Mitogen-activated protein kinase phosphorylation in the rostral ventrolateral medulla plays a key role in imidazoline (i1)-receptor-mediated hypotension.
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 microg/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)-receptor-mediated, similar hypotensive responses were elicited by intracisternal (i.c.) rilmenidine (25 microg/rat) or the highly selective alpha(2)-agonist alpha-methylnorepinephrine (4 microg/rat). An increase in RVLM MAPK(p42/44) occurred only after rilmenidine. Furthermore, pretreatment with efaroxan (0.15 microg/rat i.c.), a selective I(1)-imidazoline receptor antagonist, or with PD98059 (2'-amino-3'-methoxyflavone) (5 microg/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 alpha(2)-adrenergic receptor.
Zhang
Jian
J
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Abdel-Rahman
Abdel A
AA
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors; D008297:Male; D008526:Medulla Oblongata / Q000201:enzymology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000502:physiology*; D000077769:Rilmenidine; D015398:Signal Transduction
D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D010080:Oxazoles; D011955:Receptors, Drug; C410887:imidazoline I1 receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C062597:efaroxan; D000077769:Rilmenidine