Dharmani Murugan, Mustafa Mohd Rais, Achike Francis I, Sim Meng-Kwoon
Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Eur J Pharmacol. 2007 Apr 30;561(1-3):144-50. doi: 10.1016/j.ejphar.2007.01.037. Epub 2007 Feb 1.
Angiotensin 1-7, a heptapeptide derived from metabolism of either angiotensin I or angiotensin II, is a biologically active peptide of the renin-angiotensin system. The present study investigated the effect of angiotensin 1-7 on the vasopressor action of angiotensin II in the renal and mesenteric vasculature of Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and streptozotocin-induced diabetic rats. Angiotensin II-induced dose-dependent vasoconstrictions in the renal vasculature. The pressor response was enhanced in the SHR and reduced in the streptozotocin-diabetic rat compared to WKY rats. Angiotensin 1-7 attenuated the angiotensin II pressor responses in the renal vasculature of WKY and SHR rats. However, the ability to reduce angiotensin II response was diminished in diabetic-induced rat kidneys. The effect of angiotensin 1-7 was not inhibited by 1-[(4-(Dimethylamino)-3-methylphenyl] methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate (PD123319), an angiotensin AT(2) receptor antagonist. (D-ALA(7))-Angiotensin I/II (1-7) (D-ALA) (an angiotensin 1-7 receptor antagonist), indomethacin (a cyclo-oxygenase inhibitor), and N(omega)-Nitro-L-Arginine Methyl Ester (L-NAME)(a nitric oxide synthetase inhibitor) abolished the attenuation by angiotensin 1-7 in both WKY rats and SHR, indicating that its action is mediated by angiotensin 1-7 receptor that is either coupled to the release of prostaglandins and/or nitric oxide. The vasopressor responses to angiotensin II in mesenteric vasculature bed was also dose-dependent but smaller in magnitude compared to the renal vasculature. The responses to angiotensin II were relatively smaller in SHR but no significant difference was observed between WKY and streptozotocin-induced diabetic rats. Angiotensin 1-7 attenuated the angiotensin II pressor responses in WKY, SHR and diabetic-induced mesenteric bed. The attenuation was observed at the lower concentrations of angiotensin II in WKY and diabetic-induced rats but at higher concentrations in SHR. Similar observation as in the renal vasculature was seen with PD123319, D-ALA, and L-NAME. Indomethacin reversed the attenuation by angiotensin 1-7 only in the SHR mesenteric vascular bed. The present findings support the regulatory role of angiotensin 1-7 in the renal and mesenteric vasculature, which is differentially altered in hypertension and diabetes.
血管紧张素1-7是一种由血管紧张素I或血管紧张素II代谢产生的七肽，是肾素-血管紧张素系统的一种生物活性肽。本研究调查了血管紧张素1-7对Wistar-Kyoto（WKY）大鼠、自发性高血压大鼠（SHR）和链脲佐菌素诱导的糖尿病大鼠肾和肠系膜血管中血管紧张素II升压作用的影响。血管紧张素II在肾血管中引起剂量依赖性血管收缩。与WKY大鼠相比，SHR中的升压反应增强，而链脲佐菌素诱导的糖尿病大鼠中的升压反应减弱。血管紧张素1-7减弱了WKY和SHR大鼠肾血管中血管紧张素II的升压反应。然而，在糖尿病诱导的大鼠肾脏中，降低血管紧张素II反应的能力减弱。血管紧张素1-7的作用不受血管紧张素AT(2)受体拮抗剂1-[(4-(二甲基氨基)-3-甲基苯基]甲基]-5-(二苯基乙酰基)-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-6-羧酸二氟乙酸盐（PD123319）的抑制。（D-ALA(7)）-血管紧张素I/II（1-7）（D-ALA）（一种血管紧张素1-7受体拮抗剂）、吲哚美辛（一种环氧化酶抑制剂）和N(ω)-硝基-L-精氨酸甲酯（L-NAME）（一种一氧化氮合酶抑制剂）消除了血管紧张素1-7在WKY大鼠和SHR中的减弱作用，表明其作用是由与前列腺素和/或一氧化氮释放偶联的血管紧张素1-7受体介导的。肠系膜血管床对血管紧张素II的升压反应也是剂量依赖性的，但与肾血管相比幅度较小。SHR中对血管紧张素II的反应相对较小，但WKY和链脲佐菌素诱导的糖尿病大鼠之间未观察到显著差异。血管紧张素1-7减弱了WKY、SHR和糖尿病诱导的肠系膜床中血管紧张素II的升压反应。在WKY和糖尿病诱导的大鼠中，在较低浓度的血管紧张素II时观察到减弱作用，但在SHR中在较高浓度时观察到减弱作用。与肾血管中类似的观察结果见于PD123319、D-ALA和L-NAME。吲哚美辛仅在SHR肠系膜血管床中逆转了血管紧张素1-7的减弱作用。本研究结果支持血管紧张素1-7在肾和肠系膜血管中的调节作用，其在高血压和糖尿病中发生了不同的改变。
