Mechanism of agonistic angiotensin II type I receptor autoantibody-amplified contractile response to Ang II in the isolated rat thoracic aorta.
Agonistic autoantibody to the angiotensin II type I receptor (AT1-AA) is highly associated with preeclampsia by increasing the sensitivity of Ang II during pregnancy in rats, thus leading to a preeclampsia-like syndrome. However, the mechanism underlying this phenomenon remains unclear. The purpose of this study was to observe AT1-AA amplification of Ang II-induced vasoconstriction in rat thoracic aortic rings. It was found that exposure to low concentrations of AT1-AA (0.4 nM) caused a contraction of <5% of the maximal response to 60 mM KCl. In addition, the Ang II-induced contractile response was amplified in the presence of a threshold contraction to AT1-AA, as manifested by a leftward shift of the midpoint of the concentration-response curve with no change in the maximal response. These results showed that preincubation with low AT1-AA could amplify the Ang II dose-response curve, and this amplification could be attenuated markedly by 0.1 µM heptapeptide AFHYESQ. In calcium-free Krebs solution, 10 µM of 2-aminoethoxydiphenyl borate (an IP3 receptor inhibitor) both blocked the AT1-AA base contraction and completely abolished the amplification. Both 5 µM of U-73122 (a phospholipase C inhibitor) and 10 µM of εV1-2 (an εPKC inhibitor) could partially inhibit the Ang II-induced contractile response. εV1-2, but not U-73122, could completely inhibit the amplification response of AT1-AA to Ang II. These results suggest that AT1-AA is able to cause amplification response to Ang II probably via the calcium-independent protein kinase C pathway, which may provide a new therapy strategy for preeclampsia.
Department of Physiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
Wenhui
W
Zhang
Department of Physiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
Yanqian
Y
Zheng
Department of Ophthalmology, Tenth People's Hospital Affiliated of Tongji University, School of Medicine, Shanghai 200072, China zhjm@gmail.com arztinys@hotmail.com.
Fang
F
Liu
Department of Physiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
Xiaofang
X
Wang
Department of Physiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
Zhu
Z
Jin
Department of Physiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China zhjm@gmail.com arztinys@hotmail.com.
Jianming
J
Zhi
D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology*; D014661:Vasoconstriction / Q000187:drug effects / Q000276:immunology*
D001323:Autoantibodies; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II
agonistic angiotensin II type I receptor autoantibody; contractile response; isolated rat thoracic aorta; preeclampsic