibit K+ channel opening properties. Nicorandil and new compounds containing nitro groups have a dual mechanism of action, also activating guanylate cyclase, an effect that contributes to their cardiovascular effect profile. K+ channel openers have a wide range of effects. Some of their properties and actions are summarized, and their present applications andlor potential for future application, in e.g. hypertension, angina pectoris, asthma, bladder instability, and several other disorders are discussed. It is concluded that K + channel openening represents an interesting pharmacological principle with many potential clinical applications. However, most available drugs do not seem to have a sufficient tissue selectivity to be useful therapeutic alternatives. Before the potential of the new members of the group on clinical trials can be properly evaluated, clinical experiences are needed.

Potassium (K+) channels are ubiquitous in excitable cells. Several major types are recognized, and within each type, several subtypes exist (Cook 1988; Edwards & Weston 1990a). It is well established that opening of K+channels in cell membranes with resulting increase in K + conductance, shifts the membrane potential in a hyperpolarizing direction towards the K+ equilibrium potential (see Cook 1988; Edwards & Weston 1990a). Hyperpolarization reduces the opening probability of ion channels involved in membrane depolarization and excitation is reduced. Several endogenous compounds acting as transmitters or modulators of neurotransmission are believed to hyperpolarize smooth muscle cells either directly or indirectly. This ability is shared by the group of synthetic agents known as K + channel openers, of which cromakalim, nicorandil and pinacidil are the best known (for recent reviews, see Robertson & Steinberg 1990; Edwards & Weston 1990b; Richer et al. 1990). It has now been shown that also clinically well-known drugs for which the mechanism of action has been unclear, e.g. diazoxide (Newgreen et al. 1990; Pratz et al. 1991) and the active metabolite of minoxidil, minoxidil sulphate (Meisheri et al. 1988; Leblanc et al. 1989; Newgreen et al. 1990; Wickenden et al. 1991), exhibit K + channel opening properties. Several new compounds are currently being evaluated (for structure-activity relationships, see e.g., Edwards & Weston 1990b), among these SR 44866 (Richer et al. 1989), RP 49356 (active enantiomer: RP 52981; Richer et al. 1990), Ro 31-6930 (Paciorek et al. 1990a), SDZ PCO 400 (Quast et al. 1990), KRN 2391 (Kashiwabara et al. 1990), and NIP121 (Masuda et al. 1991). K + channel openers have a wide range of effects, which theoretically may be clinically useful. However, clinical in-

formation published on these drugs is sparse. Below, some properties and effects of K+ channel openers, particularly cromakalim, nicorandil, and pinacidil, are summarized, and their present applications and/or potential for future application are discussed. Pharmacokinetic profiles of some K' channel openers. Pinacidil. Pinacidil contains a single chiral carbon in its structure and is used as the racemate. Biological activity resides mainly in the (-)-R enantiomer (Steinberg et al. 1991). The pharmacokinetics of pinacidil have recently been reviewed by Goldberg et al. (1989) and Friedel & Brogden (1990). After oral administration of pinacidil solution, the drug is rapidly absorbed with peak plasma levels occurring less than 1 hr after intake. With other administration forms (conventional tablets, controlled release capsules), peak plasma levels will occur later; food intake has little effect on absorption. Absolute bioavailability is 57%. The peak concentration of pinacidil and its pyridyl-N-oxide metabolite is proportional to the dose of pinacidil within the concentration range 12.5-75 mg b i d . Plasma half-life is 1-3 hr after intravenous or oral administration, plasma clearance 2 7 4 0 Uhr, the apparent distribution volume 1.1-1.4 l/kg, and plasma protein binding 6&65% (Goldberg et al. 1989; Friedel & Brogden 1990). Pinacidil is eliminated from the blood primarily by metabolism in the liver by the cytochrome P 450 enzyme system, but its N-oxidation metabolite did not co-segregate with the debrisoquine and trimethylamine polymorphisms (Ayesh et al. 1989). The principal metabolite is the pyridyl-N-oxide (Eilertsen et al. 1982; Ayesh et al. 1989), which may accumulate during pinacidil treatment (McBurney et al. 1988). This

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metabolite, excreted largely by the kidney, has about 25% of the vasodilator potency of pinacidil, and a half-life of 2.5 hr (Eilertsen et al. 1982).

Cromakalim. Cromakalim contains two chiral carbon atoms with the substituents of these two atoms in the trans configuration. Cromakalim is the generic name of the racemic mixture of the two trans enantiomers. The vasorelaxing properties of the drug resides in the (-)-trans isomer (BRL 38227, lemakalim; Clapham et al. 1991), which is under clinical development. The information available on cromakalim pharmacokinetics is scarce. After oral administration to healthy volunteers cromakalim is absorbed with peak plasma levels occurring 2 4 hr after intake. Plasma half-life is 22.5 hr, oral clearance 3.42 l/hr, and volume of distribution 1 1 1 1 (Davies et al. 1988). In patients with essential hypertension, there was a linear relation between peak plasma concentration and dose within the range 0.5-2.0 mg (Carey et al. 1989). Mean values of plasma half-life were 24.5 and 25.1 hr, oral clearance 3.34 and 3.90 Uhr, and of volume of distribution 112 and 134 1 at doses 1.5 and 2.0 mg, respectively. Nicorandil. Frydman et al. (1989) described in detail the pharmacokinetics of nicorandil in man. After oral administration, nicorandil, within the dose range used clinically ( 5 4 0 mg), is rapidly absorbed with peak plasma levels occurring 0.30-1 .O hr after intake. Absolute bioavailability is 75 23%, and maximal concentration and area under the plasma concentrationtime curve of the parent drug are linearly related to dose ( 5 4 0 mg). The apparent distribution volume is 1.4 I/kg, and plasma protein binding is weak ( < 25% bound). The plasma concentrations decline according to two different processes. There is a rapid elimination phase with an apparent half-time of 1 hr (involving 96% of the dose found in plasma), and 8-24 hr after dosing (20 mg), the mean plasma concentration remains fairly constant at a low level. The significance of this is not known. Metabolism is extensive; the major route of biotransformation seems to be denitration. In the urine only small amounts of unchanged nicorandil ( - 1% of the dose) and denitrated metabolite (4%) are found. Total body clearance is 52 18 Uhr.

