Mechanism of action of minoxidil sulfate-induced vasodilation: a role for increased K+ permeability.
The mechanism of smooth muscle relaxing effect of minoxidil sulfate (MxSO4) was investigated in isolated rabbit superior mesenteric artery. MxSO4 (5 X 10(-6) M) was found to effectively relax maximal norepinephrine (NE; at 5 X 10(-6) M) contraction, but failed to relax 80 mM K+-induced contraction. MxSO4-induced relaxation was endothelium independent. When the tissues were exposed to increased extracellular K+ (10-25 mM), and then contracted with NE, the relaxation response to MxSO4 was significantly attenuated. Tetraethylammonium (5-10 mM) pretreatment caused pronounced inhibition of MxSO4-induced relaxation. Pretreatment with ouabain (0.5-5 microM) also significantly inhibited MxSO4 relaxation. This effect of ouabain was found to be due to its effect on K+ gradient. These data suggested a role of K+ permeability during MxSO4 relaxation which was further confirmed when it was found that MxSO4 can cause a significant stimulation of 42K efflux from the mesenteric artery preloaded with 42K. It is suggested that MxSO4 may act as a K+ channel agonist to affect the plasmalemmal Ca++ permeability during agonist activation. Consistent with this, MxSO4 was demonstrated to cause an inhibition of NE-stimulated 45Ca influx in this tissue. Such a strong dependence on K+ permeability makes MxSO4 a unique vasodilator among the clinically used vasodilators.
Meisheri
K D
KD
Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, Michigan.
Cipkus
L A
LA
Taylor
C J
CJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D008914:Minoxidil / Q000031:analogs & derivatives* / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010539:Permeability; D010622:Phencyclidine / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D011817:Rabbits; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D013757:Tetraethylammonium Compounds; C039516:minoxidil sulfate ester; D008914:Minoxidil; D010042:Ouabain; D010622:Phencyclidine; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine