Novel and Established Potassium Channel Openers Stimulate Hair Growth In Vitro: Implications for their Modes of Action in Hair Follicles

Abstract

Although ATP-sensitive potassium (K(ATP)) channel openers, e.g., minoxidil and diazoxide, can induce hair growth, their mechanisms require clarification. Improved drugs are needed clinically. but the absence of a good bioassay hampers research. K(ATP) channels from various tissues contain subtypes of the regulatory sulfonylurea receptor, SUR, and pore-forming, K(+) inward rectifier subunits, Kir6.X, giving differing sensitivities to regulators. Therefore, the in vitro effects of established potassium channel openers and inhibitors (tolbutamide and glibenclamide), plus a novel, selective Kir6.2/SUR1 opener, NNC 55-0118, were assessed on deer hair follicle growth in serum-free median without streptomycin. Minoxidil (0.1-100 microM, p<0.001), NNC 55-0118 (1 mM, p<0.01; 0.1, 10, 100 microM, p<0.001), and diazoxide (10 microM, p<0.01) increased growth. Tolbutamide (1 mM) inhibited growth (p<0.001) and abolished the effect of 10 microM minoxidil, diazoxide and NNC 55-0118; glibenclamide (10 microM) had no effect, but prevented stimulation by 10 microM minoxidil. Phenol red stimulated growth (p<0.001), but channel modulator responses remained unaltered. Thus, deer follicles offer a practical, ethically advantageous in vitro bioassay that reflects clinical responses in vivo. The results indicate direct actions of K(ATP) channel modulators within hair follicles via two types of channels, with SUR 1 and SUR 2, probably SUR2B, sulfonylurea receptors.

Regenerative Medicine and Hair Loss: How Hair Follicle Culture has Advanced our Understanding of Treatment Options for Androgenetic Alopecia

“…Evidence now indicates that the mechanism of action of minoxidil, or minoxidil sulfate, which is a metabolite of minoxidil, is through stimulation of hair growth by opening ATPsensitive potassium channels within the dermal papilla [45], indicating that the effect is on the hair follicle itself, rather than the surrounding microenvironment. This is further supported as other potassium channel openers such as diazoxide are capable of increasing hair growth rates in the hair follicle organ culture model, indicating a similar mode of action for promoting hair growth [46]. Moreover, the effects of both minoxidil and diazoxide on hair growth can both be abrogated by coculture with a potassium channel inhibitor, tolbutamide [46].…”

“…This is further supported as other potassium channel openers such as diazoxide are capable of increasing hair growth rates in the hair follicle organ culture model, indicating a similar mode of action for promoting hair growth [46]. Moreover, the effects of both minoxidil and diazoxide on hair growth can both be abrogated by coculture with a potassium channel inhibitor, tolbutamide [46].…”

What Ages Hair?

“…Because minoxidil has stimulated hair regrowth in several forms of alopecia, different speculations regarding its mechanism of action have been forwarded. These include immunomodulation (Fiedler and Buys, 1987, Fiedler and Buys, 1988), targeting specific follicular potassium channels (Davies et al, 2005) or induction of PGE2 synthesis in the dermal papilla fibroblasts (Michelet et al, 1997). …”

Heterocyclic N-Oxides - An Emerging Class of Therapeutic Agents

“…in the case of minoxidil known to induce opening of K-ATP channels, leading to vasodilation and hair growth stimulation. [19]…”