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Side effects of K + channel openers. Among the newer K-channel openers, comprehensive data on adverse effects are available only for pinacidil and nicorandil. For pinacidil side effects include headache, peripheral oedema (25-50%; dose-related), weight gain, palpitations, dizziness and rhinitis (Fridel & Brogden 1990). Hypertrichosis and asymptomatic T wave changes in the ECG have also been described. The latter, which were reported to occur in about 30% of the patients, include flattening or inversion of T waves, which are usually transient (Callaghan et al. 1988). The principal side effect of nicorandil is headache. Flushing, palpitations, leg oedema, nausea, vomiting, tin-

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nitus, dizziness, sleep disturbance and skin eruptions have also been reported (Kinoshita & Sakai 1990). Cromakalim may produce a dose-related headache, but oedema formation is apparently rare (Eckl & Greb 1987).

Pharmacological effects of K+ channel openers and present clinical applications. Cardiovascular effects. Vessels. The vasodilating effect of K + channel openers is believed to be produced by opening of K + channels, leading to K+-efflux, hyperpolarization, and a reduction of Ca2+ influx through voltage operated Ca2+channels. The identity of the K+-channels with which the drugs interact in the vessels is not established. Most probably an ATP-sensitive channel, which can be inhibited by glibenclamide, is involved (Standen et al. 1989; Kajioka et al. 1991), but the participation of other channel types (e.g., Ca2+-dependent Kf channels) cannot be excluded (Edwards & Weston 1990a). Cromakalim was shown to relax contractions of “electrically silent” blood vessels in which only a small part of the Ca2+ necessary for activation enters through dihydropyridine-sensitive Ca2+ channels (Bray et al. 1988a & b; Cook et al. 1988). On theoretical grounds, an increase in membrane potential can be expected to have several consequences, e.g., to interfere with the activation of voltage operated Ca2+channels insensitive to dihydropyridines, to favour the extrusion of intracellular Ca2+by N a + / Ca2+ exchange, to inhibit intracellular Ca2+-release,and to increase the uptake of, e.g. noradrenaline by the extraneuronal catecholamine transporter (Quast & Cook 1989). K + channel openers may, however, also have vasodilator mechanisms not easily explained by K + channel openening. This is the case for pinacidil and nicorandil. Thus, it has been suggested that pinacidil in high concentrations can redistribute Ca2+to peripheral intracellular sites (Erne & Hermsmeyer 1987), stimulate a plasmalemmal Ca2+extrusion mechanism (Misheri et a/. 1991), inhibit receptor-mediated phosphatidylinositol turnover (Anabuki et al. 1990), and reduce the sensitivity of contractile proteins to CaZ+(Yanagisawa et al. 1990, Meisheri et al. 1991). Supporting the latter effect, M) acted Itoh et al. (1991) showed that pinacidil directly on the contractile apparatus to inhibit Ca2+induced contraction in the rabbit mesenteric artery. Nicorandil stimulates the formation of cGMP by means of its nitrate moiety (Taira 1989). Probably because of this, nicorandil causes sustained dilatation of both venous capacitance and arterial resistance vessels (Kinoshita & Sakai 1990). In addition, nicorandil has been reported to enhance vascular prostaglandin formation (Kinoshita & Sakai 1990). Thus, nicorandil can behave both as an opener of glibenclamidesensitive K + channels, and as a directly acting nitrovasodilator. It is not clear which is the most important action. Based on studies on rabbit aorta, Kreye et al. (1991) suggested that the nitrovasodilator-like properties were primarily responsible for vasodilatation. On the other hand, Yoneyama et al. (1990) found the effect of nicorandil on the coronary circulation to be predominantly due to its K+-channel open-

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ing action. KRN2391, which contains a nitroxy group, also has a dual vasodilator action (Okada et al. 1991). Its nitroxy group was found to be of importance not only for its action as a nitrate, but also for its potency as a K + channel opener. K+ channel openers, except for nicorandil (and other compounds containing nitro groups, e.g. KRN2391), do not seem to have any effect on tissue levels of cGMP or cCAMP (Kauffman et al. 1986; Southerton et al. 1988; Nakajima et al. 1989). The release of transmitter in vascular preparations is unaffected by these drugs (Nedergaard 1989; Nakashima et al. 1990). In normotensive animals, K + channel openers decrease blood pressure in a dose-dependent manner (see Richer et al. 1990). The effects of the drugs on regional blood flows and vascular resistances seem to depend on the species of the animal investigated. In dogs, cromakalim and pinacidil were found to preferentially reduce afterload and to increase venous return (Gotanda et al. 1989). Investigations in man also suggest K + channel openers to be primarily arteriolar vasodilators (Thomas et al. 1990). In healthy men, pinacidil was found to induce vasodilatation of both small and large arteries, leading to a moderate lowering of blood pressure and to stimulation of the reninangiotensin and sympathetic nervous systems (Thuillez et al. 1991). Cromakalim had similar actions, and was shown not to affect venous capacitance (Lijnen et al. 1989; Webb et al. 1989; Donnelly et al. 1990; Fox et al. 1991). The drug had no effect on pressor responses to noradrenaline and angiotensin I1 (Donnelly et al. 1990). The vasodilating effects of pinacidil were not homogenously distributed, and the drugs affected preferentially the muscular vascular bed (Thuillez et al. 1991). Clinical application - hypertension. In hypertension, pinacidil is the best investigated drug; its actions in hypertensive patients were recently reviewed (Friedel & Brogden 1990). The efficacy of pinacidil in the treatment of mild to moderate hypertension has been demonstrated in several controlled clinical trials, some of which had a duration of more than 12 months. The daily dose has ranged from 20 to 100 mg (optimum dose 25 to 50 mg). Compared to placebo, pinacidil monotherapy controlled blood pressure to target level in 67 to 87% of patients. No tolerance to its effect was found, and there was no rebound when the drug was abruptly withdrawn. However, the response to pinacidil was limited by adverse effects related to vasodilatation which necessitated addition of a thiazide diuretic or P-adrenoceptor antagonist to maintain efficacy. The addition of a thiazide diuretic was found to improve and to alleviate the common adverse effects of oedema and weight gain. Pinacidil treatment has been found to be associated with a beneficial effect on blood lipids (Rockhold et al. 1989). In a double-blind, placebo-controlled, cross-over study, single doses of cromakalim, 1.5 mg orally, produced a reduction of supine systolic and diastolic blood pressure in hypertensive patients (Singer et al. 1989). In a dose of 0.75 mg

