Mesenteric Bed Research Articles

Theory and practice on mesentery margin in vessel-oriented complete mesentery resection of gastric cancer

The concept of mesenteric anatomy has been evolving in cognition. With the continuous development of endoscopic techniques, the submicroscopic structures of many mesenteries have been gradually understood, ultimately confirming the ubiquitous presence of mesenteries in the digestive organs. Based on various domestic and foreign mesenteric anatomical theories and combined with years of clinical practice, we have summarized and proposed a new concept and theory-vascular-guided complete mesenteric resection for gastric cancer. The theoretical basis is that, from the perspective of the embryonic development of the digestive tract, the rotation of the digestive tract and its associated mesentery is always centered on blood vessels. Therefore, the supply vessels and digestive tracts and their associated mesentery are naturally connected. The mesentery is a complex structure that encompasses blood vessels, nerves, and lymphatic tissues. The blood vessels serve as the boundary of the mesentery, ensuring that the lymphatic network that drains the tumor is maximally resected. This article focuses on the complete mesenteric resection margins in gastric cancer surgery, that is, the lateral boundary of the mesentery as the vascular-supplied guided resection boundary and its mesentery, and the base boundary as the mesenteric bed. Using precise vascular guidance to define the extent of mesenteric resection will help accurately define the mesenteric margin during radical resection for different stages of gastric cancer.

Forgotten Circulation: Reduced Mesenteric Venous Capacitance in Hypertensive Rats Is Improved by Decreasing Sympathetic Activity.

The mesenteric venous reservoir plays a vital role in mediating blood volume and pressure changes and is richly innervated by sympathetic nerves; however, the precise nature of venous sympathetic regulation and its role during hypertension remains unclear. We hypothesized that sympathetic drive to mesenteric veins in spontaneously hypertensive (SH) rats is raised, increasing mean circulatory filling pressure (MCFP), and impairing mesenteric capacitance. Arterial pressure, central venous pressure, mesenteric arterial, and venous blood flow were measured simultaneously in conscious male Wistar and SH rats. MCFP was assessed using an intraatrial balloon. Hemodynamic responses to volume changes (±20%) were measured before and after ganglionic blockade and carotid body denervation. Sympathetic venoconstrictor activity was measured in situ. MCFP in vivo (10.8±1.6 versus 8.0±2.1 mm Hg; P=0.0005) and sympathetic venoconstrictor drive in situ (18±1 versus 10±2 µV; P<0.0001) were higher in SH rats; MCFP decreased in SH rats after hexamethonium and carotid body denervation (7.6±1.4; P<0.0001 and 8.5±1.0 mm Hg; P=0.0045). During volume changes, arterial pressure remained stable. With blood loss, net efflux of blood from the mesenteric bed was measured in both strains. However, during volume infusion, we observed net influx in Wistar (+2.3±2.6 mL/min) but efflux in SH rats (-1.0±1.0 mL/min; P=0.0032); this counterintuitive efflux was abolished by hexamethonium and carotid body denervation (+0.3±1.7 and 0.5±1.6 mL/min, respectively). In SH rats, excessive sympathetic venoconstriction elevates MCFP and reduces capacitance, impairing volume buffering by mesenteric veins. We propose selective targeting of mesenteric veins through sympathetic drive reduction as a novel therapeutic opportunity for hypertension.

Membrane anatomy in right colon cancer: definition and identification of mesocolic completeness

Complete mesocolic excision (CME) and D3 resection of right colon cancer have been widely implemented, but the definition and identification of the completeness of the mesentery have not been fully agreed, especially the dorsal and medial borders. In this paper, we proposed the dorsal fascia of the colonic mesentery as the dorsal border of the mesocolon and the line connecting the roots of the ileocolic artery and the middle colic artery (ICA-MCA line) as the medial border of the CME by systematically studying the relationship between the mesentery and the mesenteric bed from the theory of membrane anatomy, combined with surgical experience and in-depth review of ontogenetic anatomy. We also proposed the visible "superior mesenteric vein notch" and "middle colic artery triangle" on surgical specimens as identifiers of mesocolic completeness.

