Peroxisome Proliferator Ameliorates Endocardial Endothelial and Muscarinic Dysfunction in Spontaneously Hypertensive Rats

Abstract

Spontaneously hypertensive rats (SHR) develop hypertension (HT) at the age of 2-6 weeks. Endocardial endothelial (EE) dysfunction, autonomic suppression, left ventricle hypertrophy (LVH), and fibrosis are hallmarks of HT. The mechanism of EE dysfunction, LVH, and fibrosis in SHR is largely unknown. It is known, however, that the levels of peroxisome proliferator-activated receptor γ (PPARγ) are negatively correlated with EE function, LVH, and HT. PPARγ ameliorates EE dysfunction and LVH, in part, by increasing endothelial nitric oxide (eNO) and muscarinic activity. Male SHR and normotensive Wistar rats (NWR) at 1 week of age were administered 8 µg/ml ciglitazone (CZ), a PPARγ agonist, in drinking water. The rats were grouped as follows: NWR, NWR+CZ, SHR, SHR+CZ, at 2 and 6 weeks(n = 6 in each group). The levels of PPARγ were low in the nuclear extracts of the left ventricle (LV) in SHR, but increased in CZ-treated rats, measured by western analysis. The contractile response to norepinephrine in cardiac rings prepared from the above groups of rats, measured in tissue myobath and normalized by tissue weight, demonstrated no difference in the maximum response to norepinephrine in any group. However, the EC₅₀ was significantly lower in SHR at 2 weeks (SHR2wk) than in any other groups, and CZ normalized this decrease. The response to acetylcholine demonstrated no difference in EC₅₀; however, the maximum response was attenuated in SHR2wk, and substantially increased in SHR6wk as compared with age-matched NWR, suggesting that early in HT eNO dysfunction in SHR2wk leads to depression of autonomic muscarinic cholinergic receptor in SHR6wk. The PPARγ agonist ameliorated both the early eNO dysfunction and late autonomic suppression in HT. The response to nitroprusside demonstrated no change in EC₅₀; however, the maximum response was attenuated only in SHR6wk. There were significant fibrosis, LVH, and increased LV pressure in SHR6wk compared with any other group, and CZ regressed LVH and LV pressure. Results suggest that early in HT, except for eNO dysfunction, other contractile responses are preserved; however, at 6 weeks there is significant nonendothelial cell dysfunction, and treatment with CZ reverses this nonendothelial dysfunction as well.