Human heart failure (NYHA classes II-IV) was associated with an approximate 30% decrease in norepinephrine uptake-1 carrier density compared with nonfailing myocardium (p<0.05).
In human heart failure, there is a presynaptic defect in the sympathetic nervous system leading to reduced norepinephrine uptake-1 activity, which may predispose to adenylyl cyclase desensitization.
Effect estimate: decreased by approximately 30%
p-value: p=< 0.05
OBJECTIVES This study investigated the role of neuronal uptake of norepinephrine (uptake-1) in human heart failure as a local factor for altering concentrations of norepinephrine at the cardiac myocyte membranes. BACKGROUND Several beta-adrenergic neuroeffector defects occur in heart failure. Whether an alteration in norepinephrine uptake-1 occurs is still unresolved. METHODS The role of norepinephrine uptake-1 was studied in electrically stimulated (1 Hz, 37 degrees C) human ventricular cardiac preparations and isolated myocardial membranes. RESULTS The effectiveness of norepinephrine in increasing the force of contraction was decreased in relation to the degree of heart failure. In contrast, the potency of norepinephrine was increased in failing hearts (New York Heart Association functional class IV) in relation to the concentrations producing 50% of the maximal effect (EC50). The EC50 values for isoproterenol, which is not a substrate for norepinephrine uptake-1, were reduced in myocardium in functional classes II to III and IV compared with those in nonfailing myocardium. The uptake inhibitors cocaine and desipramine (3 mumol/liter) potentiated the positive inotropic effects of norepinephrine in nonfailing myocardium (p < 0.05) but not in functional class IV myocardium. Radioligand binding experiments using the uptake inhibitor hydrogen-3 mazindol revealed a significant decrease by approximately 30% in norepinephrine uptake-1 carrier density in functional classes II to III and IV myocardium versus nonfailing myocardium (p < 0.05). CONCLUSIONS In human heart failure, there is a presynaptic defect in the sympathetic nervous system, leading to reduced uptake-1 activity. This defect in the failing heart can be mimicked by the effects of uptake blocking agents, such as cocaine and desipramine, in the nonfailing heart only. Compromised norepinephrine uptake-1 in functional class IV cannot be further increased by cocaine and desipramine. The pathophysiologic consequences could be an increased synaptic concentration of norepinephrine predisposing to adenylyl cyclase desensitization.
“A few years later Böhm et al. using tissue samples of the left ventricle proved that there is a presynaptic defect leading to reduced uptake-1 activity in the failing heart. This unpaired mechanism is pharmacologically mimicked by the effects of uptake blocking agents in the normal heart. The consequence is an increased synaptic concentration of noradrenaline predisposing to adenylyl cyclase desensitization.”
Böhm et al. (Sun,) conducted a other in Heart failure. Heart failure (NYHA functional classes II to IV) vs. Nonfailing myocardium was evaluated on Norepinephrine uptake-1 carrier density (decreased by approximately 30%, p=< 0.05). Human heart failure (NYHA classes II-IV) was associated with an approximate 30% decrease in norepinephrine uptake-1 carrier density compared with nonfailing myocardium (p<0.05).
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