Rutin ameliorates nitrergic and endothelial dysfunction on vessels and corpora cavernosa of diabetic animals

Endothelial dysfunction is an early complication of diabetes and it is related to both micro- and macroangiopathies. In addition, >70% of diabetic patients develop autonomic neuropathies. Increased oxidative stress has a major role in the development of both nitrergic and endothelial dysfunction. The aim of this work is to evaluate whether rutin, a potent antioxidant, could ameliorate nitrergic and/or endothelial dysfunction in diabetic animals. Primary and secondary treatment protocols with rutin were investigated on rat aortic rings and the mesenteric arteriolar bed, and on rabbit aortic rings and corpora cavernosa (RbCC) from both euglycemic and alloxan-diabetic animals. Acetylcholine endothelium-dependent and sodium nitroprusside endothelium-independent relaxations were compared in tissues from euglycemic or diabetic animals. Electrical field stimulation (EFS)-induced relaxation was performed only in the RbCC. Endothelial-dependent relaxations were blunted by 40% in vessels and neuronal relaxation was blunted by 50% in RbCC taken from diabetic animals when compared to euglycemic animals. Pre-treatment with rutin restored both neuronal and endothelial dependent relaxations in diabetic animals towards the values achieved in control euglycemic tissues. Rutin was able to ameliorate both endothelial dysfunction and nitrergic neuropathy in animal experimental models. Rutin could be a lead compound in the primary or secondary preventive ancillary treatment of endothelial and nitrergic dysfunction in the course of diabetes.

The “forgotten circulation”: Sympathetic control of mesenteric venous capacity in conscious hypertensive rats

The venous circulation is often “forgotten,” as cardiovascular research and therapeutic intervention focusses predominantly on arteries. However, systemic veins store two-thirds of blood volume at rest, with reservoir beds such as the mesenteric circulation receiving dense sympathetic innervation, suggesting a critical neurogenic role for the mobilization of blood. The impact of hypertension on sympathetic regulation of venous circulation remains unclear. We hypothesized that capacity of mesenteric vasculature is impaired in spontaneously hypertensive rats (SHR) and that reducing sympathetic drive will increase mesenteric buffering of excess volume.SHR (n=6) and Wistar rats (n=7) were instrumented with telemeters recording arterial and venous pressures, and an atrial balloon for assessment of mean circulatory filling pressure (MCFP). Arterial (inflow) and venous (outflow) mesenteric flow probes were implanted to measure total mesenteric volume fluctuation. Mesenteric vascular capacity was challenged with 20% volume load of intravenous saline. In SHR sympathetic drive was reduced via hexamethonium (10mg/kg) or via carotid body denervation (CBD).MCFP was elevated in SHR (+2.7±0.5mmHg, p&lt;0.01 vs Wistars). MCFP in SHR was reduced by hexamethonium (-2.6±0.6; p=0.01 vs Baseline, n=5) and CBD (‑2.0±0.7mmHg; p=0.04 vs Baseline, n=5). In normotensives volume load was accommodated by the mesenteric bed, with a net total influx of blood (+5.4±2.2ml; n=7). In contrast, SHR showed a counter-intuitive net efflux of blood from the mesenteric bed (-1.6±1.4ml; p=0.04 vs Wistars, n=6). Preliminary results indicate that hexamethonium and CBD tended to increase the ability of the mesenteric bed to accommodate volume (hexamethonium: +1.9±1.5, n=6; CBD: +0.8±0.6ml, n=3).We show that SHR have higher venous tone and reduced capacity to accommodate excess volume within the mesenteric vascular bed. Reductions in sympathetic drive reduced venous tone and improved the ability to accommodate volume load. Inhibiting sympathetic activity may provide a novel therapeutic opportunity to restore venous mesenteric capacity and potentially ameliorate hypertension. Marsden Fund, Royal Society of New Zealand; Health Research Council of New Zealand This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Nanomolar clodronate induces adenosine accumulation in the perfused rat mesenteric bed and mesentery-derived endothelial cells.

