Evidence that prostaglandins mediate the antihypertensive actions of angiotensin-(1-7) during chronic blockade of the renin-angiotensin system
Evidence that prostaglandins mediate the antihypertensive actions of angiotensin-(1-7) during chronic blockade of the renin-angiotensin system
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DOI：
10.1097/00005344-200007000-00015
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发表时间：
2000-07-01
影响因子：
3
通讯作者：
Chappell, MC
中科院分区：
文献类型：
--
作者：
Iyer, SN;Yamada, K;Chappell, MC
已知前列腺素参与血管紧张素转换酶（ACE）抑制和血管紧张素I型（AT（1））受体拮抗的抗高血压作用。由于血管紧张素-（1-7）[Ang-（1-7）]在长期ACE抑制剂治疗后显著升高，我们确定Ang-（1-7）的抗高血压作用是否通过释放胡枝子素介导。雄性自发性高血压大鼠（SHR，10周）用赖诺普利（20 mg/kg）或氯沙坦（10 mg/kg）或两种药物联合治疗9天。在大鼠颈动脉和颈静脉中植入导管，分别记录血压和输注药物溶液。单克隆抗体中和循环中的Ang-（1-7）导致赖诺普利或氯沙坦治疗的SHR的血压呈剂量依赖性升高，给予CGS 24592阻断Ang-（1-7）形成也导致血压升高，与抗体输注相当。然而，Ang-（1-7）阻断剂在赖诺普利和赖诺普利/氯沙坦治疗的大鼠中引起的血压升高比单独氯沙坦治疗的大鼠更大。用环氧合酶（考克斯）抑制剂吲哚美辛进行急性治疗，血压升高的程度与CGS 24592相似，并且在赖诺普利/氯沙坦组中用脑啡肽酶抑制剂阻断了血压升高。然而，在洛沙坦治疗的动物中，吲哚美辛增加血压的程度大于Ang-（1-7）抗体或CGS 24592，并且CGS 24592没有消除这些动物中对吲哚美辛的后续加压反应。与抗体或脑啡肽酶抑制剂相反，施用Ang-（1-7）拮抗剂D-[Ala（7）]-Ang-（1-7）在赖诺普利或氯沙坦治疗中以类似的程度增加血压。此外，D-[Ala（7）]-Ang-（1-7）升高血压的程度与吲哚美辛相当，并且在氯沙坦治疗的SHR中阻断了考克斯抑制剂的任何进一步升高。高分辨率乳剂放射自显影显示，在LOS和AT（2）拮抗剂PD 123319存在下，I-125-[肌氨酸（1），苏氨酸（8）]-Ang II（Sarthran）在肠系膜动脉和胸主动脉中结合。非AT（1）/非AT（2）Sarthran结合被Ang-（1-7）、DALA或Ang II取代。这些研究表明，在LIS和LIS/LOS治疗中，血管舒张性类花生酸介导内源性Ang-（1-7）的抗高血压作用。此外，在AT（1）受体阻断的情况下，Ang II可能与DALA敏感位点相互作用，促进类花生酸释放。
Prostaglandins are known to participate in the antihypertensive actions of angiotensin-converting enzyme (ACE) inhibition and angiotensin type I (AT(1))-receptor antagonism. Because angiotensin-(1-7) [Ang-(1-7)] is markedly elevated after prolonged ACE-inhibitor treatment, we determined whether the antihypertensive effects of Ang-(1-7) were mediated by release of prostaglandins. Male spontaneously hypertensive rats (SHRs, 10 weeks) were treated for 9 days with either lisinopril (20 mg/kg) or losartan (10 mg/kg) or a combination of both drugs. Rats were implanted with catheters in the carotid artery and jugular vein to record blood pressure and to infuse drug solutions, respectively. Neutralization of circulating Ang-(1-7) by monoclonal antibody resulted in a dose-dependent increase in blood pressure in SHRs treated with either lisinopril or losartan, Administration of CGS 24592 to block Ang-(1-7) formation also resulted in an increase in blood pressure that was comparable to antibody infusion. However, Ang-(1-7) blockade evoked a greater elevation in blood pressure in the lisinopril and lisinopril/losartan-treated rats in comparison to those treated with losartan alone. Acute treatment with the cyclooxygenase (COX) inhibitor indomethacin increased blood pressure to a similar extent to that of CGS 24592, as well as blocked the increase in pressure with the neprilysin inhibitor in the lisinopril/losartan group. In the losartan-treated animals, however, indomethacin increased blood pressure by a larger extent than that of the Ang-(1-7) antibody or CGS 24592, and CGS 24592 did not abolish the subsequent presser response to indomethacin in these animals. In contrast to the antibody or neprilysin inhibitor, administration of the Ang-(1-7) antagonist D-[Ala(7)]-Ang-(1-7) increased blood pressure to a similar extent in lisinopril or losartan treatments. Moreover, D-[Ala(7)]-Ang-(1-7) increased blood pressure to a comparable extent as indomethacin and blocked any further increase with the COX inhibitor in the losartan-treated SHRs. High-resolution emulsion autoradiography revealed I-125-[Sarcosine(1), Threonine(8)]-Ang II (Sarthran) binding in the mesenteric artery and thoracic aorta in the presence of both LOS and the AT(2) antagonist PD123319. The non-AT(1)/non-AT(2) Sarthran binding was displaced by Ang-(1-7), DALA, or Ang II. These studies suggest that vasodilatory eicosanoids mediate the antihypertensive effects of endogenous Ang-(1-7) in both LIS and LIS/LOS therapies. Furthermore, in the presence of AT(1)-receptor blockade, Ang II may interact with a DALA-sensitive site to promote eicosanoid release.