Activation of a renin-angiotensin system in ischemic cardiac sympathetic nerve endings and its association with norepinephrine release.
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.
Levi
Roberto
R
Department of Pharmacology, Weill Medical College of Cornell University, Room LC419, 1300 York Avenue, New York, NY 10021, USA. rlevi@med.cornell.edu
Silver
Randi B
RB
Mackins
Christina J
CJ
Seyedi
Nahid
N
Koyama
Motohiro
M
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
D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D009638:Norepinephrine