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Sensitization of ETA receptor‐mediated coronary vasoconstriction in the prediabetic metabolic syndrome

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. 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 μm) were used for in vitro functional studies and molecular analyses (quantitative real‐time PCR and Western blotting). 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. The findings of the present investigation indicate that the prediabetic metabolic syndrome is associated with sensitization of ETA receptor‐mediated coronary vasoconstriction. Such characterization of the mechanisms of coronary dysfunction in metabolic syndrome may prove beneficial in the development of novel therapeutic strategies for at‐risk populations.