Myocardial β-adrenoceptor down-regulation by norepinephrine is linked to reduced norepinephrine uptake activity

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Chronic administration of norepinephrine for 8 weeks has been shown to reduce neuronal norepinephrine uptake activity and increase interstitial norepinephrine concentration in the heart. To determine whether the changes could lead to myocardial β-adrenoceptor down-regulation or β-adrenergic subsensitivity, we measured left ventricular contractile responses to dobutamine, myocardial β-adrenoceptor density, β subtype distribution, competitive inhibition agonist binding, and adenylyl cyclase activity activation by isoproterenol, 5′-guanylylimidodiphosphate, and forskolin in dogs after a norepinephrine or saline infusion for 8 weeks. We found that norepinephrine infusion reduced myocardial β-adrenoceptor density, β 1-adrenoceptor subtype density, and high-affinity site for isoproterenol. Left ventricular contractile responses to dobutamine were reduced in the norepinephrine-infused animals. In addition, norepinephrine infusion decreased the basal adenylyl cyclase activity and the adenylyl cyclase responses to isoproterenol, 5′-guanylylimidodiphosphate, and forskolin. The findings indicate that a decrease in cardiac norepinephrine uptake predisposes the heart to norepinephrine-induced myocardial β-adrenoceptor down-regulation, and that norepinephrine, when present in a sufficient amount over a long period as it is in chronic heart failure, can reduce myocardial β-adrenergic responsiveness by both homologous and heterologous desensitization.