2006 Fiscal Year Final Research Report Summary
The study of antihypertensive mechanism of angiotensin receptor blocker
| Project/Area Number |
16590074
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Biological pharmacy
|
|---|
| Research Institution | Kobe Gakuin University |
|---|
Principal Investigator |
YAYAMA Katsutoshi Kobe Gakuin University, Faculty of Pharmaceutical Sciences, Lecturer (30248108)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OKAMOTO Hiroshi Kobe Gakuin University, Faculty of Pharmaceutical Sciences, Professor (00028870)
TAKANO Masaoki Kobe Gakuin University, Faculty of Pharmaceutical Sciences, Lecturer (30258107)
|
|---|
| Project Period (FY) |
2004 – 2006
|
| Keywords | angiotensin / bradykinin / hypertension / angiotensin receptor / eNOS |
|---|
| Research Abstract |
Angiotensin II (Ang II) exerts its effects on the cardiovascular tissues via two types of receptors, type 1 (AT_1) and type 2 (AT_2). It has been demonstrated that Ang II binding to AT_2 receptors activates counterregulatory pathway whereby the AT_1 -mediated vasoconstriction is opposed by vasodilation via the AT_2 receptor. Recently, we have found that the abdominal aortic constriction (banding) induces up-regulation of the AT_2 receptor expression in thoracic aortas of rats and mice, resulting in the decreased contractile response to Ang II in aortic rings from these animals. Ang II stimulated the cGMP production in these aortas via the AT_2 -receptor activation, and this Ang II effect was abolished by either icatibant or L-NAME, suggesting a mediation of bradykinin/NO. The AT_2-receptor-dependent vasodilation was accompanied by the B_2 -receptor-mediated phosphorylation of eNOS at Ser1177 and Ser633 via the protein kinase A-dependent signaling. Furthermore, in the presence of losartan, Ang II produced a dose-dependent dilation in the aortic rings from young SHR during the development of hypertension, but not in aortic rings from the age-matched WKY or adult SHR with established hypertension. The aortic rings from young SHR also exhibited a dose-dependent dilation to bradykinin, whereas those from the age-matched WKY or adult SHR did not respond to bradykinin, suggesting that there is a potential role of B_2 receptor in the AT_2-receptor-dependent vasodilation in young SHR. These studies suggest that the AT_2 receptors in vascular tissues are up-regulated in pathological conditions and oppose the AT_1 -receptor-mediated hypertension through bradykinin B_2 receptors.
|