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orally, cromakalim lowered systolic and diastolic blood pressure in hypertensive patients within 14 days in a 6-week study. Reflex tachycardia was observed, but apparently cromakalim did not produced oedema (Eckl & Greb 1987). In hypertensive patients (n = 10) treated with atenolol, addition of cromakalim 1 mg daily for 4 weeks, caused a modest further reduction in blood pressure. Cromakalim had no effect on apparent liver blood flow and did not change the steady-state pharmacokinetics of atenolol (Donnelly et al. 1990). The scanty information on the antihypertensive effects of cromakalim does not make a comparison with pinacidil meaningful. Apparently, both drugs have an antihypertensive effect which is clinically useful. They are effective arteriolar vasodilators and, so far, the experiences suggest that optimal clinical use of their effects necessitates combination with other drugs.

Heart. In cardiac myocytes, at least 8 different K + channels, differing in biophysical properties, regulation, and pharmacology have been described (Carmeliet 1989; Escande 1989). K + channel openers may affect ATP-sensitive channels in myocardial cells (Arena & Kass 1989; Escande 1989), but in concentrations that are considerably higher (10-100 fold) than those needed for effects on vascular smooth muscle. In guinea pig-papillary muscle and ventricular myocytes, cromakalim shortened action potential duration (Scholtysik 1987; Osterrieder 1988. This was found also in normal canine Purkinje fibres, where cromakalim (1-100 pM) produced a concentration-dependent shortening of action potential duration without change in the maximum diastolic potential, action potential amplitude or maximal upstroke velocity (Bril & Man 1990). Cromakalim suppressed spontaneous activity and antagonized the enhancement of automatic discharge induced by noradrenaline, barium or strophantidine, and reduced or abolished the oscillatory potentials induced by high [Ca2+],, suggesting antiarrhythmic activity (Liu et al. 1988). In isolated rat atrial and ventricular preparations, cromakalim had minimal functional effects (McPherson & Angus 1990), but at high doses, the drug was reported to have a negative inotropic action in the isolated, blood-perfused dog papillary muscle (Gotanda et al. 1988). However, there was more than 10-fold differences in the vasodilator and cardiodepressant potencies of cromakalim (Gotanda et al. 1988). Pinacidil (10-100 pM) caused a concentration-dependent and reversible decrease in action potential duration, without modifying resting potential or action potential amplitude (Smallwood & Steinberg 1988; Arena & Kass 1989, Spinelli et al. 1991). Pinacidil increased the current required to increase early after-depolarizations in single canine ventricular myocytes, diminished or abolished early after-depolarizations evoked by ouabain, and arrested abnormal automaticity caused by BaZf (Spinelli et al. 1991), all effects suggesting an antiarrhythmic potential. Effects on the action potential similar to those produced by cromakalim and

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pinacidil have been reported by SR 44866 in myocardium from several species, including humans (Gautier et al. 1991). In various animal models, K+ channel openers also have myocardial protective effects (see below). In animals, cromakalim and pinacidil dose-dependently increased coronary blood flow and relaxed both conductance and resistance arteries (Giudicelli et al. 1990). However, Kf channel openers do not seem to produce coronary steal even at hypotensive doses (Sakamoto et al. 1989; Giudicelli et al. 1990). In anaesthetized rabbits, cromakaliminduced coronary vasodilatation tended to be more pronounced in the outer layer of the left ventricular free wall than in the subendocardial layer (Hof et al. 1988). Coronary vasodilatation by nicorandil has been documented not only in animals (Kinoshita & Sakai 1990), but also in man (Suryapranata & Serruys 1989). Interestingly, Yoneyama et al. (1 990) comparing the ability of nicorandil, cromakalim and nitroglycerin to increase coronary blood flow in isolated, blood-perfused papillary muscle preparations of dogs, found that the effect of nicorandil was predominantly due to its mechanism of action as a Kf channel opener. On the other hand, in vivo, the vasodilator action of nicorandil in canine conductive arteries were not modified by glibenclamide (Imagawa et al. 1992). It thus seems that the vasodilator effect of nicorandil on canine resistance vessels may be due primarily to its action as a K + channel opener, and that the effects on conductive coronary vessels are mediated mainly by its nitroglycerin-like action. In 22 patients undergoing cardiac catheterization, nicorandil2040 mg given sublingually, produced a significant vasodilatation in normal as well as stenotic segments of epicardial arteries (Suryapranata & Serruys 1989). Injection of nicorandil ( 2 4 mg intravenously, or 0.02 mg in the coronary artery) caused a prompt, complete relief of both spontaneous and evoked coronary spasm in 10 patients with vasospastic angina pectoris (Aizawa et al. 1989).

Clinical application - angina pectoris. Nicorandil is the best investigated K + channel opener in angina pectoris. In a placebo-controlled single-dose study, eight patients with stable effort angina pectoris were given nicorandil in doses of 20, 40 and 60 mg (Camm & Maltz 1989). The drug significantly and dose-dependently prolonged exercise duration for at least 6 hr. There was a marked reduction in blood pressure both at rest and during exercise, which resulted in severe dizziness and fainting in 2 of 6 patients after the 60-mg dose. Significant reflex tachycardia occurred only at 2 hr after the 60-mg dose. Headache was the most common adverse effect attributable to nicorandil and was reported by 7 of the 8 patients; all 6 patients receiving the 60-mg dose had adverse effects. Meany et al. (1 989) investigated exercise capacity after single and twice-daily doses of nicorandil in 46 patients with chronic stable angina pectoris. The study had a doubleblind, parallel group design and a duration of 2 weeks. Two groups received nicorandil (final doses 10 and 20 mg twice daily), and one placebo after 2 weeks of placebo washout.

