Upregulation of imidazoline receptors in the medulla oblongata accounts for the enhanced hypotensive effect of clonidine in aortic barodenervated rats.
The present study tested the hypothesis that an upregulation of the imidazoline receptor in the rostral ventrolateral medulla (RVLM) of aortic barodenervated (ABD) rats may account for the enhanced hypotensive effect of clonidine. In vitro autoradiographic radioligand binding studies were utilized to investigate the binding characteristics of imidazoline receptors in the RVLM and nucleus tractus solitarius (NTS), areas that play critical roles in cardiovascular regulation and elicitation of clonidine responses. ABD but not sham operation (SO) caused immediate and significant (P < 0.05) increases in mean arterial pressure (MAP) and heart rate (HR) and an impairment of the baroreflex-mediated HR response (baroreflex sensitivity, BRS). Two days after ABD, these parameters, except BRS, subsided to near-control (SO) levels. Intracisternal (i.c.) administration of clonidine (0.1 micrograms) elicited a 3-fold greater decrease in BP of conscious ABD compared with SO rats (-20.3 +/- 2.6 vs. -7.4 +/- 0.9 mmHg) thus demonstrating the ability of ABD to enhance centrally-mediated hypotensive responses. Autoradiographic visualization of brain sections obtained from separate groups of ABD and SO rats 48 h after surgery preincubated with [3H]idazoxan (2.5-3.5 nM) showed that [3H]idazoxan binding in RVLM, middle NTM (mNTS) and rostral NTS (rNTS) was saturable and of high affinity. Uneven distribution of imidazoline binding sites was evident since in control (SO) rats, Scatchard analysis of binding data revealed similar densities (Bmax) of [3H]idazoxan binding sites in the RVLM and mNTS versus significantly higher density in the rNTS. In ABD rats, the binding dissociation constant (Kd) was significantly decreased in both the RVLM (8.1 +/- 3.1 vs. 21.4 +/- 5.0 nM) and rNTS (12.3 +/- 1.3 vs. 18.6 +/- 3.1 nM) compared with SO rats while the Bmax was not affected. This finding suggests an increased receptor affinity in the RVLM and rNTS of barodenervated rats. The mNTS of ABD rats exhibited significant increases in the Bmax (861 +/- 96 vs. 570 +/- 87 fmol/mg protein) compared with values of SO rats but the receptor affinity was not affected. It is concluded that: (i) aortic baroreceptors exert a tonic inhibitory influence on central imidazoline receptor function; and (ii) the enhanced hypotensive effect of clonidine in conscious ABD rats may be accounted for by the increased affinity of the medullary imidazoline receptors particularly in the RVLM.
el-Mas
M M
MM
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC, USA.
Abdel-Rahman
A A
AA
D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001012:Aorta, Abdominal; D001345:Autoradiography; D002319:Cardiovascular System / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D054755:Imidazoline Receptors; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects*; D009121:Muscle Denervation; D011311:Pressoreceptors / Q000378:metabolism / Q000648:ultrastructure*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D000959:Antihypertensive Agents; D054755:Imidazoline Receptors; D011955:Receptors, Drug; D003000:Clonidine