Minoxidil: Mechanisms of Action on Hair Growth

A.G. Messenger; J. Rundegren

Disclosures

The British Journal of Dermatology. 2004;150(2) 

In This Article

Does Minoxidil Act on Hair Growth Via Potassium Channels?

Several lines of evidence, from clinical observations, animal studies and in vitro experiments, suggest that the promotion of hair growth by minoxidil is related in some way to its action as a potassium channel opener ( Table 1 ).

In addition to minoxidil, the potassium channel openers diazoxide[31,32] and pinacidil[33] cause hypertrichosis in humans. Buhl et al.[34] tested the effect of topical application of minoxidil and three other potassium channel openers on scalp hair growth in balding macaques. Minoxidil, cromakalin and P-1075 (a pinacidil analogue) all stimulated hair growth over a 20-week treatment period. A fourth potassium channel opener, RP-49,356, was not effective.

Buhl et al.[35] carried out a series of experiments on minoxidil action using cultured mouse vibrissae follicles. In 3-day cultures, 1 mmol L-1 minoxidil preserved follicular morphology, whereas follicles cultured in the absence of minoxidil degenerated rapidly. Follicles cultured in 0.5-5 mmol L-1 minoxidil grew longer than controls and showed higher levels of uptake of radiolabelled cysteine, amino acids and thymidine. This effect appears to be mediated by minoxidil sulphate. The same results were obtained using approximately 100-fold lower concentrations of minoxidil sulphate and the response of cultured follicles to minoxidil, but not minoxidil sulphate, was blocked by diethylcarbamazine and chlorate, agents which interfere with sulphation.[17] The potassium channels openers pinacidil, cromakalin, nicorandil and P-1075 also stimulated uptake of radiolabelled cysteine in cultured vibrissae follicles, although diazoxide did not.[36] Harmon et al.[37] also reported that minoxidil, pinacidil, cromakalin and diazoxide increased uptake of thymidine in a dose-dependent fashion in 4-day cultures of mouse vibrissae follicles. These studies imply that minoxidil stimulates hair growth in this model by opening potassium channels, but attempts to verify this idea have been unsuccessful. The broad-spectrum ion channel blocker tetraethylammonium chloride and the KATP channel blockers, glyburide and tolbutamide, failed to inhibit minoxidil stimulation of cultured vibrissae follicles at doses that were not themselves toxic.[34] To test whether minoxidil opened ion channels, vibrissae follicles were labelled with [86]Rb+, an ion with specificity for potassium channels similar to K+. In this model, the potassium channel opener pinacidil increased efflux of [86]Rb+ but minoxidil did not.[34]

Human hair follicle organ culture has been used extensively in hair biology but there is only a single published report describing increased uptake of thymidine by cultured human hair follicles in response to minoxidil.[38] Minoxidil causes premature entry of follicles into anagen, and probably prolongs anagen and increases hair follicle size. Of these effects only the prolongation of anagen is possibly modelled by hair follicle organ culture and even here the alteration in follicle survival in vitro is measured in days rather than the weeks or months achieved in vivo. The rather mixed responses of cultured follicles to minoxidil may therefore be due to insensitivity or inapplicability of the model. However, minoxidil does prolong survival of cultured follicles that would otherwise undergo rapid degeneration in vitro, albeit at concentrations which are unlikely to be achieved in vivo. This effect appears to be mediated by the sulphated metabolite and there is circumstantial but, as yet, unconfirmed evidence that it involves opening of potassium channels.

Sanders et al. showed that the stimulatory effect of minoxidil on the growth of 3T3 fibroblasts is inhibited by pharmacological blockade of potassium channels.[39] As yet, however, there is no clear evidence that KATP channels are expressed in cells of hair follicle derivation. Nakaya et al. looked for potassium channels in cultured hair follicle outer root sheath and dermal papilla cells using the patch-clamp technique.[40] They identified large and small conductance calcium-activated potassium channels in cell membranes. These channels were not blocked by ATP or glibenclamide (a specific KATP channel blocker) and neither minoxidil sulphate nor pinacidil increased efflux of [86]Rb, suggesting the absence of KATP channels. However, the same group has recently reported that human dermal papilla cells express mRNA for the sulphonylurea receptor SUR2B,[41] the same sulphonylurea receptor expressed in vascular smooth muscle cells.

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