Premium
Activation of angiotensin II (AngII) type‐2 receptors (AT2R) modulates voltage‐gated Ca2+ currents in dorsomedial NTS (dmNTS) neurons through nitric oxide (NO)
Author(s) -
Wang Gang,
Coleman Christal,
Glass Michael J,
Zhou Ping,
Anrather Josef,
Pickel Virginia M,
Iadecola Costantino
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1168.7
Subject(s) - medicine , endocrinology , angiotensin ii , chemistry , losartan , agonist , nitric oxide , enos , receptor , receptor antagonist , nitric oxide synthase , antagonist
Activation of AngII type 1 receptors (AT 1 R) increases Ca 2+ fluxes in dmNTS neurons receiving cardiorespiratory afferents and contributes to neurogenic hypertension. We tested the hypothesis that AT 2 R‐induced NO production counterbalances AT 1 R‐mediated Ca 2+ fluxes. Dual‐label immuno‐electron microscopy showed that AT 2 R and nNOS are co‐expressed in rat and mouse dmNTS neurons. In the presence of the AT 1 R inhibitor losartan (Los; 3μM), AngII (100nM) increased NO production, assessed using DAF‐FM‐DA (48±11%, n=6, p<0.05). The effect was blocked by the AT 2 R antagonist PD123319 (30 μM), the NO scavenger PTIO (50 μM) or the NOS inhibitor LNNA (1mM). Los + AngII increased NO production in wild type and eNOS‐null mice (p<0.05), but not in nNOS‐null mice (p>0.05). AngII (100nM) increased voltage‐gated L‐type Ca 2+ currents in rat dmNTS neurons (+36±3%; n=4; p<0.05). However, in the presence of Los, AngII attenuated Ca 2+ currents (−23±5%, n=7, p<0.01), an effect blocked by LNNA and reproduced by the NO donor SNAP (2 μM, −26±5%, n=6, p<0.01) or the AT 2 R agonist CGP42112A (2 μM, −23±6%, n=4, p<0.05). Thus, AT 2 R activation increases nNOS‐derived NO, which, in turn, attenuates L‐type Ca 2+ currents in dmNTS neurons. The AT 2 R‐induced inhibition of Ca 2+ influx may partially offset the AT 1 R‐elicited potentiation of Ca 2+ influx, mitigating the deleterious effects of AngII on central autonomic neurons (Supported by HL18974).