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Coupling of angiotensin II AT₁ receptors to neuronal NHE activity and carrier-mediated norepinephrine release in myocardial ischemia

Departments of ¹Physiology-Biophysics and ²Pharmacology, CornellUniversity, Weill Medical College, New York, New York 10021

Submitted 7 November 2003 ; accepted in final form 15 December 2003

In ischemia, cardiac sympathetic nerve endings (cSNE) release excessive amounts of norepinephrine (NE) via the nonexocytotic Na⁺-dependent NE transporter (NET). NET, normally responsible for NE reuptake into cSNE, reverses in myocardial ischemia, releasing pathological amounts of NE. This carrier-mediated NE release can be triggered by elevated intracellular Na⁺ levels in the axoplasm. The fact that ischemia activates the intracellular pH regulatory Na⁺/H⁺ exchanger (NHE) in cSNE is pivotal in increasing intraneuronal Na⁺ and thus activating carrier-mediated NE release. Angiotensin (ANG) II levels are also significantly elevated in the ischemic heart. However, the effects of ANG II on cSNE, which express the ANG II receptor, AT₁R, are poorly understood. We hypothesized that ANG II-induced AT₁R activation in cSNE may be positively coupled to NHE activity and thereby facilitate the pathological release of NE associated with myocardial ischemia. We tested this hypothesis in a cSNE model, human neuroblastoma cells stably transfected with rat recombinant AT_1A receptor (SH-SY5Y-AT_1A). SH-SY5Y-AT_1A constitutively expresses amiloride-sensitive NHE and the NET. NHE activity was assayed in BCECF-loaded SH-SY5Y-AT_1A as the rate of the Na⁺-dependent alkalinization in response to an acute acidosis. ANG II activation of AT₁R markedly increased NHE activity in SH-SY5Y-AT_1A via a Ca²⁺-dependent pathway and promoted carrier-mediated NE release. In addition, in guinea pig cSNE expressing native AT₁R, ANG II elicited carrier-mediated NE release. In SH-SY5Y-AT_1A and cSNE, amiloride inhibited the ANG II-mediated release of NE. Our results provide a link between AT₁R and NHE in cSNE, which can exacerbate carrier-mediated NE release during protracted myocardial ischemia.

acidosis; Na⁺-dependent norepinephrine transporter; SH-SY5Y cells; cardiac sympathetic nerves

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