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The interplay between heme oxygenase and nitric oxide synthase and downstream PI3K/sGC/ERK signaling ameliorates the estrogen‐dependent depressant effect of chronic nicotine on reflex bradycardia (837.2)
Author(s) -
ElMas Mahmoud,
ElGowelli Hanan,
Fouda Mohamed,
ElGowilly Sahar
Publication year - 2014
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.28.1_supplement.837.2
Subject(s) - hemin , nitric oxide synthase , reflex bradycardia , chemistry , pharmacology , nicotine , endocrinology , heme oxygenase , medicine , allosteric modulator , nitric oxide , baroreflex , heme , receptor , agonist , biochemistry , heart rate , blood pressure , enzyme
Chronic nicotine impairs reflex bradycardia in estrogen (E 2 )‐replaced, but not depleted, female rats. We tested the hypothesis that nitric oxide synthase (NOS) and/or heme oxygenase (HO) and their downstream mitogen‐activated protein kinases mediate the nicotine‐baroreflex interaction. The depressant effect of nicotine (2 mg/kg/day i.p., 2 weeks) on reflex bradycardic responsiveness to phenylephrine in E 2 ‐replaced ovariectomized (OVXE 2 ) rats was abolished after treatment with hemin (HO inducer) or L‐arginine (NOS substrate), denoting the importance of reduced availability of their respective gaseous products, CO and NO, in the nicotine effect. The roles of CO and NO appear to be mutually facilitated because the hemin and L‐arginine effect was abolished after NOS (L‐NAME) and HO inhibition (ZnPP), respectively. Estrogen receptor blockade (ICI 182,780) reduced baroreflexes in OVXE 2 rats but failed to abolish the improved baroreflex gain caused by hemin or L‐arginine in OVXE 2 /nicotine rats. Baroreflex facilitation by hemin was eliminated after inhibition of PI3K (wortmannin), sGC (ODQ) or ERK (PD98059) in central neurons, in contrast to no effect for the inhibition of p38 (SB203580) or JNK (SP600125). Together, the upregulation of NOS/HO‐coupled PI3K/sGC/ERK signaling downstream of E 2 receptors rectifies the E 2 ‐dependent, nicotine‐evoked impairment of reflex bradycardia in female rats. Grant Funding Source : Supported by Grant STDF ID 502, Egypt