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Nicorandil improved exercise capacity both acutely and after chronic administration without significant alteration in blood pressure or heart rate. Headache was the most frequent adverse effect. In a single-blind study the effects of single-dose nicorandil 30 mg, was compared with those of propranolol 40 mg, diltiazem 60 and 120 mg, and placebo in 12 patients with chronic stable angina pectoris (Kinoshita et al. 1989). All patients performed 6 full exercise tests on separate days. Each drug increased exercise duration and time to onset of ischaemia; nicorandil was claimed to be more effective in patients with one-vessel disease than propranolol and diltiazem. Nicorandil seemed to be effective also in patients with variant angina pectoris. In a single blind study on 32 patients with this disorder, administration of nicorandil20 mg daily for 3 days, completely alleviated anginal attacks in 75% of cases and significantly suppressed S-T depression (Kishida & Murao 1987). The acute haemodynamic effects of cromakalim infused intravenously (1 5 pg/ kg) were studied in patients with stable angina pectoris (Thomas et al. 1990). The drug caused an increase of cardiac output (19-30%0), systemic arteriolar and pulmonary vascular resistances fell ( I 7-29% and 19-24%0, respectively), and there was a moderate (1 1%, not significant) increase in heart rate. This may partly be explained by a residual P-adrenoceptor antagonist effect in some of the patients receiving such therapy before the study. No adverse effects were reported. Obviously, cromakalim acts like an arteriolar vasodilator in patients with angina pectoris and reduces systemic vascular resistance. It may therefore be expected to cause reflex tachycardia and increase cardiac work, which is likely to be disadvantageous in the longterm treatment of angina pectoris, unless the drug is combined with b-adrenoceptor antagonists, or calcium antagonists like verapamil and diltiazem. The apparent lack of negative inotropic effect found at concentrations relaxing vascular smooth muscle in animal experiments (Gotanda et al. 1988; McPherson & Angus 1990) may be an advantage. The experiences with nicorandil suggest that monotherapy with this drug is effective in angina pectoris. Whether or not this can be attributed to its unique mechanism of action, or is attributable mainly to its K + channel opening effect is not established. It seems doubtful that monotherapy with cromakalim, or K+ channel openers with similar hemodynamic profile, will be a good therapeutic alternative. This does not exclude that combined treatment with these drugs can be useful.

Effects on respiratory tract. K+ channels have been demonstrated electrophysiologically in isolated airway smooth muscle (McCann &Welsh 1986). This type of muscle usually exhibits a low level of electrical activity, does not have spontaneous action potentials (Davis et al. 1982; Marthan et al. 1989), but may display slow wave activity that could represent action potentials that are attenuated by the opening of Kf channels. In isolated human airway smooth muscle, action potentials are only gen-

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erated when K+ channel activity is reduced (Marthan et al. 1989). On the other hand, an electromyographic study on asthmatic patients suggested that spontaneous action potentials may occur in the airways (Akasaka et al. 1975). These data suggest that K+ channel openers may be effective to relax isolated bronchial smooth muscle. This was also found with, e.g., cromakalim, pinacidil, Ro 316930, and RP 49356 in isolated guinea-pig trachealis muscle (Allen et al. 1986; Nielsen-Kudsk et al. 1988 & 1990; Murray et al. 1989; Paciorek et al. 1990a & b; Raeburn & Brown 1991). Lemakalim (BRL 38227), the active enantiomer of cromakalim, produced relaxation of isolated human bronchi, with either resting tone or tone induced by histamine, carbachol, neurokinin A, or KCl 20 mM. It was less active when tone was induced by KCl 80 mM. The maximum effect attained was 60 to 80% of that obtained with isoprenaline and the potency expressed as ECSo,was between 0.2 to 0.6 pM (Black et al. 1990). The effects of cromakalim, RP 49356, and lemakalim were antagonized by glibenclamide, suggesting the involvement of an ATP-dependent K+ channel. The effect of lemakalim was enhanced by simultaneous blockade of calcium channels by verapamil (Black et al. 1990). Investigations in vivo on animals and humans have also shown promising results. Thus, administration of cromakalim (10 to 400 pg/kg) to anaesthetized guinea-pigs produced a dose-related inhibition of 5-hydroxytryptamine-induced bronchoconstriction, and in conscious guinea-pigs cromakalim, given orally (2.5 to 5 mg/kg) 5 min. prior to challenge with histamine, prolonged the time to asphyxic collapse (Arch et al. 1988). Ro 31-6930 protected conscious guineapigs from histamine-induced respiratory distress (Paciorek et al. 1990b). Both in vivo (Ichinose & Barnes 1990) and in vitro (Burka et al. 1991) cromakalim was shown to depress non-adrenergic, non-cholinergic excitatory neuroeffector transmission in the guinea-pig airways. Whether this has any relation to the observation that doses of cromakalim too low to cause direct relaxation of airways smooth muscle can suppress airway hyperreactivity in laboratory animals (Chapman et al. 1991), is not known. In non-asthmatic subjects, single doses of cromakalim (2 mg orally) inhibited brochoconstriction induced by histamine administered 5 hr after cromakalim dosage (Baird et al. 1988). Cromakalim produced a slight depression of diastolic blood pressure and increase in heart rate. Clinical application - asthma. As K+ channel openers in vitro as well as in vivo have a promising effect profile, and as K + channel blockade may contribute to airway hyperresponsiveness (Black & Barnes 1990), K+ channel openers may be expected to have clinically useful effects in patients with asthma. However, clinical information is limited. Cromakalim, at dosages 0.25 and 0.5 mg, but not 1.5 mg, given orally, reduced early morning bronchoconstriction in asthmatic patients. This action was attributable to its long duration of action (Owen et al. 1989; Williams et al. 1990). The effect on morning

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asthma of cromakalim may be clinically useful; it also means that K+ channel openers may have a potential for the treatment of asthma. However, asthma is no longer considered the consequences of just bronchospasm or hyperreactive airways, but rather as an inflammatory disease (Reed 1991). If K+ channel openers can be shown to have antiinflammatory properties, their potential as future asthma drugs will increase considerably.