The vesicular nucleotide transporter (VNUT) is critical for sympathetic co-transmission and purinergic transmission maintenance. To examine this proposal, we assessed whether the bisphosphonate clodronate, claimed as a potent in vitro VNUT blocker, modified spontaneous and/or the electrically evoked overflow of ATP/metabolites and NA from mesentery sympathetic perivascular nerve terminals. Additionally, in primary endothelial cell cultures derived from this tissue, we also evaluated whether clodronate interfered with ATP/metabolite cell outflow and metabolism of N6-etheno adenosine 5'-triphosphate (eATP), N6-etheno adenosine (eADO), and adenosine deaminase enzyme activity. Rat mesenteries were perfused in the absence or presence of .01-1,000nM clodronate, 1-1,000nM Evans blue (EB), and 1-10µM DIDS; tissue perfusates were collected to determine ATP/metabolites and NA before, during, and after perivascular electrical nerve terminal depolarization. An amount of 1-1,000nM clodronate did not modify the time course of ATP or NA overflow elicited by nerve terminal depolarization, and only 10nM clodronate significantly augmented perfusate adenosine. Electrical nerve terminal stimulation increased tissue perfusion pressure that was significantly reduced only by 10nM clodronate [90.0 ± 18.6 (n = 8) to 35.0 ± 10.4 (n = 7), p = .0277]. As controls, EB, DIDS, or reserpine treatment reduced the overflow of ATP/metabolites and NA in a concentration-dependent manner elicited by nerve terminal depolarization. Moreover, mechanical stimulation of primary endothelial cell cultures from the rat mesentery added with 10 or 100nM clodronate increased adenosine in the cell media. eATP was metabolized by endothelial cells to the same extent with and without 1-1,000nM clodronate, suggesting the bisphosphonate did not interfere with nucleotide ectoenzyme metabolism. In contrast, extracellular eADO remained intact, indicating that this nucleoside is neither metabolized nor transported intracellularly. Furthermore, only 10nM clodronate inhibited (15.5%) adenosine metabolism to inosine in endothelial cells as well as in a commercial crude adenosine deaminase enzyme preparation (12.7%), and both effects proved the significance (p < .05). Altogether, present data allow inferring that clodronate inhibits adenosine deaminase activity in isolated endothelial cells as in a crude extract preparation, a finding that may account for adenosine accumulation following clodronate mesentery perfusion.

PS-B04-6: FIBROBLAST GROWTH FACTOR 21 - A POTENTIAL NEW TREATMENT FOR HYPERTENSION?

Objective: Perivascular adipose tissue (PVAT) is vital in regulation of vascular tone and blood pressure. PVAT function is lost in obesity, contributing to development of hypertension. Fibroblast growth factor-21 (FGF-21) is released by PVAT and has roles in body weight regulation and glucose homeostasis, however, there have been no studies on the direct effect of FGF-21 on vascular tone. Design and method: Wire myography was used to measure the contractility of C57BL/6J mouse second order mesenteric resistance arteries (250 μm) in response to electrical field stimulation (EFS) prior to and following incubation with the FGF-21 analogue PF-05231023 (100 μM) for 30 minutes. PVAT was collected from the entire mesenteric bed and incubated with or without PF-05231023 for 30 minutes before stimulating with EFS. The surrounding supernatant was collected and commercially available adipokine arrays were used to characterise the PVAT secretory profile. Results: PF-05231023 significantly reduced the vasoconstrictor response to EFS in both PVAT intact and PVAT denuded vessels. Using adipokine arrays, PF-05231023 significantly increased adiponectin and leptin secretion from PVAT, in addition to various pro- and anti-inflammatory adipokines. Conclusion: FGF-21 or its analogues could present a promising therapeutic tool to lower blood pressure in hypertension via both direct effects on the vasculature, and by promoting release of other vasodilatory adipokines.

Hydrogen sulfide donor GYY4137 attenuates vascular complications in mesenteric bed of streptozotocin-induced diabetic rats

