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Role of aromaticity of agonist switches of angiotensin II in the activation of the AT₁ receptor

JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第11期274卷 7103-7110页

作者： Miura, S Feng, YH Husain, A Karnik, SS Cleveland Clin Fdn Lerner Res Inst Dept Mol Cardiol Cleveland OH 44195 USA

We have shown previously that the octapeptide angiotensin II (Ang II) activates the AT, receptor through an induced-fit mechanism (Noda, K,, Feng, Y. H., Liu, X. P., Saad, Y,, Husain, A., and Karnik, S, S. (1996) Biochemistry 35, 16435-16442). In this activation process, interactions between Tyr(4) and Phe(8) of Ang II with Asn(111) and His(256) Of the AT(1) receptor, respectively, are essential for agonism, Here we show that aromaticity, primarily, and size, secondarily, of the Tyr(4) side chain are important in activating the receptor. Activation analysis of AT(1) receptor position 111 mutants by various Ang II position 4 analogues suggests that an amino-aromatic bonding interaction operates between the residue Asn(111) of the AT(1) receptor and Ty(r)4 of Ang II. Degree and potency of AT(1) receptor activation by Ang II can be recreated by a reciprocal exchange of aromatic and amide groups between positions 4 and 111 of Ang II and the AT(1) receptor, respectively. In several other bonding combinations, set up between Ang II position 4 analogues and receptor mutants, the gain of affinity is not accompanied by gain of function, Activation analysis of position 256 receptor mutants by Ang II position 8 analogues suggests that aromaticity of Phe(8) and His256 Side chains is crucial for receptor activation;however, a stacked rather than an amino-aromatic interaction appears to operate at this switch locus. Interaction between these residues, unlike the Tyr(4):Asn(111) interaction, plays an insignificant role in ligand docking.

关键词：血管紧张素ⅰ/代谢血管紧张素Ⅱ/激动剂血管紧张素Ⅱ/类似物和衍生物血管紧张素Ⅱ/化学 COS细胞苯丙氨酸/化学受体血管紧张素/激动剂受体血管紧张素/代谢酪氨酸/化学动物

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Regulation of angiotensin II production and angiotensin receptors in microvascular endothelial cells from bovine corpus luteum

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BIOLOGY OF REPRODUCTION 2000年第1期62卷 162-167页

作者： Hayashi, K Miyamoto, A Berisha, B Kosmann, MR Okuda, K Schams, D Tech Univ Munich Inst Physiol D-80350 Freising Weihenstephan Germany Obihiro Univ Agr & Vet Med Dept Anim Sci Obihiro Hokkaido 0808555 Japan Okayama Univ Fac Agr Lab Reprod Endocrinol Okayama 7008530 Japan

Recent findings suggest that the ovarian renin-angiotensin system regulates ovarian function through the paracrine/autocrine actions of angiotensin (Ang) II. The aims of this study were to investigate 1) the endothelial cell capacity to convert Ang I to Ang II, 2) the effects of endocrine and paracrine/autocrine factors on Ang II production in microvascular endothelial cells (MVE) derived from the developing corpora lutea (CL), and 3) the relationship between Ang II peptide concentration and expression of mRNA for angiotensin type 1 and 2 receptors (ATR1 and AT2R) in the bovine Ct at different stages of the estrous cycle. When Ang I was added to the MVE at a concentration of 10(-9) M, it was converted to Ang II (21%). The production of Ang II from Ang I time-dependently rose for 24 h, Addition of captopril tan inhibitor of Ang-converting enzyme [ACE]) to the MVE cultures significantly inhibited Ang II production from 6 h to 24 h (P < 0.05). Addition of estradiol-17 beta (E-2) + vascular endothelial growth factor and E-2 + basic fibroblast growth factor to MVE cultures increased Ang II production, whereas E-2 or growth factors alone had no effect Specific transcription for AT1R and AT2R was detected in bovine CL and MVE. There were no significant changes in Ang II tissue concentration or AT1R mRNA expression using reverse transcription-polymerase chain reaction during the estrous cycle. In contrast, AT2R mRNA expression decreased during the midluteal phase (P < 0.05) and increased to the highest level during the late luteal phase (P < 0.05). Results demonstrated that Ang II is generated from Ang I in MVE isolated from the developing bovine Ct, indicating that MVE have ACE activity. In addition, mRNA expression for Ang II receptors was detected in the bovine Ct and the luteal MVE. These results suggest that Ang II is produced by actions of the local renin-angiotensin system, at least in part, on MVE in the bovine Ct, and that this peptide may be involved in the regula

关键词：血管紧张素ⅰ/代谢血管紧张素Ⅱ/生物合成牛/代谢黄体/血液供给内皮生长因子/药理学内皮血管/代谢雌二醇/药理学动情期成纤维细胞生长因子2/药理学基因表达动力学淋巴因子/药理学 RNA 信使/代谢受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/遗传学血管内皮生长因子A 血管内皮生长因子类动物女(雌)性

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Vascular response to angiotensin II is exaggerated through an upregulation of AT1 receptor in AT2 knockout mice

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第1期258卷 194-198页

作者： Tanaka, M Tsuchida, S Imai, T Fujii, N Miyazaki, H Ichiki, T Naruse, M Inagami, T Tokyo Womens Med Univ Dept Med Inst Clin Endocrinol Shinjuku Ku Tokyo 1628666 Japan Vanderbilt Univ Sch Med Dept Biochem Nashville TN 37232 USA Vanderbilt Univ Sch Med Dept Pediat Nashville TN 37232 USA Univ Tsukuba Inst Appl Biochem Gene Expt Ctr Tsukuba Ibaraki 305 Japan