Effects on bladder smooth muscle. Cromakalim reduced the spike frequency in isolated guineapig bladder. In high concentrations (10-6-10-5 M) the drug abolished the spikes, and there was a concentration-dependent hyperpolarization of the cell membrane (Fujii 1987; Foster et al. 1989a). Spontaneous contractile activity was abolished. Cromakalim was shown to open a K+ channel having properties similar to those of the delayed rectifier K+ channel responsible for spike repolarization. This channel is also similar to the ATP-dependent K+ channels in vascular smooth muscle (Fujii et al. 1990). Supporting such a view, the relaxant effects of several K + channel openers in the rat detrusor were antagonized by glibenclamide (Edwards et al. 1991). Studies on isolated human detrusor muscle (Andersson et al. 1988; Foster et al. 1989b; Fovaeus et al. 1989), and on bladder tissue from several animal species (Andersson et al. 1988; Foster et al. 1989a & b; Malmgren et al. 1990; Edwards et al. 1991) have shown that K + channel openers reduce not only spontaneous contractions, but also contractions induced by electrical stimulation, carbachol, and low, but not high external K+ concentrations. The drugs also increase the outflow of 86Rbor 42Kin preloaded tissues, further supporting the view that they relax bladder tissue by K + channel opening and subsequent hyperpolarization. The K+ channel openers were particularly effective in hypertrophic rat bladder muscle in vitro (Malmgren et al. 1990), and suppressed effectively bladder hyperactivity in rats with bladder outflow obstruction (Malmgren et al. 1989). However, available K + channel openers were shown to be approximately 8 times more potent as inhibitors of the spontaneous contractions of the rat portal vein than K+-induced contractions of the rat detrusor (Edwards et al. 1991). This lack of selectivity for bladder muscle may be a limitation for their clinical use.

Clinical application - bladder hyperactivity. What is needed to treat bladder hyperactivity, particularly in patients with benign prostatic hyperplasia, is a drug which eliminates the “unstable” bladder contractions, but does not affect the normal bladder contraction necessary for bladder emptying (Andersson 1988). This cannot always be achieved by e.g. conventional antimuscarinic drugs, but the abovementioned in vitro experiments and animal studies suggest that K+ channel opening would be a useful therapeutic principle. However, in a randomized, double blind, placebocontrolled pilot study on 10 patients with benign prostatic

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hypertrophy and “unstable bladder”, pinacidil(l2.5 mg x 2) had no effects on either cystometric variables or on symptoms, but caused a significant lowering of standing blood pressure (Hedlund et al. 1991). The potential clinical usefulness of presently available K+ channel openers in states of bladder hyperactivity remains to be established.

Possible future applications. Cerebral vasospasm. The exact mechanism underlying chronic cerebral vasospasm after subarachnoid haemorrhage remains uncertain. So far, the administration of drugs inhibiting receptors mediating the response to the vasoconstrictor agonists detected in the subarachnoid fluid has yielded no success in the reversal or the prevention of vasospasm (Wilkins 1986). Trials with nimodipine has shown promising effects in the prevention of vasospasm, but the drug was not effective in reversing established spasm (Langley & Sorkin 1989). Young et al. (1986) speculated whether chronically elevated [KC], levels in areas of periarterial blood clot lyses, or brain ischemia, may initiate vascular smooth muscle depolarization and vasospasm. In a dog model, where cisternal injection of autologous blood produced spasm of the basilar artery, in vitro investigation of the vessel revealed membrane depolarization and enhanced electrical spike activity resulting from a reduction in resting K + conductance (Harder et al. 1987). Nicorandil repolarized the membrane and abolished the spike activity observed in vitro, and partially (50%) reversed the vasospasm found in vivo (Harder et al. 1987). Several investigators have presented results consistent with the occurrence of ATP-sensitive K + channels in cerebral vessels from various species, and that K+ channel openers can reverse contractions induced by agonists and increased [Kf], concentrations (Wahl 1989; Cain & Nicholson 1989; Masuzawa et al. 1990; Ksoll et al. 1991; Parsons et al. 1991). Thus, in situ, pinacidil was a powerful dilator of pial arteries (Wahl 1989). Cromakalim, pinacidil, and nicorandil relaxed 5-hydroxytryptamine-contractedrat isolated basilar artery, pinacidil and nicorandil, but not cromakalim, relaxing vessels contracted by 50 mM KCl (Ksoll et al. 1991). In contrast, McCarron et al. (1991) found that in isolated small (diameter 158 pm), pressurized rat cerebral arteries, cromakalim and pinacidil had no relaxing action at concentrations (up to 3 pM), which potently relaxed similarly sized mesenteric arteries. The reasons for this discrepancy in result are not known. Most probably, cerebral vasospasm is not merely due to a prolonged contraction of vascular smooth muscle, but proliferative changes of the arterial wall may contribute (Peerless et al. 1980). If a decreased membrane K + conductance is a major contributory factor in cerebral vasospasm, the K + channel openers may provide an effective prophylactic therapy. However, the use of Kf channel openers in the treatment of vasospasm following subarachnoid haemorrhage in man has as yet no clinical support, and in the absence of clinical data it remains purely speculative.

