Effects of the 5-lipoxygenase activating protein inhibitor MK886 on voltage-gated and Ca2+-activated K+ currents in rat arterial myocytes.
1. The effects on the voltage-gated (IK) and Ca2+ activated (I(K,Ca)) K+ currents in rat arterial myocytes of the 5-lipoxygenase activating protein (FLAP) inhibitor MK886, and its inactive analogue L583,916 were evaluated. 2. In rat pulmonary arterial myocytes (RPAMs), MK886 caused a concentration-dependent reduction of the IK, with little obvious change in the kinetics of the current. Half maximal current block was observed at 75 nM MK886. 3. MK886 application led to a concentration-dependent increase in the amplitude of the TEA-sensitive I(K,Ca) current and single channel activity in RPAMs in whole cell and inside-out configurations, respectively. The threshold concentration for this effect was approximately 300 nM and a maximal 4-5 fold increase was observed at 10 microM MK886. MK886 also increased I(K,Ca) in rat mesenteric arterial myocytes (RMAMs). 4. L538,916, an analogue of MK886 which does not block FLAP, had no effect on either IK or I(K,Ca) at a concentration of 10 microM. 5. Leukotriene C4 (100 nM) had no effect on either IK or I(K,Ca) in RPAMs. MK886 produced its usual increase in I(K,Ca) and also blocked IK, in the presence of leukotriene C4. Similarly, leukotriene E4 (100 nM) did not alter the amplitude of IK. Also, the nonselective leukotriene receptor antagonist ICI 198,615 (3 microM) did not affect IK in RPAMs, and did not affect the response to MK886. 6. Arachidonic acid (10 microM) enhanced I(K,Ca) in both RPAMs and RMAMs. 7. The results show that MK886 markedly affects both IK and I(K,Ca) in a manner similar to that of arachidonic acid and independent of the endogenous production of leukotrienes. It is therefore possible that MK886, which is thought to compete with arachidonic acid for its binding to FLAP, may similarly occupy arachidonic acid binding sites on these K+ channels, and mimic its effects. Alternatively, MK886 might act via non-selective effects on other arachidonic acid metabolites which could modify K+ channel function.
Smirnov
S V
SV
Department of Pharmacology, United Medical and Dental Schools of Guy's and St Thomas's Hospitals, London.
Knock
G A
GA
Aaronson
P I
PI
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002118:Calcium / Q000502:physiology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D015289:Leukotrienes / Q000502:physiology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D002722:Chlorobenzenes
D058927:5-Lipoxygenase-Activating Proteins; D001094:Arachidonate 5-Lipoxygenase; D002118:Calcium; D002352:Carrier Proteins; D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C548594:Alox5ap protein, rat; C060893:MK-886; D002722:Chlorobenzenes