SELECTIVE ANTIHYPERTENSIVE ACTION OF MOXONIDINE IS MEDIATED MAINLY BY I-1-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 I-1-imidazoline over alpha(2)-adrenergic receptors in the RVLM. We identified efaroxan and SK&F 86466 as selective I-1- and alpha(2)-antagonists, respectively. We tested moxonidine's action within the RVLM of spontaneously hypertensive rats (SHRs) on I-1-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 presser response to 2 nmol glutamate. To test whether I-1 or alpha(2) mediates hypotensive effects of moxonidine, the I-1/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 mu g/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 mu g/kg), Pharmacokinetic studies showed that at the peak vasodepressor response (8 min post-injection), [H-3]moxonidine spread less than i mm from the injection site. Moxonidine is a centrally acting antihypertensive with a selective action on I-1-imidazoIine receptors in RVLM.