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Erectile dysfunction. In isolated human corpus cavernosum, pinacidil abolished spontaneous contractile activity, effectively relaxed preparations contracted by noradrenaline, and inhibited contractions induced by electrical stimulation of nerves. Pinacidil also depressed contractions induced by low concentrations of K + , and concentration-dependently increased the efflux of 86Rb from preloaded tissue (Holmquist et al. 1988; 1990a). In isolated corpus cavernosum from rabbit, the effects were similar to those in human tissue. It was also shown that cromakalim was 3 to 4 times more potent than pinacidil, and up to 36 times more potent than papaverine (Holmquist et al. 1990b). Furthermore, in rabbit tissue, the effects of pinacidil on contracted preparations and on 86Rb efflux were blocked by glibenclamide, suggesting involvement of ATP-dependent K + channels (Holmquist & Andersson, unpublished results). Giraldi & Wagner (1990) showed that pinacidil in high concentrations (> M) may relax even completely depolarized corpus cavernosum tissue. This effect is most probably not related to pinacidil’s K + channel opening action. Intracavernous injection of pinacidil produced tumescene or erection in 16 out of 17 monkeys, a result similar to that obtained with papaverine (Giraldi & Wagner 1990). Although the systemic blood pressure dropped in only one of the five monkeys in which the blood pressure was monitored, the potential risk of systemic side effects should not be disregarded. No experiences of intracorporal injection of K + channel openers in man seem available in the literature. Whether or not K + channel openers, alone or together with other vasoactive agents, can be used for diagnosis and treatment of erectile dysfunction warrants further investigations. Myocardial protection. Pharmacological protection against myocardial damage caused by ischaemia and reperfusion of ischaemic myocardium is currently a field of intensive research, partly as a consequence of the success of thrombolytic therapy in myocardial infarction. In myocardial ischaemia, there is a progressive damage of the myocardium starting with a loss of ATP, creatine phosphate and K f . The increase in the extracellular K+ concentration is possibly due to an opening of ATP sensitive K f channels, but it is not clear how the opening of such channels can result in protective activity. Kantor et al. (1990) found that glibenclamide reduced both early K + loss as well as ischaemic arrhytmias in the isolated perfused rabbit heart. There is a shortening in the action potential duration in myocardial ischaemia (Escande, 1989), which has been suggested to be an important adaptive mechanism for protection of the myocardium. Glibenclamide decreased action potential shortening, elicited arrhythmias and enhanced myocardial damage caused by ischaemic reperfusion in the arterially perfused guinea-pig right ventricular wall. In contrast, pinacidil had the opposite effect (Cole et al. 1991). In anesthetized rabbits, glibenclamide attenuated action potential shortening during ischaemia in a dose-

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related manner, but did not reduce the susceptibility to electrically-induced ventricular fibrillation in dogs subjected to acute ischaemia (Smallwood et al. 1990). These conflicting results make it an open question whether or not K t channel openers will be useful in acute myocardial ischaemia. The effects of K t channel openers may mimic the mechanisms counteracting the harmful effects of ischaemia, but the drugs may also be potentially arrythmogenic. Several investigations, using different animal model, have shown that K + channel openers can have beneficial effects during ischaemia and reperfusion. Nicorandil (Gross et al. 1989; Grover et al. 1990b), pinacidil, cromakalim (Grover et af. 1989 & 1990a), RP 52891 (Richer et al. 1990), and KRN2391 (Ohta et af. 1991) produced significant improvement in reperfusion function of isolated rat hearts subjected to global ischaemia followed by reperfusion, or of hearts of anaesthetized dogs. The actions of the different drugs in this respect are not necessarily identical. Thus, the protection exerted by cromakalim was accompanied by a dramatically reduced lactate dehydrogenase release, but the effect of pinacidil was not (Grover et al. 1989). The cardioprotective effect of cromakalim was shown to be stereoselective, and was prevented by glibenclamide (Grover et al. 1989 & 1991). Also the cardioprotective effects of KRN239 1 were reversed by glibenclamide (Ohta et al. 1991). In dogs with coronary stenosis, Sakamoto et af.(1989) found that pinacidil reduced myocardial blood flow in the infarct zone and increased infarct size. Contributing to such an effect could be that the animals received a pinacidil dose lowering blood pressure by 25 mmHg, which evoked an increase in heart rate, cardiac output, and left ventricular dP/dt. Notably, Rademacher et al. (1990) found that intracoronary administration of cromakalim, which did not affect the peripheral circulation, had myocardial protective effects in anaesthetized dogs. The possible arrhythmogenic potential of Kf channel openers, may be enhanced by reflex activation of the sympathetic nervous system. Thus, Chi et al. (1990) found that pinacidil, in doses causing hypotension and tachycardia, increased the potential for development of ventricular fibrillation in a subset of conscious dogs after myocardial infarction. As mentioned previously, pinacidil have actions suggesting antiarrhythmic activity (Liu et af. 1988; Spinelli et af. 1991), and the drug was found to antagonize arrhythmias present in conscious dogs 22-24 hr after coronary artery occlusion (Kerr et al. 1985). It may thus be that K+ channel openers can have beneficial effects on ischaemic and reperfused myocardium, which may be clinically useful provided that the vascular actions do not provoke a reflex activation of the sympathetic nervous system. Other conditions. Beside the effects discussed above, K + channel openers have a variety of other actions that may be applied clinically. Thus, their vascular effects may make them useful in, e.g., chronic occlusive arterial disease (Angersbach & Nicholson 1988), and possibly congestive heart failure (Solal et af.

1989). Another example is a possible anticonvulsant action (Gandolfo et af. 1989a & b), suggesting a potential role for K + channel openers in the prophylactic treatment of epilepsy. However, clinical information is needed to guide further exploration of these actions of the drugs. Conclusion. K+ channel openening represents an interesting pharmacological principle with theoretically many important clinical applications. However, presently available drugs have an insufficient tissue selectivity for many indications. Clinical experiences with several of the new members of the group are awaited. Such information is needed before the potential of the drugs for treatment of e.g. hypertension, asthma, and for myocardial protection can be properly evaluated.