Hydrogen sulfide (H2S) has been reported to have beneficial effects in different pathological conditions. Objectives: the effects of chronic treatment of diabetic rats with GYY4137 (slow releasing H2S donor) or NaHS (fast releasing H2S donor) on the reactivity of the mesenteric bed to vasoactive agonists and the changes in its downstream effectors, ERK1/2 and p38 MAP Kinase have been investigated. In addition, the levels of nitric oxide (NO) and H2S in all groups were measured. Methods: diabetes was induced by a single intraperitoneal (ip) injection of streptozotocin (STZ; 55 mg/kg). Sprague Dawley (SD; n = 10–12/group) rats were randomly divided into six groups: control, STZ-induced diabetic rats, GYY4137-treated control, NaHS-treated control, GYY4137-treated diabetic, and NaHS-treated diabetic. After 28 days of treatment, rats were sacrificed and mesenteric beds were isolated for functional or biochemical studies. The vascular reactivity of the perfused mesenteric bed to norepinephrine, carbachol and sodium nitroprusside were determined by measurement of changes in perfusion pressure. Western blotting was performed to measure the protein expression of ERK1/2, p38, eNOS, and H2S biosynthesizing enzymes cystathionine-β-synthase and cystathionine-γ-lyase. NO and H2S levels were measured in all groups in isolated mesenteric tissues or plasma. Results: diabetes resulted in a significant increase in vasoconstrictor responses to norepinephrine (e.g., 129.6 ± 6.77 mmHg in diabetic vs 89.3 ± 8.48 mmHg in control at 10−7 dose), and carbachol-induced vasodilation was significantly reduced in diabetic mesenteric bed (e.g., 68.9 ± 4.8 mmHg in diabetic vs 90.6 ± 2.2 mmHg in control at 10−7 dose). Chronic treatment of the diabetic rats with GYY4137 resulted in a significant improvement in the response to norepinephrine (e.g., 86.66 ± 8.04 mmHg in GYY4137-treated diabetic vs 129.6 ± 6.77 mmHg in untreated diabetic at 10−7 dose) or carbachol (e.g., 84.90 ± 2.48 mmHg in GYY4137-treated diabetic vs 68.9 ± 4.8 mmHg in untreated diabetic at 10−7 dose). The biochemical studies showed a marked reduction of the protein expression of ERK and p38 and a significant upregulation of the expression of eNOS and H2S synthesizing enzymes after chronic treatment with GYY4137. Plasma levels of NO and H2S were significantly elevated after treatment with GYY4137. However, H2S production in the mesenteric bed showed a marginal elevation in diabetic tissues compared to controls. Conclusion: the results indicate that GYY4137 may be a novel therapeutic tool to prevent diabetes-associated vascular dysfunction.

Retrospective Study of Outpatient Treatment of Acute Mesenteric Circulatory Disorders

Introduction. Acute violation of mesenteric blood circulation is one of the most severe urgent diseases of the abdominal cavity. The number of patients, and the mortality rate resulted from this pathology, is steadily increasing every year. The number of patients has only increased during the pandemic of new coronavirus infection COVID-19.The aim of study was to develop options to prevent severe outcomes of this pathology at the pre-hospital stage identifying patients with high risk of developing mesenteric thrombosis.Materials and methods. The study was a retrospective analytical study that included 279 (100%) patients and their outpatient records. All patients were diagnosed with acute mesenteric circulation disorder and treated at the hospital surgery clinic in Smolensk in 2013-2020. When conducting a thorough analysis of patients findings, special attention was paid to: past medical history, in particular, the presence of abdominal pain syndrome, features, localization and intensity of pain; the nature of labour activity during life; existing comorbidity; surgical interventions of the abdominal organs, objective examination findings, and laboratory and instrumental test findings. The data obtained were processed using methods of statistical analysis described in the book "Statistics in biology and medicine" by Medik V.A., Tokmachev M.S., Fishman B.B. (2001), and MS Excel 2019.Results. A retrospective analysis revealed that 63 (22.5%) patients had a burdened anamnesis of acute mesenteric circulatory disorders in close relatives. An increased number of "bad" lipoproteins of low and very low density was noted, this being an unfavorable factor in the development of atheromatous lesion of the mesenteric vascular bed followed by the manifestation of acute mesenteric circulatory disorders. The analysis revealed a group of patients with ischemic colitis that included 139 patients (49.1 %). The diagnosis was supported by fibrocolonoscopy. In addition, it was found that 4 0.7 years (from 3 to 4.5 years) passed from the onset of symptoms to hospitalization for acute mesenteric circulatory disorders in patients with abdominal symptoms.Conclusions. All patients with acute mesenteric circulatory disorders had manifested clinical signs of the disorder 3-4.5 years before it was diagnosed; this allowed suspecting violations along the mesenteric bed. Patients with a burdened anamnesis of the cardiovascular system (coronary heart disease-93.7%, arterial hypertension 86.1%, various forms of atrial fibrillation 83.4%) were mostly at risk. Identification of a risk group at the outpatient stage for potential occurrence of acute mesenteric circulatory disorders can help reduce incidence of this pathology.

Clinical Update on Vasopressors and Titration Strategies.

Clinical Update on Vasopressors and Titration Strategies.

Anthocyanins Activate Membrane Estrogen Receptors With Nanomolar Potencies to Elicit a Nongenomic Vascular Response Via NO Production.

