Calcium antagonism and norepinephrine release in myocardial ischemia.
In myocardial infarction, adrenergic stimulation of the heart is thought to cause cell damage and malignant arrhythmias. In rat hearts as well as in human cardiac tissue, ischemia induces norepinephrine (NE) release, which results in micromolar catecholamine concentrations in the interstitial space of the ischemic myocardium. It has been found that local metabolic, rather than centrally evoked NE release, plays the crucial role in excess adrenergic activation of the ischemic myocardium. NE release in ischemia is nonexocytotic and has been characterized as a two-step process. (a) Induced by energy deficiency, NE escapes from its storage vesicles and accumulates in the axoplasm. (b) NE is transported across the plasma membrane into the extracellular space via the neuronal NE carrier (uptake1), which has reversed its normal transport direction because of increased intracellular sodium concentration. NE release induced by ischemia is independent of the presence of calcium in the extracellular space and is not altered by blockade of N-type (neuronal) calcium channels. Furthermore, modulation of protein kinase C does not interfere with NE liberation in the ischemic myocardium. This independence of extracellular calcium, calcium entry into the neuron, and protein kinase C activity is in contrast to the strong calcium dependence of exocytotic transmitter release, which is found under physiological conditions. On the basis of these findings, it was unexpected that calcium antagonists such as gallopamil, verapamil, diltiazem, felodipine, and nifedipine suppress ischemia-induced NE release. The most potent effect was found for gallopamil with a concentration of 50% inhibition (IC50) of 300 nmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)
Schömig
A
A
Department of Cardiology, Technical University of Munich, Germany.
Rehmert
G
G
Kurz
T
T
Richardt
G
G
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D014693:Ventricular Fibrillation / Q000209:etiology
D002121:Calcium Channel Blockers; D009638:Norepinephrine