Potassium channel openers

Vasodilators having potassium channel opener activity relax smooth muscle ia low (5—20 mM) K+ coaceatratioa but aot ia high (>80 mAf)K + solutioa, and glibenclamide [10238-21-8] should be able to reverse the iaduced relaxation (242,245—249). They also iacrease potassium efflux. 

There are at least 13 primary types of K+ channels known. In addition, within each type there are several subtypes. The best known chemical classes of potassium channel openers are nicorandil, piaacidil, and cromakalim. They are aU potent smooth muscle relaxants. PharmacologicaUy, they behave as classical vasodilators, lowering blood pressure and causiag tachycardia and fluid retention. 

Nicorandil. Nicorandil is a potassium channel opener that can lower blood pressure 21, 20, and 29 mm Hg after single oral doses of 10, 20, and 30 mg, respectively (250). There are no significant changes ia heart rate. Headache is the primary side effect. Nicorandil has potent coronary vasodilator effects. It causes sustained vasodilation of arteriolar resistance and venous capacitance blood vessels, thus reduciag cardiac preload and aftedoad. 

Pinacidil. Piaacidil is a poteat vasodilator, actiag through potassium channel opening effects (242,251—253). Its antihyperteasive effect is greater than that of hydrala2iae and pra2osia ia chronic treatmeat. Its fast oaset of actioa also makes it suitable for use ia hyperteasive crisis. 

Dihydropyridine Z0947 (108) has been identified as a potassium channel opener for use in urinary urge incontinence and an asymmetric synthesis was required for long-... 

Potassium channel openers Hypertrichosis (minoxidil) lupus-like reactions and pedal edema (hydralazine)... 

Katp channels are the targets for two classes of therapeutic agents, hypoglycaemic drugs like glibencla-mide or nateglinide and potassium channel openers like... 

A number of fused thiopyranopyrazolopyrimidines with potential as potassium channel openers have been prepared by a three-component Hantzsch-type reaction between a ketone, an aldehyde, and an aminopyrazole. These reactions give a mixture of isomers, with and without ring junction heteroatoms (Equation 49) <2002BML1481> among the compounds of particular interest are those in which the ketone is a derivative of thiopyran or its A,A-dioxide. 

Zell M., Erdin H.R., and Hopfgartner G., 1997a. Simultaneous dtermination of a potassium channel opener and its metabolite in rat plasma with column-switching liquid chromatography using atmospheric pressure chemical ionization. J Chromatogr B 694 135. 

Shivkumar, K. and Valderrabano, M. (2004) Use of potassium channel openers for pharmacologic modulation of cardiac excitability. Journal of Cardiovascular Electrophysiology, 15, 821-823. 

BMS-204352, a novel substituted 3-fluorooxindole, is a potassium channel opener being developed for the treatment of stroke. Nassar et al. [96] reported on the development of a non-aqueous parenteral formulation of BMS-204352. This formulation was composed of a mixture of PEG 300, polysorbate 80, ethanol and water. The authors reported on the formation of 1-hydroxymethyl adduct of BMS-204352 (formaldehyde adduct), which was linked with residual levels of formaldehyde in the polymeric excipients. 

Diazoxide is a potassium channel opener with a rapid antihypertensive action after intravenous administration. Diazoxide causes hyperglycaemia which may underlie side-effects such as nausea and vomiting, cardiac dysrhythmia and ketosis. Diazoxide was used occasionally in the management of hypertensive emergencies, but it is now largely abandoned for this indication. Diazoxide is an alternative for glucagons in patients with hypogycaemia. 

Vlll.a. Well-Known Potassium Channel Openers... 

NS-8 and ZD-0947 are calcium sensitive potassium channel openers, that have no effects on the cardiovascular system. They are currently being developed for the treatment of bladder hyperactivity (Phase II) (Figure 8.81). 

Beta blockers, calcium channel blockers and potassium channel openers detailed pharmacology is given in chapter Antihypertensive drugs. ... 

Nicorandil and several other investigational antianginal agents appear to combine the activity of nitric oxide release with potassium channel-opening action, thus providing an additional mechanism for causing vasodilation. 

The excitable membrane of nerve axons, like the membrane of cardiac muscle (see Chapter 14) and neuronal cell bodies (see Chapter 21), maintains a resting transmembrane potential of -90 to -60 mV. During excitation, the sodium channels open, and a fast inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane toward the potassium equilibrium potential (about -95 mV) repolarization returns the sodium channels to the rested state with a characteristic recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues. 

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