K+ Channel Openers

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Vasodilators are a group of dtugs, which relax the smooth muscle cells of the blood vessels and lead to an increased local tissue blood flow, a reduced arterial pressure and a reduced central venous pressure. Vasodilators reduce the cardiac pre-load as well as after-load and thereby reduce cardiac work. They are used in a variety of conditions including hypertension, cardiac failure and treatment/prevention of angina pectoris. Major groups are Ca2+-channel blockers (e.g. dihydropyridines), NO-donators (e.g. organic nitrates), K+-channel openers (minoxidil), phosphodiesterase inhibitors (e.g. sildenafil), Rho-kinase inhibitors (e.g. Y27632) or substances with unknown mechanism of action (e.g. hydralazine). Inhibitors of the... 

Kaxp Channel Knop Channel K+ Channel Openers K Channels... 

Phase 3 begins at the peak of the action potential. At this point, the Ca++ channels close and K+ channels open. The resulting efflux of K+ ions causes the repolarization phase of the action potential. 

Nelson At high K+ there is a convergence, but at lower K+ the K+ equilibrium potential and the membrane potential are different. A K+ channel opener can still work at low (e.g. 20 mM) K+. 

Spector, P.S., Curran, M.E., Keating, M. T. and Sanguinetti, M.C. (1996) Class III antiarrhyfhmic drugs block hERG, a human cardiac delayed rectifier K+ channel. Open channel block by methanesulfonalides. Circulation Research, 78, 499-503. 

Phase 3 Repolarization occurs as Ca2+ channels close and K+ channels open. Efflux of K+ from within the cell repolarizes the cell fairly rapidly compared with Ca2+-dependent depolarization. 

Phase 1 Repolarization begins to occur as Na+ channels close and K+ channels open. Phase 1 is short in duration and does not cause repolarization below 0 mV. 

Despite these challenges, the area of K+ channel openers (PCOs) is emerging as an active area of drug design. Over the past 5-10 years, eight novel structural classes of PCOs have received systematic development benzopyrans (e.g., cromakalim, 7.27), cyanoguanidines (e.g., pinacidil, 7.28), thioformamides (e.g., aprikalim, 7.29), pyridyl nitrates (e.g., nicorandil, 7.30), benzothiadiazines (e.g., diazoxide, 7.31), pyrimidine sulphates (e.g., minoxidil sulphate, 7.32), tertiary carbinols, and dihydropyridines. These various classes have been subjected to analog preparation with compound optimization via structure-activity studies. 

Different K+ channels can be distinguished by their characteristic electrophysiological properties as well as differential sensitivities to pharmacological modulation. For example, Kv channels are blocked by 4-aminopyridine (4-AP), tetraethylammonium (TEA) and millimolar concentrations of Ba. In contrast, Kir channels are also blocked by TEA but show selective sensitivity to sub-millimolar concentrations of Ba2+. Furthermore, certain peptide toxins (e.g. dendrotoxins, tertiapin) can sometimes discriminate between K+ channels belonging to the same family. The K+ channel openers diazoxide, pinacidil and cromakalim (see below) act on the three SUR subunits with a differential order of potency thereby affecting KATP channels in a cell type-specific manner (Yokoshiki et al., 1998). 

G Edwards, AH Weston. Structure-activity relationships of K+ channel openers. TIPS 11 417-422, 1990. 

Hallbrucker, C., Ritter, M., Lang, F., Gerok, W., Haussinger, D. (1993). Hydroperoxide metabolism in rat liver. K+ channel opening, cell volume changes and eicosanoid formation. Eur. J. Biochem. 211,449-458. 

The diagonal element Mh = — (N — k)a — kb determines the distribution fft) of dwell times in a state with k channels open ... 

First note that each time interval with at least k > 0 channels open must start with a transition k — 1 — k. Then the next change in k is either, with probability 4/(4 + Uk), back to k — 1 and that is the end of that interval or, with probability Uk/(dk + Uk), a jump up to k + 1, after which the system dwells with more than k channels open for a period of time distributed according to gk+1, after which it will return to k and we are back at square one. Thus, after the initial transition from k — 1 to k, the number of open channels may jump back and forth between k and more than k any number of times (possibly zero) and finally the interval ends with a transition from k back to k — 1. 

Rundgeldt C (1999) Characterization of the K+ channel opening effect of the anticonvulsant retigabine in PC12 cells. Epilepsy Res 35 99-107... 

K+-channels open resulting in K+ an outward current leading to membrane repolarization. 

In heart, muscarinic receptors inhibit adenylyl cyclase, via activation of PTX-sensitive G (35,80,81,136,137). However, K+ channel opening in response to muscarinic stimulation is not the result of decreased levels of cAMP [138,139], Evidence obtained using patch-clamped cells [160] argues against involvement of any second messenger at all [141-143] in regulation of the K+ channel. Moreover, experiments with inside-out patches demonstrate unequivocally that K+ channels couple directly to a receptor-regulated G protein [144,145], We call this functionally identified G protein Gk. 

Neither non-activated Gj nor non-activated or GTPyS-preactivated Gs elicit K+ channel opening under these conditions. Further, addition of complexes of a-GTP S of Gk resolved from (3y subunits, but not of /3-y subunits, mimic the action of Gk on atrial membrane patch K+ channels [150], This indicates that Gk acts on K+ channels via its a subunit as does Gs acting on adenylyl cyclase and T acting on cGMP-specific PDE. Figure 3 summarizes evidence that led to identification of Gk as the link between acetylcholine receptors and cardiac muscarinic K+ channels. Figure 4 presents key experiments that show direct activation of K+ channels by Gk and its a subunit. 

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