Selective antihypertensive action of moxonidine is mediated mainly by I1-imidazoline receptors in the rostral ventrolateral medulla.
The rostral ventrolateral medulla (RVLM) is the primary region maintaining vasomotor tone, and a site of action for central antihypertensive agents. In vitro [125I]p-iodoclonidine binding studies showed that moxonidine was selective for I1-imidazoline over alpha 2-adrenergic receptors in the RVLM. We identified efaroxan and SK&F 86466 as selective I1- and alpha 2-antagonists, respectively. We tested moxonidine's action within the RVLM of spontaneously hypertensive rats (SHRs) on I1-imidazoline or alpha 2-adrenergic receptors, and determined whether the RVLM mediates the action of systemic moxonidine. SHRs were anesthetized, paralyzed, and ventilated and the RVLM was localized by testing for a pressor response to 2 nmol glutamate. To test whether I1 or alpha 2 mediates hypotensive effects of moxonidine, the I1/alpha 2 antagonist efaroxan (4 nmol) or the alpha 2-blocker SK&F 86466 (10 nmol) was administered 15 min before 4 nmol moxonidine. Efaroxan elevated blood pressure and abolished the action of moxonidine, whereas alpha 2-blockade with SK&F 86466 slightly lowered blood pressure and only partially attenuated moxonidine's effect. The depressor effect of intravenous moxonidine (40 micrograms/kg) was reversed within 10 min by microinjection of 10 nmol efaroxan into the RVLM. Prior bilateral microinjections of efaroxan (10 nmol in 80 nl/site) into the RVLM prevented the hypotensive action of moxonidine given i.v. (40 micrograms/kg). Pharmacokinetic studies showed that at the peak vasodepressor response (8 min post-injection), [3H]moxonidine spread less than 1 mm from the injection site. Moxonidine is a centrally acting antihypertensive with a selective action on I1-imidazoline receptors in RVLM.
Haxhiu
M A
MA
Department of Medicine and Neuroscience, Case Western Reserve University, Cleveland, Ohio 44106.
Dreshaj
I
I
Schäfer
S G
SG
Ernsberger
P
P
D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000345:Affinity Labels; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology; D001572:Benzofurans / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D001795:Blood Pressure Determination; D002417:Cattle; D003000:Clonidine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy*; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D054755:Imidazoline Receptors; D066298:In Vitro Techniques; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D008845:Microinjections; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D000345:Affinity Labels; D000959:Antihypertensive Agents; D001552:Benzazepines; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D011955:Receptors, Drug; C053113:4-iodoclonidine; C043482:moxonidine; C062597:efaroxan; D003000:Clonidine; C039139:benalfocin