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Upregulation of Cardiac Uptake1 Carrier in Ischemic and Nonischemic Rat Heart
From the 1. Medizinische Klinik der Technischen Universität München.
Correspondence to Dr Martin Ungerer, 1. Medizinische Klinik der Technischen Universität München, Klinikum rechts der Isar, Ismaningerstr. 22, 81675 München, Germany.
Abstract Neuronal uptake1 constitutes the main elimination process of cardiac norepinephrine under normoxic conditions. Uptake1 may be subject to changes during myocardial ischemia. We therefore studied the regulation of the uptake1 carrier in isolated perfused rat hearts, comparing ischemic and nonischemic conditions. Radioligand binding with [3H]mazindol was used to determine carrier densities and affinities, whereas cardiac clearance of [3H]norepinephrine served as a measure of the transport capacity of the uptake1 carrier. When exocytotic norepinephrine release was induced in nonischemic rat hearts by electrical field stimulations, we observed an increase in the cardiac density of uptake1 carriers (Bmax) to 210±5 fmol/mg protein (versus 134±3 fmol/mg in control hearts). Simultaneously, the cardiac clearance of [3H]norepinephrine increased to 41±4% versus 30±4% in control hearts. Both carrier density and norepinephrine clearance returned to baseline values within a period of 40 minutes after stimulation. Carrier affinities (Kd values) did not differ between the groups. Stop-flow ischemia induced a substantial overflow of norepinephrine by itself. Additionally, carrier density was increased to 144% after 40 minutes of stop-flow ischemia (P<.005 versus control hearts). When ischemia was followed by 20 minutes of reperfusion, the Bmax of the uptake1 carrier remained significantly elevated. With a further extension of the reperfusion period to 40 minutes, however, carrier density declined to baseline values. Kd values were not influenced by any of these interventions. Clearance of [3H]norepinephrine was suppressed (to 5±2%) in the first minutes of reperfusion, which may reflect the inverse transport direction of the norepinephrine carrier known to occur in ischemia. After 20 minutes of reperfusion, clearance increased to 39±5% (P<.005 versus control hearts) and then fell to 29±5% after 40 minutes of reperfusion (NS). These results demonstrate that after both electrical field stimulation and myocardial ischemia, the density of uptake1 carrier proteins temporarily increases, which may result in an increased transport capacity for norepinephrine.
Key Words: ischemia • norepinephrine • rat heart • uptake1 carrier
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