Ischemia promotes renin activation and angiotensin formation in sympathetic nerve terminals isolated from the human heart: contribution to carrier-mediated norepinephrine release.
We recently reported that in the ischemic human heart, locally formed angiotensin II activates angiotensin II type 1 (AT(1)) 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% N(2,) 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 AT(1) 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 AT(1) 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 AT(1) receptors.
Department of Pharmacology, Cornell University Weill Medical College, 1300 York Avenue, New York, NY 10021, USA.
Nahid
N
Seyedi
Motohiro
M
Koyama
Christina J
CJ
Mackins
Roberto
R
Levi
D000804:Angiotensin II / Q000502:physiology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D005260:Female; D006325:Heart Atria; D006329:Heart Conduction System / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D009638:Norepinephrine / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology*; D012083:Renin / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000502:physiology / Q000503:physiopathology*; D013574:Synaptosomes / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology
D000959:Antihypertensive Agents; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D012083:Renin; C066026:losartan carboxylic acid; D019808:Losartan; D009638:Norepinephrine