Sensitization of Coronary α -Adrenoceptor Vasoconstriction in the Prediabetic Metabolic Syndrome

Objective: This study tested whether α -adrenoceptor-mediated coronary vasoconstriction is augmented in the metabolic syndrome and is accompanied by the alteration of specific α1- and α2-coronary adrenoceptors. Methods: Studies were conducted in control and chronically high-fat-fed (6 weeks of 60% calories from fat) dogs with metabolic syndrome. Alterations in coronary α 1B-, α1D-, and α2A-adrenoceptor mRNA and protein expression were examined by real-time PCR and Western analyses, respectively. Coronary blood flow and its response to intracoronary infusion of either the α1-adrenoceptor agonist methoxamine (0.1-3 mg) or the α2-adrenoceptor agonist BHT-933 (0.1-3 mg) were measured in anesthetized dogs. Results: Basal plasma epinephrine and norepinephrine levels were higher in the high-fat-fed dogs compared to controls. Real-time PCR revealed no alterations of coronary artery or arteriole α1B-, α1D-, and α2A-adrenoceptor mRNA expression. However, Western blot analysis showed a significant decrease in α2A-adrenoceptor protein density with no change in α1B- or α 1D-adrenoceptors. Methoxamine and BHT-933 produced dose-dependent decreases in coronary blood flow, but the decrease in coronary flow to methoxamine was significantly greater (∼ 20%) in dogs with the metabolic syndrome. No differences in the coronary flow response to BHT-933 were noted. Conclusions: These results indicate that the metabolic syndrome is associated with sensitization of α1- and α2-adrenoceptor signaling that could significantly limit control of coronary blood flow when the sympathetic nervous system is activated.