Background: The rostral ventrolateral medulla (RVLM), location of the
sympathetic premotor neurons, plays a pivotal role in central cardiovascular
regulation. The peroxisome proliferator-activated receptors-£^ (PPAR£^) agonist
is commonly prescribed for the treatment of type II diabetes mellitus by its
insulin sensitizing ability. Intriguingly, both animal and human studies
revealed that PPAR£^ agonist also possesses blood pressure lowering effect
although the underlying mechanism is unknown. We designed a study to
evaluate the hypothesis that activation of PPAR£^ in the RVLM mediates the
blood pressure lowering effect of PPAR£^ agonist, rosiglitazone.
Materials and Methods: The 12-week spontaneously hypertensive rats (SHR)
and the age-matched normotensive Wistar Kyoto (WKY) rats were used in
this study. Basal systemic arterial pressure (SAP) and heart rate (HR) were
measured for one week, followed by oral administration of a synthetic PPAR£^
agonist, rosiglitazone (80 mg/kg/day), or saline for 7 days. The hemodynamic
profile was recorded for 4 weeks post treatment. The role of PPAR£^ in the
RVLM on blood pressure lowering effect of rosiglitazone was examined by
microinjection bilaterally into the RVLM of the PPAR£^ antagonist, GW9662
(5 nmol). In a separated series of experiments, the RVLM of SHR or WKY
rats was removed at the end of rosiglitazone or saline treatment. Protein
expression of PPAR£\, PPAR£]/£_ or PPAR£^ in the RVLM was analyzed by
Western blotting. To ascertain that changes in protein expression are not
secondary to perturbation of SAP, expression of PPARs was also examined inSHR that received oral administration of a calcium channel inhibitor,
amlodipine (16 mg/kg/day), for 7 days.
Results: Compared to saline intake, rosiglitazone significantly lowered the
mean SBP (MSBP, 159.2¡Ó9.9 mmHg vs. 139.8¡Ó12.6 mmHg) in SHR, but not
WKY rats. This blood pressure lowering effect of rosiglitazone in SHR lasted
for at least 10 days post treatment. Rosiglitazone treatment, on the other hand,
had no significant effect on HR in SHR or WKY rats. At the end of 7-day
treatment, microinjection bilaterally into the RVLM of PPAR£^ antagonist,
GW9662 (5 nmol), significantly reversed the blood pressure lowering effect of
rosiglitazone in SHR. In addition, protein expression of PPAR£\ or PPAR£^
was significantly upregulated in the RVLM of the SHR but not WKY rats that
received rosiglitazone treatment. Oral intake of amlodipine (16 mg/kg/day) for
7 days in SHR significantly lowered MSBP (164.8¡Ó7.7 mmHg to 131.8¡Ó7.8
mmHg), but did not affect protein expression of PPAR£\, PPAR£]/£_ or PPAR£^
in the RVLM of SHR.
Conclusion: These results suggest that oral administration of rosiglitazone
exerts blood pressure lowering effect via activation of PPARs in the RVLM of
SHR. Moreover, upregulation of PPAR£\ or PPAR£^ in the RVLM may
underlie the antihypertensive effect of rosiglitazone.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0828108-142435 |
| Date | 28 August 2008 |
| Creators | Kung, Sui-sum |
| Contributors | Julie Y.H. Chan, Alice Y.W. Chang, Samuel H.H. Chan |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0828108-142435 |
| Rights | restricted, Copyright information available at source archive |
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