Impaired arachidonic acid-mediated activation of large-conductance Ca2+-activated K+ channels in coronary arterial smooth muscle cells in Zucker Diabetic Fatty rats.
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 micromol/l AA enhanced BK current by 274% in lean and by 98% in ZDF rats. After incubation with 10 micromol/l indomethacin, 1 micromol/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 micromol/l AA was reduced by 44% in ZDF rats. [3H]6-keto-prostagladin F1alpha ([3H]6-keto-PGF1alpha,), 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-PGF1alpha. 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.
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA. lu.tong@mayo.edu
Tong
T
Lu
Xiao-Li
XL
Wang
Tongrong
T
He
Wei
W
Zhou
Terry L
TL
Kaduce
Zvonimir S
ZS
Katusic
Arthur A
AA
Spector
Hon-Chi
HC
Lee
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D001483:Base Sequence; D003331:Coronary Vessels / Q000503:physiopathology*; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D009765:Obesity / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics*; D051381:Rats; D011924:Rats, Zucker
D017931:DNA Primers; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D016718:Arachidonic Acid