Biochemical mechanisms by which minoxidil sulfate influences mammalian cells.
The antihypertensive effect of minoxidil has been shown to occur via direct vasodilation induced by its active metabolite, minoxidil sulfate (MxSO4). Thus, an in vitro vascular smooth muscle preparation was used as a model to investigate cellular biochemical mechanisms influenced by MxSO4. In rabbit isolated superior mesenteric artery, the contractions produced by receptor agonists such as norepinephrine (NE) were relaxed by about 85% with MxSO4. In contrast, MxSO4 was without any effect on 80 mM KCl-induced contraction. Furthermore, pretreatment of the tissues with tetraethlammonium (TEA, a K+ channel blocker), or ouabain, or 10-25 mM KCl, all caused pronounced inhibition of MxSO4-induced relaxation of NE-induced contraction. These investigations revealed that MxSO4-induced relaxation could be effectively inhibited by treatments that interfere with plasmalemmal K+ permeability. It is proposed that MxSO4 acts like a K+ channel agonist to enhance K+ permeability; this should result in hyperpolarization and cause reduction in agonist-stimulated Ca2+ influx. The end result is a decrease in cytoplasmic free Ca2+ concentration, and thus relaxation. Consistent with this, we could also demonstrate enhancement of 42K efflux as well as inhibition of NE-stimulated 45Ca influx. The above-proposed mechanism appears specific for MxSO4 since it was not shared by forskolin (a cyclic-AMP-increasing agent), sodium nitroprusside (a cyclic-GMP-increasing agent) or D600 (a Ca2+ antagonist). The relevance of the proposed unique cellular mechanism (i.e. K+ permeability) of MxSO4 to its hair growth effect remains to be examined.(ABSTRACT TRUNCATED AT 250 WORDS)
Meisheri
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Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, Mich.
Cipkus
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D000818:Animals; D066298:In Vitro Techniques; D008914:Minoxidil / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D010042:Ouabain / Q000494:pharmacology; D011188:Potassium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011817:Rabbits; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D013757:Tetraethylammonium Compounds; D008914:Minoxidil; D010042:Ouabain; D019789:Tetraethylammonium; D011188:Potassium; D009638:Norepinephrine