Vasodilators 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. 

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. 

Minoxidil is a vasodilator selective for arterioles rather than for veins, similar to diazoxide and hydralazine. Like the former, it acts through its sulphate metabolite as an ATP-dependent potassium channel opener. It is highly effective in severe hypertension, but causes increased cardiac output, tachycardia, fluid retention and hypertrichosis. The hair growth is generalised and although a cosmetic problem in women, it has been exploited as a topical solution for the treatment of baldness in men. 

The potassium-channel openers are thought to work by opening a subset of K -channels, which leads to membrane stabilization. Agents such as this have so far been proposed as vasodilators for the treatment of hypertension or heart failure, e.g. nicorandil. They may, however, become used for their smooth muscle relaxant action at other sites, e.g. in the aihvays as ANTIASTHMATIC AGENTS, or for bladder hyperexcitability. Other examples of drugs that work at least partly by this mechanism are cromakalim, diazoxide, pinacidil and minoxidil. See POTASSIUM-CHANNEL ACTIVATORS. 

Potassium Channel Opening and Coronary Vasodilation by Halothane... 

Minoxidil (6-amino-l,2-dihydro-l-hydroxy-imino-4-piperidino pyrimidine) has been shown to regrow hair with minimal side effects. This drug is a vasodilator and a potassium channel opener. It was originally developed... 

Nevertheless, it is assumed that treatment with minoxidil lengthens and thickens the small vellus hairs and decreases shedding. Minoxidil is a potassium channel opener that causes vasorelaxation [132] and stimulates cutaneous blood flow to the scalp [133]. Minoxidil sulfate, a metabolite of minoxidil, is a potent vasodilator. Uptake and conversion of minoxidil to minoxidil sulfate occurs within the HE, suggesting a direct action on the follicle [134]. The most probable site of action of minoxidil is the DP [135], and the mechanism of action has been linked to its effects on the Kir6.1/SUR2B potassium channel expressed by the derma papilla [136-138]. 

Hemostatic and mild hypotensive activities have been reported (bradly). In an in vitro study, the aqueous extract of U. dioica dose dependently inhibited thrombin-induced platelet aggregation. The observed effect has been attributed to the flavonoid constituents of the extract. The hypotensive effects of U. dioica extracts (aqueous and methanohc, in vivo and in isolated organs) have also been reported by more than one group and the mechanism of action is suggested to be through vasodilation mediated by nitric oxide release, potassium channel opening, and negative inotropic action. ... 

Minoxidil is a potent vasodilator predominantly with respect to resistance vessels. Vasodilatation is brought about, at least in part, by the opening of potassium channels, thus causing hyperpolarisation... 

The Di receptor is typically associated with the stimulation of adenylyl cyclase (Table 9-1) for example, Di-receptor-induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator. D2 receptors have been found to inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx. 

Minoxidil is a very efficacious orally active vasodilator. The effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely. Like hydralazine, minoxidil dilates arterioles but not veins. Because of its greater potential antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe hypertension, who do not respond well to hydralazine. 

Nicorandil is an effective vasodilator through two actions. It acts as a nitrate by activating cyclic GMP (see above) but also opens the ATP-dependent potassium channel to allow potassium efflux and h5rperpolarisation of the membrane which reduces calcium ion entry and induces muscular relaxation. It is indicated for use in angina, where it has similar efficacy to p-blockade, nitrates or calcium channel blockade. It is administered orally and is an alternative to nitrates when tolerance to these is a problem, or to the other classes when these are contraindicated by asthma or cardiac failure. Adverse effects to nicorandil are similar to those of nitrates, with headache reported in 35% of patients. It is the only antianginal drug for which at least one trial has demonstrated a beneficial influence upon outcome. ... 

Drugs that dilate blood vessels by acting directly on smooth muscle cells through nonautonomic mechanisms are useful in treating many hypertensive patients. Three major mechanisms are utilized by vasodilators release of nitric oxide, opening of potassium channels (which leads to hyperpolarization), and blockade of calcium channels (Table 11-3). Compensatory responses are marked for some vasodilators (especially hydralazine and minoxidil) and include salt retention and tachycardia (Table 11-2). 

Calcium is the positively charged equivalent of phosphate, producing mechanical effects within organisms. Thus potassium causes vasoconstriction and vasodilation. When a muscle fibre receives a nerve impulse, ion channels in the muscle cell open, allowing caldum ions to... 

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