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.