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

Abstract

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. 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 alpha1-adrenoceptor agonist methoxamine (0.1-3 mg) or the alpha(2)-adrenoceptor agonist BHT-933 (0.1-3 mg) were measured in anesthetized dogs. 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 alpha1B-, 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 (approximately 20%) in dogs with the metabolic syndrome. No differences in the coronary flow response to BHT-933 were noted. These results indicate that the metabolic syndrome is associated with sensitization of alpha1- and alpha2-adrenoceptor signaling that could significantly limit control of coronary blood flow when the sympathetic nervous system is activated.