Abstract
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. 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.
Highlights
Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid by epoxygenase enzymes
Epoxyeicosatrienoic acids have cardiovascular actions that implicate them as important contributors to vascular function and blood pressure control (Zeldin, 2001; Spector et al, 2004; Imig, 2005; Figure 7 | NUDSA decreases blood pressure in blood pressure in spontaneously hypertensive rats (SHR)
We generated a series of 11,12-EET analogs and determined their vascular actions in vitro and subsequently tested a subset of this series for their ability to lower blood pressure in hypertension when administered chronically
Summary
Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid by epoxygenase enzymes. These EETs have biological actions that suggest that EETs would be beneficial in combating cardiovascular diseases (Zeldin, 2001; Spector et al, 2004; Imig, 2005; Fleming, 2007). EETs have been demonstrated to preserve organ function when added to a transplantation preservation solution (Yang et al, 2003). Myocardial infarct size following ischemia reperfusion is decreased by the presence of EETs in the reperfusion solution (Seubert et al, 2007; Gross et al, 2008). Given the cardiovascular actions attributed to EETs it has been postulated that modulation of EETs in cardiovascular diseases has potential therapeutic value
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