Abstract
Objective:The purpose of the present investigation was to test the hypothesis that coronary vasoconstrictor responses to endothelin-1 are augmented in the prediabetic metabolic syndrome.
Methods:ELISA was used to measure plasma endothelin-1 and intracoronary endothelin-1 dose-response experiments were conducted in vivo on normal control and high-fat-fed prediabetic dogs. Additionally, isolated left circumflex (LCX) coronary arteries and arterioles (< 160 μ m) were used for in vitro functional studies and molecular analyses (quantitative real-time PCR and Western blotting).
Results:Plasma endothelin-1 concentrations were not different between control and prediabetic dogs. Coronary vasoconstriction to endothelin-1 was similar in control and prediabetic dogs, both in vivo and in isolated arterioles. Nonetheless, real-time PCR analysis revealed significant decreases in ETA receptor transcript levels in LCX coronary arteries and arterioles. Also, Western blotting revealed a significant decrease in ETA receptor protein in LCX coronary arteries.
Conclusions:The findings of the present investigation indicate that although ETA receptor-signaling is sensitized by induction of the metabolic syndrome, endothelin-mediated coronary vasoconstriction does not significantly contribute to coronary dysfunction at this early stage of prediabetes.
We thank Pfizer for providing CI-1020. We also thank Michael Morris and Jeremy James for technical assistance. This study was supported by National Institutes of Health grants HL-67804 (to J.D. Tune) and P20-RR-018766 (to G.M. Dick).