Blood pressure is elevated and presser response to angiotensin II (Ang II) is exaggerated in AT2 null mice. The purpose of the present study was to elucidate the mechanism for the increased responsiveness to Ang II in the mice. The contraction of aortic strips generated by Ang II was significantly greater in the AT2 gene-deleted mice than the control, which was completely abolished by AT1 antagonist losartan, The aortic content of AT1 receptor was significantly increased (P < 0.05, n = 5) in the AT2 null mice (212 +/- 58.2 fmol/mg protein) compared with the control (98.2 +/- 55.9 fmol/mg protein). While both AT1 and AT2 mRNAs were expressed in the aorta of the control mice, only AT1 mRNA was expressed in the AT2 knockout mice. The expression of AT1 mRNA in the AT2 knockout mice was significantly higher (1.5-fold, P < 0.05, n = 5) than that in the control. The present study clearly demonstrated that the increased vascular reactivity to Ang II in AT2 knockout mice is at least partly due to an increased vascular AT1 receptor expression and suggested that AT2 counteracts AT1-mediated vascular action of Ang II through downregulation of AT1 receptor by a crosstalk between these receptors by some as yet unknown mechanisms. (C) 1999 Academic Press.

关键词：醛固酮/血液血管紧张素ⅰ/代谢血管紧张素Ⅱ/遗传学血管紧张素Ⅱ/代谢血管紧张素Ⅱ/药理学主动脉/药物作用主动脉/生理学碱基序列结合竞争性 DNA引物小鼠近交C57BL 小鼠基因敲除肌收缩/药物作用蛋白质结合受体血管紧张素/代谢逆转录聚合酶链反应动物男(雄)性小鼠

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Structural comparison between type I and type II antagonists: Possible implications in the drug design of AT1 antagonists

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第8期10卷 755-758页

作者： Roumelioti, P Tselios, T Alexopoulos, K Mavromoustakos, T Kolocouris, A Moore, GJ Matsoukas, JM Natl Hellen Res Fdn Inst Organ & Pharmaceut Chem Athens 11635 Greece Univ Patras Dept Chem Patras 26500 Greece Univ Calgary Dept Pharmacol & Therapeut Calgary AB T2N 4N1 Canada

Analogues of sarilesin (type I AT1 antagonists), and sarmesin (type II AT1 antagonists) with homoserine (hSer) at position 8 were prepared and bioassayed. The presence of a Tyr(4)-Ile(5)-His(6) bend found in sarmesin but not in sarilesin was identified. The obtained results coupled with conformational analysis studies, using a combination of NMR spectroscopy and computational chemistry, propose important conformational and stereoelectronic properties for agonist and antagonist activity at ATI receptors. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：血管紧张素ⅰ/代谢血管紧张素Ⅱ/类似物和衍生物血管紧张素Ⅱ/化学合成血管紧张素Ⅱ/化学血管紧张素Ⅱ/代谢血管紧张素Ⅱ/药理学血管紧张素受体拮抗剂药物设计磁共振波谱学模型分子受体血管紧张素/代谢构效关系子宫/药物作用动物女(雌)性大鼠

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In vivo assessment of captopril selectivity of angiotensin I-converting enzyme inhibition: Differential inhibition of acetyl-Ser-Asp-Lys-Pro and angiotensin I hydrolysis

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期289卷 1257-1261页

作者： Junot, C Menard, J Gonzales, MF Michaud, A Corvol, P Ezan, E CEA Serv Pharmacol & Immunol F-91191 Gif Sur Yvette France INSERM U367 Paris France Coll France INSERM U36 F-75231 Paris France

Angiotensin I-converting enzyme (ACE) is a zinc metallopeptidase that plays a major role in blood pressure regulation. The demonstration that the hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a natural and specific substrate of the N-active site of ACE suggests that this enzyme may have a new physiological role such as the modulation of hematopoietic stem cells, In vitro studies have shown that ACE inhibitors displayed various potencies in inhibiting the degradation of different natural or synthetic substrates of ACE, among which captopril inhibits AcSDKP hydrolysis more potently than angiotensin I hydrolysis. To look for this selectivity in vivo, we investigated the pharmacodynamic effect of increasing doses of captopril (0.01-10 mg/kg) during the 90 min after i.v. administration to spontaneously hypertensive rats. Plasma and urinary AcSDKP levels were measured, The renin-angiotensin system was evaluated by measurements of ACE activity in plasma samples, using the synthetic substrate Hip-His-Leu, by determinations of plasma renin concentrations and measurements of arterial blood pressure. The results showed that captopril (0.01-0.3 mg/kg) selectively inhibited AcSDKP hydrolysis, with limited effects on the renin-angiotensin system. AcSDKP levels in plasma and urine rose to a plateau 4 times the basal level for doses more than 0.3 mg/kg, All of the parameters reflecting the renin-angiotensin system were significantly affected at doses of 1 and 10 mg/kg. The present study therefore confirms that captopril can be used to protect hematopoietic stem cells during antitumor chemotherapy while having only a limited effect on cardiovascular homeostasis.

关键词：血管紧张素ⅰ/代谢血管紧张素转换酶抑制药/药理学卡托普利/投药和剂量卡托普利/药理学水解作用注射静脉内动力学寡肽类/药代动力学肽基二肽酶A/血液大鼠近交SHR 肾素/血液底物特异性时间因素动物男(雄)性大鼠

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RENIN-ANGIOTENSIN SYSTEM IN AQUEOUS-HUMOR OF RABBITS, DOGS AND MONKEYS

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EXPERIMENTAL EYE RESEARCH 1978年第6期27卷 723-725页

作者： IKEMOTO, F YAMAMOTO, K Department of Pharmacology Osaka City University Medical School 1-4-54 Asahicho Abeno Osaka 545 Japan

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