15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Obesity

Determining how obesity affects function in human myometrial arteries, to help understand why childbirth has poor outcomes in obese women.. Myometrial arteries were studied from 84 biopsies. Contraction (vasopressin and U-46619) and relaxation (carbachol, bradykinin, SNAP) was assessed using wire myography. eNOS activity was assessed using L-NAME. Cholesterol was reduced using methyl-β-cyclodextrin to determine whether it altered responses. Differences in endothelial cell intracellular Ca. The effects of BMI on relaxation were agonist specific and very marked; all vessels, irrespective of BMI, relaxed to bradykinin but 0% of vessels (0/13) from obese women relaxed to carbachol, compared to 59% (10/17) from normal weight women. Cholesterol-lowering drugs did not restore carbachol responses (n = 6). All vessels, irrespective of BMI, relaxed when NO was directly released by SNAP (n = 19). Inhibition of eNOS with L-NAME had a significant effect in normal but not overweight/obese vessels. Compared to bradykinin, a lower proportion of endothelial cells responded to carbachol and the amplitude of the calcium response was significantly less, in all vessels. Furthermore, a significantly lower proportion of endothelial cells responded to carbachol in the overweight/obese group compared to control. In contrast to relaxation, the effect of contractile agonists was unchanged with increasing BMI.. The ability of human myometrial arteries to relax is significantly impaired with obesity, and our data suggest this is due to a deficit in endothelial calcium signalling. This inability to recover following compression during contractions, might contribute to poor labours in obese women.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Arginine Vasopressin; Arteries; beta-Cyclodextrins; Bradykinin; Calcium Signaling; Carbachol; Endothelial Cells; Female; Humans; Myometrium; NG-Nitroarginine Methyl Ester; Obesity; Obstetric Labor Complications; Pregnancy; S-Nitroso-N-Acetylpenicillamine; Uterine Contraction

We investigated the potential effects of monosodium glutamate (MSG)-induced obesity with regards to nitric oxide and prostanoid production, as well as potassium channel function, in rat thoracic arteries. Newborn male Wistar rats were injected intraperitoneally with typically reported MSG (4.0 mg/g) once daily for 4 consecutive days. At 90 days postnatal, the rats were sacrificed and the thoracic aortas were evaluated for vascular responses and for prostanoid production. Nitric oxide was studied with calcium ionophore (A23187), acetylcholine (ACh) and sodium nitroprusside (SNP). The release of prostanoids was measured under basal and ACh-stimulated conditions, and the vasomotor effect of exogenous thromboxane A

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Aorta, Thoracic; Down-Regulation; Food Additives; Injections, Intraperitoneal; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Obesity; Potassium Channels; Prostaglandins; Rats; Rats, Wistar; Sodium Glutamate; Thoracic Arteries; Thromboxane A2; Vasoconstrictor Agents

To characterise Chorionic Plate Artery (CPA) function in maternal obesity, and investigate whether leptin exposure reproduces the obese CPA phenotype in normal-BMI women.. CPA responses to the thromboxane-A(2) mimetic U46619 (pre/post leptin incubation), to the nitric oxide donor sodium nitroprusside (SNP) and the occurrence of tone oscillations (pre/post leptin incubation) were assessed in 46 term placentas from women of normal (18.5-24.9) or obese (>30) Body Mass Index (BMI).. Area Under the dose response Curve (AUC), maximum response (V(max)), sensitivity (EC(50)) to U46619 (pre/post leptin) and SNP; average vessel tone, oscillation amplitude and frequency (pre/post leptin).. U46619 vasoconstriction was similar between BMI categories (p > 0.05), however vasodilatation to SNP was reduced in obesity (AUC p = 0.02, V(max)p = 0.04) compared to normal-BMI women. Leptin incubation altered responses to U46619 in both normal-BMI (EC(50) at 100 ng/ml leptin; p < 0.05) and obese women (AUC at 50 ng/ml; p < 0.05) but vasomotion was unaffected (p > 0.05).. Maternal obesity is associated with altered placental vascular function which may adversely affect placental oxygen and nutrient transport, placing the fetus at risk. Leptin incubation altered CPA vascular function but did not reproduce the obese phenotype.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adolescent; Adult; Arteries; Body Mass Index; Chorion; Dose-Response Relationship, Drug; Female; Gestational Age; Humans; Leptin; Nitroprusside; Obesity; Placenta; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Vasoconstrictor Agents; Vasodilator Agents; Young Adult

The metabolic syndrome is associated with elevated peripheral vascular disease risk, characterized by mismatched blood flow delivery/distribution and local metabolism. The obese Zucker rat (OZR) model of the metabolic syndrome exhibits myriad vascular impairments, although their integrated impact on functional hyperaemia remains unclear. In this study, arterial pressor responses and skeletal muscle perfusion were assessed in lean Zucker rats (LZRs) and OZRs during adrenergic stimulation (phenylephrine), challenge with thromboxane (U46619) and endothelium-dependent dilatation (methacholine). The OZRs were hypertensive compared with the LZRs, but this was abolished by adrenoreceptor blockade (phentolamine); pressor responses to U46619 were similar between strains and were abolished by blockade with the prostaglandin H(2)/thromboxane A(2) receptor antagonist, SQ-29548. Depressor reactivity to methacholine was impaired in OZRs, but was improved by antioxidant treatment (TEMPOL). Across levels of metabolic demand, blood flow to in situ gastrocnemius muscle was restrained by adrenergic constriction in OZRs, although this diminished with increased demand. Oxygen extraction, reduced in OZRs compared with LZRs across levels of metabolic demand, was improved by TEMPOL or SQ-29548; treatment with phentolamine did not impact extraction, and neither TEMPOL nor SQ-29548 improved muscle blood flow in OZRs. While oxygen uptake and muscle performance were consistently reduced in OZRs versus LZRs, treatment with all three agents improved outcomes, while treatment with individual agents was less effective. These results suggest that contributions of vascular dysfunction to perfusion, oxygen uptake and muscle performance are spatially distinct, with adrenergic constriction impacting proximal resistance and endothelial dysfunction impacting distal microvessel-tissue exchange. Further, these data suggest that increasing skeletal muscle blood flow in OZRs is not sufficient to improve performance, unless distal perfusion inhomogeneities are rectified.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antioxidants; Arteries; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hyperemia; Hypertension; In Vitro Techniques; Male; Metabolic Syndrome; Methacholine Chloride; Muscle Fatigue; Muscle, Skeletal; Obesity; Oxygen; Perfusion; Peripheral Vascular Diseases; Phenylephrine; Rats; Rats, Zucker; Vasoconstriction

