Nonexocytotic release of endogenous noradrenaline in the ischemic and anoxic rat heart: mechanism and metabolic requirements.

Abstract

The release of endogenous noradrenaline and its deaminated metabolite dihydroxyphenylglycol in the myocardium have been studied in the isolated perfused heart of the rat subjected to three models of energy depletion: ischemia, anoxia, and cyanide intoxication. Anoxia and cyanide intoxication were combined with substrate deficiency at constant perfusion flow. All three energy-depleting procedures caused a similar overflow of noradrenaline which, following a constant delay of 10 minutes without increased release, amounted to more than 25% of total heart content within 40 minutes. This noradrenaline overflow was not diminished in the absence of extracellular calcium and was inhibited by the uptake1 blocker desipramine in all three experimental models, indicating a common and nonexocytotic release mechanism. In the presence of glucose, neither anoxia nor cyanide intoxication resulted in a measurable noradrenaline overflow. Conversely, blockade of glycolysis or glucose depletion prior to ischemia or cyanide poisoning accelerated the noradrenaline overflow, demonstrating a key role of the sympathetic nerve cells' energy status in causing nonexocytotic catecholamine release. Blockade of energy metabolism in the presence of oxygen (cyanide model) resulted in the overflow of high amounts of dihydroxyphenylglycol that was not inhibited by uptake1 blockade. The release of the lipophilic dihydroxyphenylglycol by diffusion reflects deamination of axoplasmic noradrenaline by monoamine oxidase. Since saturation of the enzyme could be excluded in this model dihydroxyphenylglycol release can be taken as a mirror of cytoplasmic noradrenaline concentration. The results obtained by these studies indicate that nonexocytotic catecholamine release is a two-step process induced by energy deficiency in the sympathetic varicosity. In a first step, noradrenaline is lost from storage vesicles, resulting in increasing axoplasmic concentrations. The second step is the rate-limiting transport of intracellular noradrenaline across the cell membrane by the uptake1 carrier that has reversed its normal net transport direction.

Brief Episode of Myocardial Ischemia Before Prolonged Ischemia Attenuates Cardiac Sympathetic Nerve Injury

“…2,15 In previous studies 4,15 and our preliminary study, NE release was not induced by ischemia of short duration (<10 min) and, therefore, the reduction of NE release during subsequent, prolonged ischemia was not caused by release or degradation of NE during the brief ischemia.…”

“…4,5 MIBG is an analog of NE and shares the same uptake and storage mechanism with NE at the sympathetic nerve terminals. 13,14 Preserved 123 I-MIBG uptake in patients with pre-infarction angina may, therefore, imply less impairment of sympathetic nerve function after MI.…”

“…4 Activation of the KATP channel may be important in ischemic PC of sympathetic nerves. [15][16][17] However, Schömig et al reported that reduced activation of the Na + -H + exchange after brief ischemia may result in the suppression of NE release during subsequent, prolonged ischemia.…”

“…2,3 This reduction of NE release may reflect attenuation of sympathetic neuronal dysfunction caused by the sustained ischemia (ie, neural PC), because the nonexocytotic NE release that occurs during ischemia is a consequence of energy starvation of the sympathetic nerve terminals. 4,5 Miyazaki and Zipes demonstrated that PC preserved the efferent sympathetic and vagal responses, as assessed by measuring effective refractory periods during coronary artery occlusion in dogs. 6 However, it remains unknown whether the attenuation of sympathetic neural dysfunction could be induced by a transient ischemic attack before the onset of myocardial infarction (MI) in human hearts, and whether the attenuated NE release during sustained ischemia can lead to preservation of neural function.…”

Plasma Catecholamines and Ischemic Heart Disease

“…3,4 In addition, high amounts of norepinephrine are released from the sympathetic nerve terminals of the heart 3,4 and massive accumulation of norepinephrine occurs in the extracellular space of the ischemic area. 5 The release is determined by local energy exhaustion and occurs in parallel with the development of membrane defects within the ischemic area in which the sympathetic neurons progressively deplete from norepinephrine. 6,7 Catecholamines are considered to have major effects on the course of AMI.…”