Beta-adrenoceptor downregulation in pacing-induced heart failure is associated with increased interstitial NE content

We used the rapid ventricular pacing model to examine myocardial norepinephrine (NE) uptake kinetics in congestive heart failure. Dogs subjected to pacing at 225 beats/min for 8 wk developed heart failure as evidenced by elevated left atrial pressure, depressed first derivative of left ventricular pressure with respect to time, and depressed cardiac output compared with dogs paced at 100 beats/min for 8 wk. Fast-paced dogs also exhibited an elevated plasma NE and reduced myocardial NE content. Myocardial NE uptake kinetics and interstitial NE concentration were measured in vivo using a triple-isotope intracoronary tracer technique. The rate constant of neuronal uptake of NE was significantly depressed in the fast-paced animals (0.224 +/- 0.027 vs. 0.725 +/- 0.097 s-1, P < 0.001), while the interstitial NE concentration was significantly increased in the heart (1.12 +/- 0.15 vs. 0.17 +/- 0.07 ng/ml, P < 0.001). Myocardial beta-adrenoceptor density was significantly reduced in the fast-paced animals (49 +/- 7 vs. 86 +/- 6 fmol/mg, P < 0.001), and there was a significant inverse correlation between beta-adrenoceptor density and interstitial NE concentration. Thus we conclude that excess myocardial interstitial NE content contributes to the abnormalities in the beta-adrenoceptor system.