Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions
Epoxyeicosatrienoic acids (EETs) contribute importantly to the regulation of vascular tone and blood pressure control. The purpose of this study was to develop stable EET analogs and test their in vivo blood pressure lowering effects in hypertensive rats. Using the pharmacophoric moiety of EETs, eth...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2010-12-01
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| Series: | Frontiers in Physiology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphys.2010.00157/full |
| _version_ | 1818111306423599104 |
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| author | John D Imig Ahmed eElmarakby Kasem eNithipatikom Shouzou eWei Jorge H Capdevila Venugopal R Tuniki Bhavani eSangras Siddam eAnjaiah Vijaya L Manthati D. Sudarashan Reddy John R Falck |
| author_facet | John D Imig Ahmed eElmarakby Kasem eNithipatikom Shouzou eWei Jorge H Capdevila Venugopal R Tuniki Bhavani eSangras Siddam eAnjaiah Vijaya L Manthati D. Sudarashan Reddy John R Falck |
| author_sort | John D Imig |
| collection | DOAJ |
| description | Epoxyeicosatrienoic acids (EETs) contribute importantly to the regulation of vascular tone and blood pressure control. The purpose of this study was to develop stable EET analogs and test their in vivo blood pressure lowering effects in hypertensive rats. Using the pharmacophoric moiety of EETs, ether EET analogs were designed with improved solubility and resistance to auto-oxidation and metabolism by soluble epoxide hydrolase (sEH). Ether EET analogs were chosen based on their ability to dilate afferent arterioles and subsequently tested for blood pressure lowering effects in rodent models of hypertension. Initially, 11,12-ether-EET-8-ZE failed to lower blood pressure in angiotensin hypertension or spontaneously hypertensive rats (SHR). Esterification of the carboxylic group of 11,12–ether-EET-8-ZE prevented blood pressure increase in SHR when injected at 2 mg/day for 12 days (MAP Δ change at day 8 of injection was -0.3±2 for treated and 12± 1 mmHg for control SHR). Amidation of the carboxylic group with aspartic acid produced another EET analog (NUDSA) with a blood pressure lowering effect when injected at 3 mg/day in SHR for 5 days. Amidation of the carboxylic group with lysine amino acid produced another analog with minimal blood pressure lowering effect. These data suggest that esterification of the carboxylic group of 11,12–ether-EET-8-ZE produced the most effective ether-EET analog in lowering blood pressure in SHR and provide the first evidence to support the use of EET analogs in treatment of cardiovascular diseases. |
| first_indexed | 2024-12-11T03:00:57Z |
| format | Article |
| id | doaj.art-b3ad7da4ab0b4927ae4676009e3a8107 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-11T03:00:57Z |
| publishDate | 2010-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-b3ad7da4ab0b4927ae4676009e3a81072022-12-22T01:23:03ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2010-12-01110.3389/fphys.2010.001577260Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actionsJohn D Imig0Ahmed eElmarakby1Kasem eNithipatikom2Shouzou eWei3Jorge H Capdevila4Venugopal R Tuniki5Bhavani eSangras6Siddam eAnjaiah7Vijaya L Manthati8D. Sudarashan Reddy9John R Falck10Medical College of WisconsinMedical College of GeorgiaMedical College of WisconsinVanderbilt UniversityVanderbilt UniversityUniversity of Texas Southwestern Medical CenterUniversity of Texas Southwestern Medical CenterUniversity of Texas Southwestern Medical CenterUniversity of Texas Southwestern Medical CenterUniversity of Texas Southwestern Medical CenterUniversity of Texas Southwestern Medical CenterEpoxyeicosatrienoic acids (EETs) contribute importantly to the regulation of vascular tone and blood pressure control. The purpose of this study was to develop stable EET analogs and test their in vivo blood pressure lowering effects in hypertensive rats. Using the pharmacophoric moiety of EETs, ether EET analogs were designed with improved solubility and resistance to auto-oxidation and metabolism by soluble epoxide hydrolase (sEH). Ether EET analogs were chosen based on their ability to dilate afferent arterioles and subsequently tested for blood pressure lowering effects in rodent models of hypertension. Initially, 11,12-ether-EET-8-ZE failed to lower blood pressure in angiotensin hypertension or spontaneously hypertensive rats (SHR). Esterification of the carboxylic group of 11,12–ether-EET-8-ZE prevented blood pressure increase in SHR when injected at 2 mg/day for 12 days (MAP Δ change at day 8 of injection was -0.3±2 for treated and 12± 1 mmHg for control SHR). Amidation of the carboxylic group with aspartic acid produced another EET analog (NUDSA) with a blood pressure lowering effect when injected at 3 mg/day in SHR for 5 days. Amidation of the carboxylic group with lysine amino acid produced another analog with minimal blood pressure lowering effect. These data suggest that esterification of the carboxylic group of 11,12–ether-EET-8-ZE produced the most effective ether-EET analog in lowering blood pressure in SHR and provide the first evidence to support the use of EET analogs in treatment of cardiovascular diseases.http://journal.frontiersin.org/Journal/10.3389/fphys.2010.00157/fullBlood PressureHypertensionVasodilationafferent arterioleepoxyeicosanoids |
| spellingShingle | John D Imig Ahmed eElmarakby Kasem eNithipatikom Shouzou eWei Jorge H Capdevila Venugopal R Tuniki Bhavani eSangras Siddam eAnjaiah Vijaya L Manthati D. Sudarashan Reddy John R Falck Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions Frontiers in Physiology Blood Pressure Hypertension Vasodilation afferent arteriole epoxyeicosanoids |
| title | Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions |
| title_full | Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions |
| title_fullStr | Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions |
| title_full_unstemmed | Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions |
| title_short | Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions |
| title_sort | development of epoxyeicosatrienoic acid analogs with in vivo anti hypertensive actions |
| topic | Blood Pressure Hypertension Vasodilation afferent arteriole epoxyeicosanoids |
| url | http://journal.frontiersin.org/Journal/10.3389/fphys.2010.00157/full |
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