Regional Myocardial Downregulation of the Inhibitory

emia occur, has been available. We have used a method that Regional myocardial ischemia is associated with increased levels of adenosine and norepinephrine, factors that may alter activation of the ,-adrenergic receptor (,6AR)-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 6AR-G protein-adenylyl cyclase pathway occur in the setting ofchronic 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 fIAR number (P < 0.005). Despite regional downregulation of myocardial BAR number, adenylyl cyclase activity was similar in the ischemic and control beds. Quantitative immunoblotting showed that the cardiac inhibitory GTP-binding protein, Gia2, was decreased in the ischemic bed (P = 0.02). In contrast, the cardiac stimulatory GTP-binding protein, Gsa, was increased in endocardial sections from the ischemic bed (P = 0.05). Decreased Gia2 content was associated with decreased inhibition of adenylyl cyclase. Reduced Gia2 content, in conjunction with increased Gsa content in the endocardium, may provide a means by which adrenergic activation is maintained in the setting of chronic episodic myocardial ischemia. (J. Clin. Invest. 1993. 92:2644-2652.)