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.
Lu
Tong
T
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA. lu.tong@mayo.edu
Wang
Xiao-Li
XL
He
Tongrong
T
Zhou
Wei
W
Kaduce
Terry L
TL
Katusic
Zvonimir S
ZS
Spector
Arthur A
AA
Lee
Hon-Chi
HC
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