Regional myocardial downregulation of the inhibitory guanosine triphosphate-binding protein (Giα₂) and β-adrenergic receptors in a porcine model of chronic episodic myocardial ischemia

Regional myocardial ischemia is associated with increased levels of adenosine and norepinephrine, factors that may alter activation of the β-adrenergic receptor (αAR)-G protein-adenylyl cyclase pathway in the heart. We have used the ameroid constrictor model to determine whether alterations in myocardial signal transduction through the αAR-G protein-adenylyl cyclase pathway occur in the setting of chronic episodes of reversible ischemia. Pigs were instrumented with ameroid occluders placed around the left circumflex coronary artery. 5 wk later, after ameroid closure, flow and function were normal in the ischemic bed, but flow (P = 0.001) and function (P < 0.03) were abnormal when metabolic demands were increased. The ischemic bed showed a reduction in myocardial βAR number (P < 0.005). Despite regional downregulation of myocardial βAR number, adenylyl cyclase activity was similar in the ischemic and control beds. Quantitative immunoblotting showed that the cardiac inhibitory GTP-binding protein, Giα₂, was decreased in the ischemic bed (P = 0.02). In contrast, the cardiac stimulatory GTP-binding protein, Gs α, was increased in endocardial sections from the ischemic bed (P = 0.05). Decreased Giα₂ content was associated with decreased inhibition of adenylyl cyclase. Reduced Giα₂ content, in conjunction with increased Gsα content in the endocardium, may provide a means by which adrenergic activation is maintained in the setting of chronic episodic myocardial ischemia.