title: The estrogen-dependent baroreflex dysfunction caused by nicotine in female rats is mediated via NOS/HO inhibition: Role of sGC/PI3K/MAPKERK.
abstract: We have previously reported that estrogen (E2) exacerbates the depressant effect of chronic nicotine on arterial baroreceptor activity in female rats. Here, we tested the hypothesis that this nicotine effect is modulated by nitric oxide synthase (NOS) and/or heme oxygenase (HO) and their downstream soluble guanylate cyclase (sGC)/phosphatidylinositol 3-kinase (PI3K)/mitogen-activated protein kinases (MAPKs) signaling. We investigated the effects of (i) inhibition or facilitation of NOS or HO on the interaction of nicotine (2mg/kg/day i.p., 2 weeks) with reflex bradycardic responses to phenylephrine in ovariectomized (OVX) rats treated with E2 or vehicle, and (ii) central pharmacologic inhibition of sGC, PI3K, or MAPKs on the interaction. The data showed that the attenuation by nicotine of reflex bradycardia in OVXE2 rats was abolished after treatment with hemin (HO inducer) or l-arginine (NOS substrate). The hemin or l-arginine effect disappeared after inhibition of NOS (Nω-Nitro-l-arginine methyl ester hydrochloride, L-NAME) and HO (zinc protoporphyrin IX, ZnPP), respectively, denoting the interaction between the two enzymatic pathways. E2-receptor blockade (ICI 182,780) reduced baroreflexes in OVXE2 rats but had no effect on baroreflex improvement induced by hemin or l-arginine. Moreover, baroreflex enhancement by hemin was eliminated following intracisternal (i.c.) administration of wortmannin, ODQ, or PD98059 (inhibitors of PI3K, sGC, and extracellular signal-regulated kinases, MAPKERK, respectively). In contrast, the hemin effect was preserved after inhibition of MAPKp38 (SB203580) or MAPKJNK (SP600125). Overall, NOS/HO interruption underlies baroreflex dysfunction caused by nicotine in female rats and the facilitation of NOS/HO-coupled sGC/PI3K/MAPKERK signaling might rectify the nicotine effect.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Fouda
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
authors.forename: Hanan M
authors.initials: HM
authors.lastname: El-Gowelli
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
authors.forename: Sahar M
authors.initials: SM
authors.lastname: El-Gowilly
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt. Electronic address: mahelm@hotmail.com.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: El-Mas
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D017704:Baroreflex / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D006427:Hemin / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D009538:Nicotine / Q000009:adverse effects*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010656:Phenylephrine / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
chemical_list: D004791:Enzyme Inhibitors; D004967:Estrogens; D018160:Receptors, Cytoplasmic and Nuclear; D010656:Phenylephrine; C026512:arginine methyl ester; D009538:Nicotine; D006427:Hemin; D001120:Arginine; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D019331:NG-Nitroarginine Methyl Ester
keywords: Arterial baroreceptors; Estrogen; Heme oxygenase; Mitogen activated protein kinases; Nicotine; Nitric oxide synthase