Dermatologica · 2009 · 13 citations · 0 references
Life SciencesPharmacologyPhysiologyBiochemical PharmacologyCell SignalingSignal TransductionCardiovascular PhysiologyCirculatory PhysiologyHemodynamicsMuscle PhysiologyVasoactive Drug TherapyVasodilator TherapyAdrenergic Receptor AgonistsAntihypertensive PharmacologyAntihypertensive TreatmentMinoxidil TherapyVascular Smooth Muscle PharmacologyVascular Smooth Muscle RegulationVascular Smooth Muscle RelaxationVasoactive Drug Mechanisms
The antihypertensive effect of minoxidil has been shown to occur via direct vasodilation induced by its active metabolite, minoxidil sulfate (MxSO<sub>4</sub>). Thus, an in vitro vascular smooth muscle preparation was used as a model to investigate cellular biochemical mechanisms influenced by MxSO<sub>4</sub>. In rabbit isolated superior mesenteric artery, the contractions produced by receptor agonists such as norepinephrine (NE) were relaxed by about 85% with MxSO<sub>4</sub>. In contrast, MxSO<sub>4</sub> was without any effect on 80 mM KCl-induced contraction. Furthermore, pretreatment of the tissues with tetraethylammonium (TEA, a K+ channel blocker), or ouabain, or 10–25 mM KCl, all caused pronounced inhibition of MxSO<sub>4</sub>-induced relaxation of NE-induced contraction. These investigations revealed that MxSO<sub>4</sub>-induced relaxation could be effectively inhibited by treatments that interfere with plasmalemmal K+ permeability. It is proposed that MxSO<sub>4</sub> 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 MxSO<sub>4</sub> 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 MxSO<sub>4</sub> to its hair growth effect remains to be examined. However, it is suggested that the understanding of the cellular mechanism of one biological effect of minoxidil (i.e. antihypertensive action) may provide a basis for further understanding its other biological effect (i.e. hair growth).