The role of peroxisome proliferator-activated receptors in the rostral ventrolateral medulla in blood pressure lowering effect of rosiglitazone in spontaneously hypertensive rat

• Main Authors: Sui-sum Kung, 龔瑞琛
• Other Authors: Alice Y.W. Chang
• Format: Others
• Language: en_US
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/tt7e7r

碩士 === 國立中山大學 === 生物科學系研究所 === 96 === 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-γ (PPARγ) 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 PPARγ agonist also possesses blood pressure lowering effect although the underlying mechanism is unknown. We designed a study to evaluate the hypothesis that activation of PPARγ in the RVLM mediates the blood pressure lowering effect of PPARγ 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 PPARγ agonist, rosiglitazone (80 mg/kg/day), or saline for 7 days. The hemodynamic profile was recorded for 4 weeks post treatment. The role of PPARγ in the RVLM on blood pressure lowering effect of rosiglitazone was examined by microinjection bilaterally into the RVLM of the PPARγ 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 PPARα, PPARβ/δ or PPARγ 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±9.9 mmHg vs. 139.8±12.6 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 PPARγ antagonist, GW9662 (5 nmol), significantly reversed the blood pressure lowering effect of rosiglitazone in SHR. In addition, protein expression of PPARα or PPARγ 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±7.7 mmHg to 131.8±7.8 mmHg), but did not affect protein expression of PPARα, PPARβ/δ or PPARγ 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 PPARα or PPARγ in the RVLM may underlie the antihypertensive effect of rosiglitazone.