SELECTIVE ANTIHYPERTENSIVE ACTION OF MOXONIDINE IS MEDIATED MAINLY BYI-1-IMIDAZOLINE RECEPTORS IN THE ROSTRAL VENTROLATERAL MEDULLA

The rostral ventrolateral medulla (RVLM) is the primary region maintai ning vasomotor tone, and a site of action for central antihypertensive agents. In vitro [125I]p-iodoclonidine binding studies showed that mo xonidine was selective for I-1-imidazoline over alpha(2)-adrenergic re ceptors in the RVLM. We identified efaroxan and SK&F 86466 as selectiv e 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 anesth etized, paralyzed, and ventilated and the RVLM was localized by testin g for a presser response to 2 nmol glutamate. To test whether I-1 or a lpha(2) mediates hypotensive effects of moxonidine, the I-1/alpha(2) a ntagonist efaroxan (4 nmol) or the alpha(2)-blocker SK&F 86466 (10 nmo l) 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 p artially attenuated moxonidine's effect. The depressor effect of intra venous moxonidine (40 mu g/kg) was reversed within 10 min by microinje ction of 10 nmol efaroxan into the RVLM. Prior bilateral microinjectio ns of efaroxan (10 nmol in 80 nl/site) into the RVLM prevented the hyp otensive action of moxonidine given i.v. (40 mu g/kg), Pharmacokinetic studies showed that at the peak vasodepressor response (8 min post-in jection), [H-3]moxonidine spread less than i mm from the injection sit e. Moxonidine is a centrally acting antihypertensive with a selective action on I-1-imidazoIine receptors in RVLM.