Endothelin-1 and norepinephrine overflow from cardiac sympathetic nerve endings in myocardial ischemia

Abstract

In protracted myocardial ischemia, sympathetic activation with carrier-mediated excessive norepinephrine (NE) release from its nerve endings due to reversal of NE transporter in an outward direction is a prominent cause of arrhythmias and cardiac dysfunction. Endothelin-1 (ET-1) and its receptors are intimately involved in the regulation of this carrier-mediated NE overflow in protracted myocardial ischemia. The ET-1 system is often complex, sometimes involving opposing actions depending on which receptor subtype is activated, which cells are affected, and whether stimuli are endogenously generated or exogenously applied. Therefore, a detailed understanding of the ET-1 system is important for applying drugs acting on this system in clinical settings for the treatment of ischemic cardiac disease. This article provides a detailed analysis of how the ET-1 system is involved in the regulation of carrier-mediated NE release from sympathetic nerve endings in protracted myocardial ischemia.

Figure 1

Summarizing scheme illustrating the interaction between the ET-1 system and carrier-mediated NE release in protracted myocardial ischemia. Stimulation of ET_ARs existing in sympathetic nerve endings by endogenously generated or exogenously applied ET-1 increases neuronal NHE activity, thus potentiating carrier-mediated NE release. In contrast, exogenously applied big ET-1 is converted to ET-1 by cell surface ECE-1, and this ET-1 preferentially binds to ET_BRs located on NOS containing cells to produce NO. Endogenously generated NO works to prevent carrier-mediated NE release. NCX, Na⁺/Ca²⁺ exchanger; VMAT: vesicular monoamine transporter.