BackgroundThe vascular pharmacodynamics of anthocyanins is only partially understood. To examine whether the anthocyanin‐induced vasorelaxation is related to membrane estrogen receptor activity, the role of ERα or GPER antagonism was ascertained on anthocyanins or 17‐β estradiol‐(E2) induced vasodilatations and NO production.Methods and ResultsThe rat arterial mesenteric bed was perfused with either anthocyanins or corresponding 3‐O‐glycosides, or E2, to examine rapid concentration‐dependent vasorelaxations. The luminally accessible fraction of NO in mesenteric perfusates before and after anthocyanins or E2 administration was quantified. Likewise, NO‐DAF signal detected NO production in primary endothelial cells cultures incubated with anthocyanins or E2 in the absence and presence of ERα (ICI 182,780) or GPER (G‐36) selective antagonists. Anthocyanins or corresponding glycosides elicited, within minutes, vasodilation with nanomolar potencies; half maximal anthocyanin response reached 50% to 60% efficacy, in contrast to acetylcholine. The vasorelaxation is of rapid onset and exclusively endothelium‐dependent; NOS inhibition annulled the vasorelaxation. The delphinidin vascular response was not modified by 100 nmol/L atropine but significantly attenuated by joint application of ICI plus G‐36 (52±4.6 versus 8.5±1.5%), revealing the role of membrane estrogen receptors. Moreover, the anthocyanin or E2‐induced NO production was antagonized up to 70% by these antagonists. NO‐DAF signal elicited by anthocyanins was annulled by NOS inhibition or by ICI plus G‐36 addition.ConclusionsThe biomedical effect of anthocyanins or 3‐O‐glycosylates derivatives contained in naturally purple‐colored foods or berries is due to increased NO production, and not to the phytochemical's antioxidant potential, highlighting the nutraceutical role of natural products in cardiovascular diseases.

I nverse Relationship Between Vascular Size and Stiffness in the Presence and Absence of Diabetes

Vascular stiffness is increasingly garnering more interest in part as a result of data over the recent past demonstrating that macrovascular stiffness is associated with increased cardiovascular disease and mortality. Our past data has demonstrated vascular bed-specific differences in stiffness among the diabetic aorta, mesenteric, and coronary beds. Recent pilot data from our laboratory suggested that macrovessels appeared to have reduced stiffness when compared to microvessels from the same animal; however, there is a paucity of data in the literature to support this notion in a well-controlled study. The current study sought to test the hypothesis that macrovessels are less stiff compared to microvessels under normal and diabetic conditions. Large mesenteric arteries (1°/2° branches; average internal diameters: ~325-380 µm), small mesenteric arteries (3°/4° branches; average internal diameters: ~200-208 µm), and small mesenteric microvessels (5°/6° branches; average internal diameters: ~121-132 µm) were dissected from the same 16 week-old normal Db/db and type 2 diabetic db/db mice and mounted on a pressure myograph for passive structural and biomechanical measurements. In normal mice, incremental elastic modulus (Einc between 75-125 mmHg), a measure of vascular stiffness, of large arteries averaged 3.29x105 ± 1.00x105 dyn/cm2, which was significantly lower than small artery (7.47x106 ± 0.72x106 dyn/cm2, p<0.01) and microvessel Einc (9.95x106 ± 1.68x106 dyn/cm2, p<0.001). Similarly in db/db mice, Einc of large arteries averaged 9.35x105 ± 3.95x105 dyn/cm2, which was significantly lower than small artery (7.80x106 ± 1.10x106 dyn/cm2, p<0.01) and microvessel Einc (9.21x106 ± 1.76x106 dyn/cm2, p<0.05). The clinically-relevant beta stiffness index followed a similar pattern in vessels isolated from both normal and diabetic mice. Pearson correlation analyses revealed significant inverse correlations between mesenteric internal diameter and Einc (Normal: r=-0.71, p<0.001; db/db: r=-0.63, p<0.05). A similar association was found between internal diameter and beta stiffness index (Normal: r=-0.74, p<0.001; db/db: r=-0.57, p<0.05). These data show that, in a well-controlled animal model and within the same vascular bed, as vessel size increases, stiffness decreases regardless of glycemic status. The reasons for this finding are currently unclear, but they could involve differences in the composition and biomechanics of the extracellular matrix, vascular cell stiffness, and/or linkage of the ECM and cell cytoskeleton through integrins.