In non-obese diabetic animals, protease-activated receptor-2 (PAR2) agonists are more effective vasodilators, which is attributed to increased COX-2 and endothelial NOS (eNOS) activities. Under conditions of diabetes and obesity, the effectiveness of PAR2 agonists is unknown. We compared the vasodilator responses of small calibre mesenteric arteries from obese diabetic B6.BKS(D)-Lepr(db) /J (db/db) induced by PAR2-activating agonists 2-furoyl-LIGRLO-amide (2fly) and trypsin to those obtained in controls [C57BL/6J (C57)], and assessed the contributions of COX, NOS and calcium-activated potassium channels (K(Ca)) to these responses.. Arteries mounted in wire myographs under isometric tension conditions were contracted submaximally by U46619 then exposed to vasodilators. mRNA and protein expression of PAR2, eNOS and soluble GC (sGC) were determined by real-time PCR and Western blots.. ACh- and nitroprusside-induced relaxations were attenuated in db/db compared with C57. In contrast, 2fly- and trypsin-induced relaxations were largely retained in db/db. A NOS inhibitor partly inhibited ACh- and 2fly-induced relaxations in C57, but not those in db/db. Inhibitors of the COX-cAMP pathway (FR122044, SC560, NS398, SC58125, SQ22536, CAY10441) did not affect these relaxation responses in either strain. Charybdotoxin (BK(Ca), SK3.1 blocker), but not iberiotoxin (BK(Ca) blocker), inhibited responses to the PAR2 agonists in db/db. In db/db protein levels of eNOS were higher, whereas those of sGC were lower than in C57. PAR2 mRNA expression in db/db was higher than in C57.. PAR2-mediated vasodilatation is protected against the negative effects of obesity and diabetes in mice. In diabetic vascular dysfunction, preserved PAR2 vasodilatation was linked to activation of SK3.1.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholinesterase; Alcohol Oxidoreductases; Animals; Arteries; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Endothelium, Vascular; Gene Expression Regulation, Enzymologic; Glucose; Glycosuria; Male; Mice; Mice, Inbred C57BL; Nitroprusside; Obesity; Oligopeptides; Phenylephrine; Potassium; Receptor, PAR-2; Receptors, Leptin; RNA, Messenger; Vasodilation

Obesity, insulin resistance, dyslipidemia, and hypertension are components of the pathophysiological state known as metabolic syndrome. Adrenergic vasoconstriction is mediated through increases in cytosolic Ca2+ and the myofilaments' sensitivity to Ca2+. In many pathophysiological states, there is an enhanced role for Rho kinase (ROK)-mediated increases in Ca2+ sensitivity of the contractile apparatus. Thus we hypothesized that there is a greater role for ROK-mediated increases in Ca2+ sensitivity in alpha1-adrenergic vasoconstriction in arteries from obese Zucker (OZ) rats. Therefore, small gracilis muscle arteries from 11- to 12-wk-old and 16- to 18-wk-old lean and OZ rats were isolated, cannulated, and pressurized to 75 mmHg. For some experiments, vessels were loaded with fura 2-AM. Changes in luminal diameter and vessel wall Ca2+ concentration ([Ca2+]) were measured in response to phenylephrine (PE), the thromboxane mimetic U-46619, and KCl. alpha1-Adrenergic vasoconstriction was similar between 11- to 12-wk-old lean and obese animals and greater in older obese animals compared with controls. PE-induced increases in vascular smooth muscle cell [Ca2+] were blunted in OZ animals compared with lean controls in both age groups of animals. KCl and U-46619 elicited similar vasoconstriction and vascular smooth muscle cell [Ca2+] in both groups. ROK inhibition attenuated PE vasoconstriction to a greater degree in arteries from 11- to 12-wk-old OZ rats compared with lean animals; ROK inhibition in arteries from older rats right shifted both concentration-response curves to the same point. Total RhoA and ROKalpha protein expressions were similar between groups. These results suggest an enhanced role for the ROK pathway in alpha1-adrenergic vasoconstriction in metabolic syndrome.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenergic Agents; Aging; Amides; Animals; Arteries; Calcium Signaling; Gene Expression Regulation; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Male; Muscle, Skeletal; Muscle, Smooth, Vascular; Obesity; Phenylephrine; Potassium Chloride; Protein Serine-Threonine Kinases; Pyridines; Rats; Rats, Zucker; rho-Associated Kinases; rhoA GTP-Binding Protein; Thinness; Vasoconstriction