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Impaired Arachidonic Acid–Mediated Activation of Large-Conductance Ca²⁺-Activated K⁺ Channels in Coronary Arterial Smooth Muscle Cells in Zucker Diabetic Fatty Rats

¹ Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
² Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota
³ Department of Biochemistry, University of Iowa, Iowa City, Iowa

We studied the arachidonic acid (AA)-mediated modulation of large-conductance Ca²⁺-activated K⁺ (BK) channels in coronary arterial smooth myocytes from lean control and Zucker Diabetic Fatty (ZDF) rats. A total of 1 µmol/l AA enhanced BK current by 274% in lean and by 98% in ZDF rats. After incubation with 10 µmol/l indomethacin, 1 µmol/l AA increased BK currents by 80% in lean and by 70% in ZDF rats. Vasoreactivity studies showed that the dilation of small coronary arteries produced by 1 µmol/l AA was reduced by 44% in ZDF rats. [³H]6-keto-prostagladin F₁ ([³H]6-keto-PGF₁,), the stable metabolite of prostacyclin (PGI₂), was the major [³H]AA metabolite produced by coronary arteries of lean vessels, but ZDF vessels produced only 15% as much [³H]6-keto-PGF₁. BK channel activation and vasorelaxation by iloprost were similar in lean and ZDF rats. Immunoblots showed a 73% reduction in PGI₂ synthase (PGIS) expression in ZDF vessels compared with lean vessels, and there was no change in cyclooxygenase (COX) and BK channel expressions. Real-time PCR studies showed that mRNA levels of PGIS, COX-1, and COX-2 were similar between lean and ZDF vessels. We conclude that PGI₂ is the major AA metabolite in lean coronaries, and AA-mediated BK channel activation is impaired in ZDF coronaries due to reduced PGIS activity.

Abbreviations: 6-keto-PGF₁, 6-keto-prostagladin F₁; 12-HETE, 12-hydroxyeicosatetraenoic acid; AA, arachidonic acid; BK, large-conductance Ca²⁺-activated K⁺; COX, cyclooxygenase; CYP, cytochrome P450; DMEM, Dulbecco’s modified Eagle’s medium; IBTX, iberiotoxin; IP, PGI₂ receptor; LOX, lipoxygenase; PGI₂, prostacyclin; PGIS, PGI₂ synthase

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