Site-dependent inhibition of neuronal c-jun in the brainstem elicited by imidazoline I1 receptor activation: role in rilmenidine-evoked hypotension.
Clonidine (a mixed alpha2-adrenoceptor and imidazoline I1 receptor agonist)-evoked hypotension was associated with dissimilar reductions in c-jun gene expression in the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarius (NTS) in normotensive rats. In the present study, we investigated the relative contribution of the alpha2-adrenoceptor vs. the imidazoline I1 receptor to the reduction in c-jun gene expression in these two brainstem areas. In conscious spontaneously hypertensive rats (SHRs), equihypotensive doses of three centrally acting hypotensive drugs with different selectivity for the two receptors were administered intracisternally (4 microl) to limit their actions to the brain. As a control, a similar hypotensive response was elicited by i.v. hydralazine. Clonidine (0.5 microg), or alpha-methylnorepinephrine (alpha-MNE, 4 microg), a highly selective alpha2-adrenoceptor agonist, similarly reduced c-jun mRNA expression in the NTS and rostral ventrolateral medulla. In contrast, a similar hypotensive response (-37+/-3.5 mm Hg) caused by the selective imidazoline I1 receptor agonist rilmenidine (25 microg) was associated with reduction in c-jun mRNA expression in the rostral ventrolateral medulla, but not in the NTS. Further, intra-rostral ventrolateral medulla rilmenidine (40 nmol) reduced c-Jun protein expression in rostral ventrolateral medulla and blood pressure and both responses were antagonized by selective imidazoline I1 receptor (efaroxan, 4 nmol), but not alpha2-adrenoceptor (SK&F 86466, 10 nmol) blockade. These results suggest: (1) the c-jun containing neurons in the brainstem are involved in the centrally mediated hypotension elicited by centrally acting antihypertensive agents, and (2) the alpha2-adrenoceptor modulates c-jun gene expression in the NTS and rostral ventrolateral medulla implicated in centrally mediated hypotension, and (3) the imidazoline I1 receptor mediated inhibition of c-jun gene expression in the rostral ventrolateral medulla, but not in the NTS, contributes to the centrally mediated hypotension by the second generation drugs.
Wang
Xu
X
Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA.
Li
Guichu
G
Abdel-Rahman
Abdel A
AA
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000502:physiology; D003000:Clonidine / Q000494:pharmacology; D003243:Consciousness; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors; D007150:Immunohistochemistry; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D008771:Nordefrin / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077769:Rilmenidine; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D001552:Benzazepines; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D010080:Oxazoles; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C410887:imidazoline I1 receptors; D006830:Hydralazine; C062597:efaroxan; D003000:Clonidine; D000077769:Rilmenidine; D008771:Nordefrin; C039139:benalfocin