esculetin and Hypertension

The arachidonic cascade involves three types of metabolic pathways; cyclo-oxygenase, lipoxygenase(LO), and cytochrome P450. The products of LO pathway participate in the pathogenesis of variety of disease such as allergic diseases and hypertension. In particular, 12-hydroxyeicosatetraenoic acid(12-HETE); product of 12-LO pathway, is concerned in the development of hypertension induced by angiotensin-II. In fact, several investigators have reported that 12-HETE has a critical role in hypertension and LO inhibitors have antihypertensive effects in experimental animals. And so, we can expect organ-protective effects of LO inhibitors as well as antihypertensive effects. Besides 12-LO, several investigators mentioned that 5- and 15-LO also have influences to cardiovascular systems. Therefore, we can expect further elucidation of the mechanism of 12-LO's participation in the organ damage and the clinical roles of 12-LO inhibitors to prevent from organ failure in future.

Topics: Animals; Cardiovascular Agents; Hypertension; Lipoxygenase; Lipoxygenase Inhibitors; Umbelliferones

Esculetin (6, 7- dihydroxycoumarin) was found to be protective against hepatic and renal damage associated with Streptozotocin (STZ) induced type 1 diabetes, because of its radical scavenging property. However, there are no reports regarding its effect on vascular dysfunction under hyperinsulinemic and hyperglycemic conditions. Hence, the present study aimed to investigate the effect of esculetin on vascular dysfunction under these conditions. Non-genetic model of hyperinsulinemia and hyperglycemia were developed by high fat diet (HFD) feeding and HFD + Streptozotocin (STZ, 35 mg/kg, I.P) treatment in Wistar rats, respectively. Esculetin was administered at 50 and 100 mg/kg/day (P.O, 2 weeks) doses and biochemical, vascular reactivity and immunohistochemical experiments were performed to assess the effect of esculetin on vascular dysfunctions. Esculetin treatment significantly attenuates metabolic perturbations, alleviates insulin levels in hyperinsulinemic condition. Thoracic aorta of hyperinsulinemic and hyperglycemic rats showed hyper-responsiveness to Ang II mediated contraction and impaired acetylcholine mediated relaxation, and esculetin attenuates alterations in vascular reactivity to Ang II and acetylcholine challenges. In addition, immunohistochemical evaluations revealed that esculetin prevents increase in AT1R, AT2R, Keap1, TGF-β, and decrease in ACE2 expression in aorta of hyperinsulinemic and hyperglycemic rats.

Topics: Acetylcholine; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Antioxidants; Aorta; Blood Pressure; Diabetes Mellitus, Experimental; Hyperglycemia; Hyperinsulinism; Hypertension; Male; Peptidyl-Dipeptidase A; Rats, Wistar; Transforming Growth Factor beta; Umbelliferones

Two currently available edible oils-olive and canola-and two oil blends of plant origin having different n-3/n-6 polyunsaturated fatty acid (PUFA) ratios were evaluated for their ability to modify vascular dysfunction in the spontaneously hypertensive rat (SHR). Synthetic diets supplemented with test oils (5% w/w) were fed for 12 weeks, and segments of thoracic aorta used to assess vascular function. Vessels from the SHR displayed a spontaneous constrictor response after the inhibition of endothelial cell nitric oxide (NO) with N(omega)-nitro-L-arginine (NOLA). Dietary alpha -linoleate enrichment led to a reduction (P<0.05) in this abnormality with a dietary n-3/n-6 PUFA ratio of 1.0 (blend-1) yielding the best outcome. Relaxation to acetylcholine (ACh) was unaffected by dietary lipid supplementation. NOLA treated rings also displayed contractions to ACh that were abolished by indomethacin, thromboxane antagonists SQ29548, picotamide and flavonoids kaempferol and quercetin. In contrast, alpha-tocopherol, rutin and the lipoxygenase inhibitor esculetin resulted in only partial (30-55%) inhibition, and were ineffective against the NOLA-induced contraction suggesting the operation of different biochemical mechanisms in mediating the spontaneous and Ach-induced contractions. Results implicate plant-based oils and antioxidants as potential modulators of vascular function.

Topics: Acetylcholine; alpha-Tocopherol; Animals; Antioxidants; Aorta; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Agents; Diet; Dose-Response Relationship, Drug; Endothelium, Vascular; Fatty Acids, Unsaturated; Flavonoids; Hydrazines; Hypertension; Indomethacin; Kaempferols; Lipid Metabolism; Nitric Oxide; Phthalic Acids; Plant Oils; Platelet Aggregation Inhibitors; Quercetin; Rats; Rats, Inbred SHR; Rutin; Umbelliferones