Imidazoline receptors associated with noradrenergic terminals in the rostral ventrolateral medulla mediate the hypotensive responses of moxonidine but not clonidine.
We determined whether the cardiovascular actions of central anti-hypertensive agents clonidine and moxonidine are dependent on noradrenergic or serotonergic innervation of the rostral ventrolateral medulla (RVLM) in conscious rabbits. 6-Hydroxydopamine (6-OHDA) or 5,6-dihydroxytriptamine (5,6-DHT) was injected into the RVLM to deplete noradrenergic and serotonergic terminals respectively. One, 2 and 4 weeks later, responses to fourth ventricular (4V) clonidine (0.65 microg/kg) and moxonidine (0.44 microg/kg) were examined. Destruction of noradrenergic pathways in the RVLM by 6-OHDA reduced the hypotensive response to 4V moxonidine to 62%, 47% and 60% of that observed in vehicle treated rabbits at weeks 1, 2 and 4 respectively. The moxonidine induced bradycardia was similarly attenuated (to 46% of vehicle). Conversely, 6-OHDA had no effect on the hypotensive or bradycardic effects of 4V clonidine. Efaroxan (I(1)-imidazoline receptor/alpha(2)-adrenoceptor antagonist; 3.5, 11, 35 microg/kg) and 2-methoxyidazoxan (alpha(2)-adrenoceptor antagonist; 0.3, 0.9, 3 microg/kg) equally reversed the hypotension to 4V clonidine, suggesting a mainly alpha(2)-adrenoceptor mechanism. Efaroxan preferentially reversed responses to moxonidine in both vehicle and 5,6-DHT groups and in the 1st week after 6-OHDA, suggesting a mechanism involving mainly I(1)-imidazoline receptors. This selectivity was subsequently lost in the 2nd and 4th weeks when the remaining hypotension was mainly mediated by alpha(2)-adrenoceptors. Depletion of serotonergic terminals did not alter the responses to either agonist nor did it change the relative effectiveness of the antagonists. Western blots of RVLM tissues probed with imidazoline and alpha(2)-adrenoceptor antisera showed a pattern of bands close to that reported in other species. The main effect of 6-OHDA was an 18% lower level of the 42 kDa imidazoline protein (P<0.05). We conclude that the hypotensive and bradycardic actions of moxonidine but not clonidine are mediated through imidazoline receptors and are dependent on intact noradrenergic pathways within the RVLM. Furthermore, the noradrenergic innervation may be associated with a 42 kDa imidazoline receptor protein.
Chan
C K S
CK
Neuropharmacology Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia.
Burke
S L
SL
Zhu
H
H
Piletz
J E
JE
Head
G A
GA
D015115:5,6-Dihydroxytryptamine / Q000494:pharmacology; D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D015153:Blotting, Western; D001919:Bradycardia / Q000503:physiopathology; D002851:Chromatography, High Pressure Liquid; D003000:Clonidine / Q000008:administration & dosage*; D005260:Female; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology*; D007093:Imidazoles / Q000008:administration & dosage*; D054755:Imidazoline Receptors; D048288:Imidazolines / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology
D018663:Adrenergic Agents; D000959:Antihypertensive Agents; D007093:Imidazoles; D054755:Imidazoline Receptors; D048288:Imidazolines; D011955:Receptors, Drug; D018490:Serotonin Agents; D012701:Serotonin; D016627:Oxidopamine; C043482:moxonidine; D003000:Clonidine; D015115:5,6-Dihydroxytryptamine; D009638:Norepinephrine