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Meisheri, D., L. A. Cipkus & C. J. Taylor: Mechanism of action of minoxidil sulphate-induced vasodilatation: a role for increased K+ permeability. J. Pharmacol. Exp. Therap. 1988,245,751-760. Meisheri, K. D., M. A. Swirtz, S. S. Purohit, L. A. Cipkus-Dubray, S. A. Khan & J. J. Oleynek: Characterization of K + channeldependent as well as independent components of pinacidil-induced vasodilation. J. Pharmacol. Exp. Therap. 1991, 256, 492499. Murray, M. A., J. P. Boyle & R. C. Small: Cromakalim-induced relaxation of guinea pig isolated trachealis: antagonism by glibenclamide and by phentolamine. Brit. J. Pharmacol. 1989, 98, 865-874. Nakajima, S., K. Kurokawa, N. Imamura & M. Ueda: A study on the hypotensive mechanism of pinacidil: Relationship between its vasodilating effect and intracellular Ca2+levels. Jap. J. Pharmacol. 1989, 49, 205-213. Nakashima, M., Y. Li, N. Seki & H. Kuriyama: Pinacidil inhibits neuromuscular transmission indirectly in the guinea-pig and rabbit mesenteric arteries. Brit. J. Pharmacol. 1990, 101, 581-586. Nedergaard, 0. A.: Effect of pinacidil on sympathetic neuroeffector transmission in rabbit blood vessels. Pharmacology & Toxicology 1989, 65, 287-294. Newgreen, D. T., K. M. Bray, A. D. McHarg, A. H. Weston, S. Duty, B. S. Brown, P. B. Kay, G. Edwards, J. Longmore & J. S. Southerton: The action of diazoxide and minoxidil sulphate on rat blood vessels: a comparison with cromakalim. Brit. J. Pharmacol. 1990, 100, 605413. Nielsen-Kudsk, J. E., S. Mellemkjaer, C. Siggard & C. B. Nielsen: Effects of pinacidil on guinea-pig airway smooth muscle contracted by asthma mediators. Eur. J. Pharmacol. 1988, 157,221-226. Nielsen-Kudsk, J. E., L. Bang & A. M. Bronsgaard: Glibenclamide blocks the relaxant action of pinacidil and cromakalim in airway smooth muscle. Eur. J. Pharmacol. 1990, 180, 291-296. Ohta, H., Y. Jinno, K. Harada, N. Ogawa, H. Fukushima & K. Nishikori: Cardioprotective effects of KRN239 1 on ischemic dysfunction in perfused rat heart. Eur. J. Pharmacol. 1991, 204, 171-177. Okada, Y., T. Yanagisawa & N. Taira: An analysis of the nitrate-like and K channel opening actions of KRN2391 in canine coronary arterial smooth muscle. Brit. J. Pharmacol. 1991, 104, 829-838. Osterrieder, W: Modification of K+ conductance of heart cell membrane by BRL 349 15. Naunyn-SchmiedebergS Arch. Pharmacol. 1988, 337, 93-97. Owen, S., S. Church, P. Stone, B. Bosch, S. Webster, E. Lavender, A. Williams & A. Woodcock: Randomised, double blind, placebo controlled, crossover (RDBPCC) study of a potassium channel activator (KCA) in morning dipping. Thorax 1989, 44,852P. Paciorek, P. M., D. T. Burden, Y. M. Burkem, I. S. Cowlrick, R. S. Perkins, J. C. Taylor & J. F. Waterfall: Preclinical pharmacology of Ro 31-6930, a new potassium channel opener. J. Cardiovasc. Pharmacol. 1990a, 15, 188-197. Paciorek, P. M., I. S. Cowlrick, R. S. Perkins, J. C. Taylor, G. F. Wilkinson & J. F. Waterfall: Evaluation of the bronchodilator properties of RO 31-6930, a novel potassium channel opener, in the guinea-pig. Brit. J. Pharmacol. 1990b, 100, 289-294. Parsons, A. A,, E. Ksoll, J. R. L. Mackert, L. Schilling & M. Wahl: Comparison of cromakalim-induced relaxation of potassium precontracted rabbit, cat, and rat isolated cerebral arteries. NaunynSchmiedeberg's Arch. Pharmacol. 1991, 343, 384-392. Peerless, S. J., N. F. Kassell, K. Komatsu & 1. G. Hunter: Cerebral vasospasm: acute proliferative vasculopathy? 2. Morphology. In: Cerebral arterial spasm. Ed.: R. H. Wilkins. William & Wilkins, Baltimore 1980, pp. 96-99. Pratz, J., S. Mondot, F. C. Montier & I. Cavero: Effect of the K + channel activators, RP 52891, cromakalim, and diazoxide, on the plasma insulin level, plasma renin activity, and blood pressure in rats. J. Pharmacol. Exp. Therap. 1991, 258, 216-222. Quast, U., S. Blarer, P. W. Manley, N. S. Cook, C. Pally & J. R. Fozard: The cardiovascular effects of SDZ PCO 400 in vivo: comparison with cromakalim. Brit. J. Pharmacol. 1990, 99, 7P.

