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Research ArticleCARDIOVASCULAR

Ischemia Promotes Renin Activation and Angiotensin Formation in Sympathetic Nerve Terminals Isolated from the Human Heart: Contribution to Carrier-Mediated Norepinephrine Release

Nahid Seyedi, Motohiro Koyama, Christina J. Mackins and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics August 2002, 302 (2) 539-544; DOI: https://doi.org/10.1124/jpet.302.2.539
Nahid Seyedi
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Motohiro Koyama
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Christina J. Mackins
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Roberto Levi
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Abstract

We recently reported that in the ischemic human heart, locally formed angiotensin II activates angiotensin II type 1 (AT1) receptors on sympathetic nerve terminals, promoting reversal of the norepinephrine transporter in an outward direction (i.e., carrier-mediated norepinephrine release). The purpose of this study was to assess whether cardiac sympathetic nerve endings contribute to local angiotensin II formation, in addition to being a target of angiotensin II. To this end, we isolated sympathetic nerve endings (cardiac synaptosomes) from surgical specimens of human right atrium and incubated them in ischemic conditions (95% N2, sodium dithionite, and no glucose for 70 min). These synaptosomes released large amounts of endogenous norepinephrine via a carrier-mediated mechanism, as evidenced by the inhibitory effect of desipramine on this process. Norepinephrine release was further enhanced by preincubation of synaptosomes with angiotensinogen and was prevented by two renin inhibitors, pepstatin-A and BILA 2157BS, as well as by the angiotensin-converting enzyme inhibitor enalaprilat and the AT1 receptor antagonist EXP 3174 [2-N-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl]imidazole-5-carboxylic acid]. Western blot analysis revealed the presence of renin in cardiac sympathetic nerve terminals; renin abundance increased ∼3-fold during ischemia. Thus, renin is rapidly activated during ischemia in cardiac sympathetic nerve terminals, and this process eventually culminates in angiotensin II formation, stimulation of AT1 receptors, and carrier-mediated norepinephrine release. Our findings uncover a novel autocrine/paracrine mechanism whereby angiotensin II, formed at adrenergic nerve endings in myocardial ischemia, elicits carrier-mediated norepinephrine release by activating adjacent AT1 receptors.

Footnotes

  • Abbreviations:
    Ang II
    angiotensin II
    NE
    norepinephrine
    AT1
    angiotensin II type 1
    AT1R
    AT1 receptors
    Ang I
    angiotensin I
    ACE
    angiotensin-converting enzyme
    KHS
    Krebs-Henseleit solution
    HBS
    HEPES-buffered saline solution
    TBS
    Tris-buffered saline
    DMI
    desipramine hydrochloride
    EIPA
    5-(N-ethyl-N-isopropyl)-amiloride
    EXP 3174
    2-N-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid
    NHE
    Na+/H+ exchanger
    ANOVA
    analysis of variance
    OD
    optical density
    • Received October 4, 2001.
    • Accepted April 29, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 2
1 Aug 2002
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Research ArticleCARDIOVASCULAR

Ischemia Promotes Renin Activation and Angiotensin Formation in Sympathetic Nerve Terminals Isolated from the Human Heart: Contribution to Carrier-Mediated Norepinephrine Release

Nahid Seyedi, Motohiro Koyama, Christina J. Mackins and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 539-544; DOI: https://doi.org/10.1124/jpet.302.2.539

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Research ArticleCARDIOVASCULAR

Ischemia Promotes Renin Activation and Angiotensin Formation in Sympathetic Nerve Terminals Isolated from the Human Heart: Contribution to Carrier-Mediated Norepinephrine Release

Nahid Seyedi, Motohiro Koyama, Christina J. Mackins and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 539-544; DOI: https://doi.org/10.1124/jpet.302.2.539
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