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CARDIOVASCULAR

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

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina

Our previous study showed that rilmenidine, a selective I₁-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 I₁-receptor activation in vivo. Systemic rilmenidine (600 µg/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 I₁-receptor-mediated, similar hypotensive responses were elicited by intracisternal (i.c.) rilmenidine (25 µg/rat) or the highly selective ₂-agonist -methylnorepinephrine (4 µg/rat). An increase in RVLM MAPK_p42/44 occurred only after rilmenidine. Furthermore, pretreatment with efaroxan (0.15 µg/rat i.c.), a selective I₁-imidazoline receptor antagonist, or with PD98059 (2'-amino-3'-methoxyflavone) (5 µg/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 I₁-receptor activation and presents in vivo evidence that distinguishes the neuronal responses triggered by the I₁-receptor from those triggered by the ₂-adrenergic receptor.

Address correspondence to: Dr. Abdel A. Abdel-Rahman, Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834. E-mail: abdelrahmana{at}mail.ecu.edu

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