Mitogen-Activated Protein Kinase Phosphorylation in the Rostral Ventrolateral Medulla Plays a Key Role in Imidazoline (I₁)-Receptor-Mediated Hypotension

Abstract

Our previous study showed that rilmenidine, a selective I 1 -imidazoline receptor agonist, enhanced the phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 , via the phosphatidylcholine-specific phospholipase C pathway in the pheochromocytoma cell line (PC12). In the present study, we tested the hypothesis that enhancement of MAPK phosphorylation in the rostral ventrolateral medulla (RVLM) contributes to the hypotensive response elicited by I 1 -receptor activation in vivo. Systemic rilmenidine (600 g/kg i.v.) elicited hypotension and bradycardia along with significant elevation in MAPK p42/44 , detected by immunohistochemistry, in RVLM neurons. To obtain conclusive evidence that the latter response was I 1 -receptormediated, similar hypotensive responses were elicited by intracisternal (i.c.) rilmenidine (25 g/rat) or the highly selective ␣ 2 -agonist ␣-methylnorepinephrine (4 g/rat). An increase in RVLM MAPK p42/44 occurred only after rilmenidine. Furthermore, pretreatment with efaroxan (0.15 g/rat i.c.), a selective I 1 -imidazoline receptor antagonist, or with PD98059 (2Ј-amino-3Ј-methoxyflavone) (5 g/rat i.c.), a selective extracellular signal-regulated kinase 1/2 inhibitor, significantly attenuated the hypotensive response and the elevation in RVLM MAPK p42/44 elicited by i.c. rilmenidine. The findings suggest that MAPK phosphorylation in the RVLM contributes to the hypotensive response induced by I 1 -receptor activation and presents in vivo evidence that distinguishes the neuronal responses triggered by the I 1 -receptor from those triggered by the ␣ 2 -adrenergic receptor.

Brainstem Phosphorylated Extracellular Signal-Regulated Kinase 1/2-Nitric-Oxide Synthase Signaling Mediates the Adenosine A2A-Dependent Hypotensive Action of Clonidine in Conscious Aortic Barodenervated Rats

“…In the RVLM, pERK1/2 is implicated in decreases or increases in blood pressure, depending on the experimental conditions and the preparation used (Seyedabadi et al, 2001;Springell et al, 2005;Zhang and Abdel-Rahman, 2005). In cell culture studies, A 2A R activation leads to This study was supported in part by National Institutes of Health Grant 2R01 AA07839.…”

“…Brains were then transferred into 30% sucrose in TBS for infiltration until they sank. Brain sections that contained the RVLM were cut serially at Ϫ24°C with a microtome cryostat (HM 505 E; Microm International GmbH, Walldorf, Germany) in accordance with Paxinos and Watson (1982) as in our previous study (Zhang and Abdel-Rahman, 2005). Brain sections (16 m each) were collected in each well of a cell culture plate (12 wells; BD Biosciences, San Jose, CA) containing ice-cold TBS.…”

“…These findings, which established a link between the molecular targets for clonidine, ␣ 2A R, and/or I 1 receptor, and central adenosine receptor signaling, are consistent with the physiological role of central A 2A R. It is noteworthy that in the RVLM, the major neuroanatomical target of clonidine, activation of the adenosine A 2A R causes hypotension (Thomas et al, 2000). However, the cellular mechanism implicated in the hypotension mediated by the activation of central adenosine A 2A R has not been investigated.In the RVLM, pERK1/2 is implicated in decreases or increases in blood pressure, depending on the experimental conditions and the preparation used (Seyedabadi et al, 2001;Springell et al, 2005;Zhang and Abdel-Rahman, 2005). In cell culture studies, A 2A R activation leads to This study was supported in part by National Institutes of Health Grant 2R01 AA07839.…”

“…In cell culture studies, A 2A R activation leads to pERK1/2 generation (Schulte and Fredholm, 2003), and clonidine-like drugs, whose hypotensive action is dependent on central adenosine A 2A R (Nassar and Abdel-Rahman, 2006a,b), enhance the production of pERK1/2 in the RVLM (Zhang and Abdel-Rahman, 2005). The possibility has not been investigated that pERK1/2 generation in the RVLM contributes to the A 2A R-dependent hypotension caused by clonidine.…”

“…In the RVLM, pERK1/2 is implicated in decreases or increases in blood pressure, depending on the experimental conditions and the preparation used (Seyedabadi et al, 2001;Springell et al, 2005;Zhang and Abdel-Rahman, 2005). In cell culture studies, A 2A R activation leads to pERK1/2 generation (Schulte and Fredholm, 2003), and clonidine-like drugs, whose hypotensive action is dependent on central adenosine A 2A R (Nassar and Abdel-Rahman, 2006a,b), enhance the production of pERK1/2 in the RVLM (Zhang and Abdel-Rahman, 2005).…”