Investigation of the vascular effects of short chain fatty acids in rat mesenteric resistance arteries

Fiber rich diets have been shown to prevent the onset and reduce severity of hypertension1, a condition affecting 20-30% of adults in North America. High fiber diets facilitate the production of short chain fatty acids (SCFAs) by gut bacteria of which, in humans, acetate is the most abundant, followed by propionate and butyrate. It has been proposed that these three SCFAs may have direct effects on blood vessels and so may contribute to regulation of blood pressure2. Further research is needed to determine the mechanisms underlying the vascular actions of SCFAs. We tested the hypothesis that SCFAs can induce vasodilation and limit nerve-evoked vasoconstriction in rat mesenteric vasculature. Direct effects on vascular tone were assessed by constructing cumulative concentration-response curves to SCFAs in isolated third order rat mesenteric arteries mounted in a wire myograph and pre-stimulated with phenylephrine (PE) to increase tone. The effects of SCFAs on nerve-evoked vasoconstriction were assessed by constructing frequency-responses curves to perivascular nerve stimulation in a perfused rat mesenteric bed in the presence and absence of SCFAs added to the perfusate. In both experimental approaches, pharmacological tools were used to investigate the mechanism of action of SCFAs. Propionate (3 μM - 1 mM) and acetate (0.3 μM - 1 mM) caused reductions in PE-evoked tone with maximum relaxation of 32.7 ± 7% and 31.6 ± 8.2%, respectively, and attenuated nerve-evoked vasoconstriction in mesenteric arteries at 10 mM - 60 mM propionate and 30 mM - 50 mM acetate. These effects were inhibited by blockers of nitric oxide (NO) synthase (L-NG-nitroarginine methyl ester, L-NAME, 100 μM) and endothelial Ca2+-activated K+ (KCa) channels (apamin, 50 nM; TRAM-34, 1 μM). L-NAME alone significantly inhibited relaxations elicited by acetate indicating a predominant role for NO, whereas the actions of propionate were significantly inhibited by apamin and TRAM-34, indicating a predominant role for endothelial KCa channels in this response. These data indicate that SCFAs may cause vasodilation in mesenteric resistance arteries via activation of endothelial pathways and that there may be a differential contribution of NO and KCa channels to responses of individual SCFAs. 1. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336(16):1117-1124. doi:10.1056/NEJM199704173361601 2. Pluznick J. A novel SCFA receptor, the microbiota, and blood pressure regulation. Gut Microbes. 2014;5(2):202-207. doi:10.4161/gmic.27492

Losartan prevents mesenteric vascular bed alterations in high-fat diet fed rats

Dysfunction of perivascular adipose tissue of mesenteric bed participates in the pathophysiology of high blood pressure linked to metabolic syndrome. Thus, it might consider a new therapeutic objective to take account in cardiovascular and metabolic diseases. Besides its antihypertensive effect, there is a growing interest on the pleiotropic actions of losartan, an angiotensin II type 1 (AT1) receptor antagonist. The aim of the study was to analyze the actions of losartan treatment on adiposity index and prostanoids release from mesenteric vascular bed and its relationship with blood pressure as well as homeostasis model of assessment of insulin resistance (HOMA-IR) in Sprague-Dawley rats under a high-fat (HF) diet for 8 weeks. Four groups were used: control (C), HF diet (HF, 50%, w/w bovine fat), losartan-treated (CL8, 30mg/kg/body weight/day in the drinking water) and losartan-treated HF diet (HFL, both treatments). A high-fat diet incremented systolic blood pressure, HOMA-IR, adiposity of mesenteric vascular bed and the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 and prostaglandin (PG) F2α as well as PGE2, an inflammatory prostanoid in a context of insulin resistance and hypertension. We found a positive correlation between adiposity index and systolic blood pressure. Also, both parameters are positive correlated with the HOMA IR index. Moreover, we also found that these prostanoids release correlate with systolic blood pressure as well as with mesenteric vascular bed adiposity index. Losartan treatment prevented all these alterations and normalized the PGI2/TXA2 ratio in high-fat fed rats. We conclude that losartan may play beneficial actions on perivascular adipose tissue alterations and endothelial dysfunction through restoration of normal balance of vasoactive substances in this model.

