Sensitization of coronary α-adrenoceptor vasoconstriction in the prediabetic metabolic syndrome

Objective: This study tested whether alpha-adrenoceptor-mediated coronary vasoconstriction is augmented in the metabolic syndrome and is accompanied by the alteration of specific alpha(1)- and alpha(2)-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 alpha(1B)-, alpha(1D)-, and alpha(2A)-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 alpha(1)-adrenoceptor agonist methoxamine (0.1-3 mg) or the alpha(2)-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 alpha(1B)-, alpha(1D)-, and alpha(2A)-adrenoceptor mRNA expression. However, Western blot analysis showed a significant decrease in alpha(2A)-adrenoceptor protein density with no change in alpha(1B)- or alpha(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 (similar to 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 alpha(1)- and alpha(2)-adrenoceptor signaling that could significantly limit control of coronary blood flow when the sympathetic nervous system is activated.