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Quast, U. & N. S. Cook: Moving together: K+-channel openers and ATP-sensitive K+-channels. Trenh Pharmacol. Sci. 1989,10, 431435. Rademacher, C., T. Ehring & V. Thamer: BRL 34915 ameliorates oxygen supply in ischemic myocardium by a simultaneous enhancement of coronary blood flow and a reduction of myocardial function. J. Cardiovasc. Pharmacol. 1990, 15, 808-81 5. Raeburn, D. & T. J. Brown: RP 49356 and cromakalim relax airway smooth muscle in vitro by opening a sulphonylurea-sensitive K+channel: a comparison with nifedipine. J. Pharmacol. Exp. Therup. 1991, 256, 480-485. Reed, C. E. (Editorial): Aerosol steroids as primary treatment of mild asthma. New Engl. J. Med. 1991, 325, 425426. Richer, C., P. Mulder, M. P. Doussau & J. F. Giudicelli: Agonistes potassiques: profil vasodilatateur regional chez le rat. Arch. Mal. Coeur 1989, 82, 1333-1337. Richer, C., J. Pratz, P. Mulder, S. Mondot, J. F. Giudicelli & I. Cavero: Cardiovascular and biological effects of K+ channel openers, a class of drugs with vasorelaxant and cardioprotective properties. Life Sci. 1990, 47, 1693-1705. Robertson, D. W. & M. I. Steinberg: Potassium channel modulators: scientific applications and therapeutic promise. J. Med. Chem. 1990, 33, 1529-1541. Rockhold, F. W., M. R. Goldberg & W. L. Thompson: Beneficial effects of pinacidil on blood lipids: comparisons with prazosin and placebo in patients with hypertension. J. Lab. Clin. Med. 1989, 114, 646-654. Sakamoto, S., C. Liang, C. K. Stone & W. B. Hood, Jr.: Effects of pinacidil on myocardial blood flow and infarct size after acute left anterior descending coronary artery occlusion and reperfusion in awake dogs with and without a coexisting left circumflex coronary artery stenosis. J. Cardiovasc. Pharmacol. 1989,14,747-755. Scholtysik, G.: Evidence for inhibition by ICS 205-930 and stimulation by BRL 34915 of a K+ conductance in cardiac muscle. Naunyn-Schmiedeberg 's Arch. Pharmacol. 1981, 335, 692-696. Singer, D. R. J., N. D. Markandu, M. A. Miller, A. L. Sugden & G. A. MacGregor: Potassium channel stimulation in normal subjects and in patients with essential hypertension: an acute study with cromakalim (BRL 34915). J. Hypertension 1989, 7, 294-295. Smallwood, J. K., P. J. Ertel & M. I. Steinberg: Modification by glibenclamide of the electrophysiological consequences of myocardial ischemia in dogs and rabbits. Naunyn Schmiedeberg S Arch. Pharmacol. 1990, 342, 214-220. Smallwood, J. K. & M. I. Steinberg: Cardiac electrophysiological effects of pinacidil and related pyridylcyanoguanidines: relationship to antihypertensive activity. J. Cardiovasc. Pharmacol. 1988, 12, 102-109. Solal, A. C., P.Jaeger, J. Bouthier, J.-M. Juliard, M. Dahan & R. Gourgon: Hemodynamic action of nicorandil in chronic congestive heart failure. Amer. J. Cardiol. 1989, 63, 445485. Southerton, J. S., A. H. Weston, K. M. Bray, D. T. Newgreen & S. G. Taylor: The potassium channel opening action of pinacidil; studies using biochemical, ion flux and microelectrode techniques. Naunyn Schmiedeberg 's Arch. Pharmacol. 1988, 338, 3 10-318. Spinelli, W., S. Sorota, M. Siegal & B. F. Hoffman: Antiarrhythmic actions of the ATP-regulated K + current activated by pinacidil. Circ. Res. 1991, 68, 1127-1 137. Standen, N. B., J. M. Quayle, N. W. Davies, J. E. Brayden, Y. Huang & M. T. Nelson: Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science 1989, 245, 177-180. Steinberg, M. I., S. A. Wiest, K. M. Zimmerman, P. J. Ertel, G. Bemis & D. W. Robertson: Chiral recognition of pinacidil and its 3-pyridyl isomer by canine cardiac and smooth muscle: antagonism by sulfonylureas. J. Pharmacol. Exp. Therap. 1991, 256, 222-229. Suryapranata, H. & P. W. Serruys: Coronary vasodilatory action after nicorandil: a quantitative angiographic study. Amer. J. Cardiol. 1989, 63, 805-855.

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Taira, N.: Nicorandil as a hybrid between nitrates and potassium channel activators. Amer. J. Cardiol. 1989, 63, 18J-24J. Thomas, P., M. S. Dixon, S. J. Winterton & D. J. Sheridan: Acute haemodynamic effects of cromakalim in patients with angina pectoris. Brit. J. Clin. Pharmacol. 1990, 29, 325-331. Thuillez, C., E. Pussard, E. Bellisant, C. Richer, R. Kechrid & J.F. Giudicelli: Arterial vasodilating profile and biological effects of pinacidil in healthy volunteers. Brit. J. Clin. Pharmacol. 1991, 31, 33-39. Wahl, M.: The effects of pinacidil and tolbutamide in feline pial arteries in situ. Pjliiger’s Arch. 1989, 415, 250-252. Webb, D. J., N. Benjamin & P.Vallance: The potassium channel opening drug cromakalim produces arterioselective vasodilation in the upper limbs of healthy volunteers. Brit. J. Clin. Pharmacol. 1989,21,151-761. Wickenden, A. D., S. Grimwood, T. L. Grant & M. H. Todd: Comparison of the effects of the K+-channel openers cromakalim and minoxidil sulphate on vascular smooth muscle. Brit. J. Pharmacol. 1991,103, 1148-1152.

MiniReview

Williams, A. J., T. H. Lee, G. M. Cochrane, A. Hopkirk, I. Vyse, F. Chiew, E. Lavender, D. H. Richards, S. Owen, P. Stone, S. Church & A. A. Woodcock: Attenuation of nocturnal asthma by cromakalim. Lancet 1990, ii, 334336. Wilkins, R. H.: Attempts at prevention or treatment of intracranial spasm: an update. Neurosurgery 1986, 18, 808-825. Yanagisawa, T., T. Teshigawara & N. Taira: Cytoplasmic calcium and the relaxation of canine coronary arterial muscle produced by cromakalim, pinacidil and nicorandil. Brit. J. Pharmacol. 1990, 101, 151-165. Yoneyama, F., K. Satoh & N. Taira: Nicorandil increases coronary blood flow predominantly by K-channel opening mechanism. Cardiovasc. Drugs Ther. 1990, 4, 11 19-1 126. Young, H. A., R. C. Kolbeck, H. Schmidek & J. N. Evans: Reactivity of rabbit basilar artery to alterations in extracellular potassium and calcium after subarachnoid hemorrhage. Neurosurgery 1986, 19, 346349.