title: Activation of a renin-angiotensin system in ischemic cardiac sympathetic nerve endings and its association with norepinephrine release.
abstract: We had reported that in the ischemic heart, locally formed bradykinin (BK) and angiotensin II (Ang II) activate B2- and AT1-receptors on sympathetic nerve terminals (SNE), promoting reversal of the norepinephrine (NE) transporter in an outward direction (i.e., carrier-mediated NE release). Although both BK and Ang II contribute to ischemic NE release, Ang II is likely to play a more important role. Since BK is formed by ischemic SNE, we questioned whether cardiac SNE also contribute to local Ang II formation, in addition to being a target of Ang II. SNE were isolated from surgical specimens of human right atrium and incubated in ischemic conditions. These SNE released large amounts of endogenous NE via a carrier-mediated mechanism, as evidenced by the inhibitory effect of desipramine on this process. Moreover, two renin inhibitors, pepstatin-A and BILA 2157 BS, the ACE inhibitor enalaprilat and the AT1-receptor antagonist EXP3174 prevented ischemic NE release. Western blot analysis revealed the presence of renin in cardiac SNE. Renin abundance increased more than three-fold during ischemia. Thus, renin is present in cardiac SNE and is activated during ischemia, eventually culminating in Ang II formation, stimulation of AT1-receptors and carrier-mediated NE release. Our findings uncover a novel autocrine mechanism, by which Ang II, formed at SNE in myocardial ischemia, elicits carrier-mediated NE release by activating prejuntional AT1-receptors.
authors.affiliation: Department of Pharmacology, Weill Medical College of Cornell University, Room LC419, 1300 York Avenue, New York, NY 10021, USA. rlevi@med.cornell.edu
authors.forename: Roberto
authors.initials: R
authors.lastname: Levi
authors.forename: Randi B
authors.initials: RB
authors.lastname: Silver
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Mackins
authors.forename: Nahid
authors.initials: N
authors.lastname: Seyedi
authors.forename: Motohiro
authors.initials: M
authors.lastname: Koyama
mesh_terms: D000818:Animals; D006325:Heart Atria / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D009638:Norepinephrine / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology*; D013574:Synaptosomes / Q000378:metabolism / Q000502:physiology
chemical_list: D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D009638:Norepinephrine