Neuronal sodium homoeostatis and axoplasmic amine concentration determine calcium-independent noradrenaline release in normoxic and ischemic rat heart.

Abstract

Calcium-independent noradrenaline release was studied in the isolated perfused rat heart under conditions of normoxia, cyanide intoxication, and ischemia. The release of endogenous noradrenaline and dihydroxyphenylglycol were determined by high-performance liquid chromatography. The release of dihydroxyphenylglycol, the main neuronal noradrenaline metabolite, was used as an indicator of the free axoplasmic amine concentration. When storage function of neuronal vesicles was disturbed by Ro 4-1284 or trimethyltin, high dihydroxyphenylglycol release was observed without concomitant overflow of noradrenaline. If, however, these agents were combined with inhibition of Na+K+-ATPase or with veratridine-induced entry of sodium into the neuron, both dihydroxyphenylglycol and noradrenaline were released. Noradrenaline release was independent of extracellular calcium and was suppressed by blockade of neuronal catecholamine uptake (uptake1), indicating nonexocytotic noradrenaline liberation from the sympathetic nerve ending. This release critically depended on two conditions: 1) increased cytoplasmic concentrations of noradrenaline within the sympathetic neuron and 2) intraneuronal sodium accumulation. Both conditions together were required to induce noradrenaline efflux across the plasma membrane using the uptake1 carrier in reverse of its normal transport direction. A disturbed energy status of the sympathetic neuron, induced by cyanide intoxication or ischemia, likewise caused calcium-independent noradrenaline release by interfering with both vesicular storage function and neuronal sodium homoeostatis. Again, release was sensitive to uptake1 blockade. Since neuronal sodium accumulation was the rate-limiting step, release was further accelerated when residual Na+,K+-ATPase activity was inhibited. Na+-H+ exchange was identified as the predominant pathway of sodium entry into the sympathetic nerve ending in ischemia, and its inhibition by amiloride and ethylisopropylamiloride markedly suppressed ischemia-induced noradrenaline release.

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

“…[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. 5 Taken together, the findings suggest that the mechanism for reducing ischemiainduced NE release may involve inhibition of intracellular Na + accumulation. The suppression of NE release by PC might reduce NE-derived free radical formation, 18,19 thereby contributing to the preservation of neural function after prolonged 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.…”

“…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.…”

Aldosterone augments Na+-induced reduction of cardiac norepinephrine reuptake

“…For isolated perfusion, hearts were prepared according to a modified Langendorff technique, as previously described in detail (5,24,52). Rats were anesthetized with thiopental (100 mg/kg ip).…”

Regulated Expression and Function of the Somatodendritic Catecholamine Neurotransmitter Transporters

“…ATP depletion induced by hypoxia and hypoglycemia causes inhibition of Na + ,K + -ATPase, resulting in the accumulation of intracellular Na + . Intracellular acidification at that time activates Na + ,H + antiporter, so that it facilitates Na + accumulation (27). Is there any route for Na + influx under physiological conditions?…”