Losartan prevents mesenteric vascular bed alterations in high-fat diet fed rats

Dysfunction of perivascular adipose tissue of mesenteric bed participates in the pathophysiology of high blood pressure linked to metabolic syndrome. Thus, it might consider a new therapeutic objective to take account in cardiovascular and metabolic diseases. Besides its antihypertensive effect, there is a growing interest on the pleiotropic actions of losartan, an angiotensin II type 1 (AT1) receptor antagonist. The aim of the study was to analyze the actions of losartan treatment on adiposity index and prostanoids release from mesenteric vascular bed and its relationship with blood pressure as well as homeostasis model of assessment of insulin resistance (HOMA-IR) in Sprague-Dawley rats under a high-fat (HF) diet for 8 weeks. Four groups were used: control (C), HF diet (HF, 50%, w/w bovine fat), losartan-treated (CL8, 30mg/kg/body weight/day in the drinking water) and losartan-treated HF diet (HFL, both treatments). A high-fat diet incremented systolic blood pressure, HOMA-IR, adiposity of mesenteric vascular bed and the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 and prostaglandin (PG) F2α as well as PGE2, an inflammatory prostanoid in a context of insulin resistance and hypertension. We found a positive correlation between adiposity index and systolic blood pressure. Also, both parameters are positive correlated with the HOMA IR index. Moreover, we also found that these prostanoids release correlate with systolic blood pressure as well as with mesenteric vascular bed adiposity index. Losartan treatment prevented all these alterations and normalized the PGI2/TXA2 ratio in high-fat fed rats. We conclude that losartan may play beneficial actions on perivascular adipose tissue alterations and endothelial dysfunction through restoration of normal balance of vasoactive substances in this model.

Abstract P040: Pressure Natriuresis In Female Sprague Dawley Rats: Characteristics And Mechanisms

Raising blood pressure stimulates pressure natriuresis (P-Nat). In males (M) Sprague Dawley rats (SDR), Na + reabsorption (T Na ) is acutely reduced by retraction of proximal tubule (PT) NHE3 to microvillar base and NaPi2 internalization. In females (F), at baseline PT NHE3 is already at microvillar base and NaPi2 is less abundant than in M. We AIM to determine characteristics and mechanisms of P-Nat in F (vs M) rats. Methods: Inactin anesthetized F and M SDR (n=5/group) were provoked by vasoconstriction (or sham). Mean arterial pressure (MAP) was recorded via carotid artery, urine collected via bladder, Na + transporters’ abundance assessed via immunoblot and localization by immunohistochemistry. Results (Fig 1A): Baseline MAP (mmHg) was lower in F vs. M (91 ± 5 vs.105 ± 3, P =0.04) while urine volume (UV) and electrolyte excretion (UNaV, UKV) were similar. After celiac and mesenteric bed constriction, MAP rose to 128 ± 3 mmHg in both sexes; UNaV, UV and C Na increased 12 to 15-fold in F (all P &lt;0.01) vs 6-fold in M ( P &gt;0.08). Constriction of abdominal aorta further raised UNaV in F with less impact in M. Na + transporters . In F, NHE3 remained at PT microvillar base and NaPi2 was internalized with vasoconstriction. NHE3P (indicating inactivation) abundance increased 29% in F, P =0.058. Lithium clearance, measure of volume flow leaving early nephron, increased 9-fold in F ( P =0.02) vs. 5-fold in M ( P =0.07). F mTAL NHE3, NKCC2p, and SPAKp (co-transporter kinase) abundances were 22, 24, and 43% lower vs shams ( ANOVA P &lt;0.0001). Summary: F vs M SDR exhibit more robust P-Nat associated with less T Na in early nephron and reductions in PT-mTAL Na + transporters, consistent with higher UNaV at any given BP (Fig 1B).

Hemodynamic and Metabolic Determinants of End-Organ Perfusion and Microcirculation in an Animal Model of Thoracoabdominal Aortic Repair

Introduction - Open repair of thoracoabdominal aorta (TAA) requires prolonged aortic crossclamping and extracorporeal circulation. Hybrid repair with proximal endovascular graft fixation can reduce ischemic time and eliminate the need for the pump. We measured the effects of hybrid approach on intraoperative and recovery hemodynamics in an experimental pig model. Methods - Four approaches were compared; group 1: open surgical TAA repair, group 2: 1st generation SPIDER graft, group 3: 2nd generation SPIDER with loop graft for implantation of lumbar arteries, and group 4: 3rd generation SPIDER graft with volume-based resuscitation. Hemodynamic variables, tissue perfusion, branch vessel flow, and clinical laboratory values were measured at baseline, at end-operation and at six hours (6H) postoperatively. Organ microperfusion was measured by gold-standard fluorescent microsphere (MS) technique. Data were analyzed by hierarchical linear mixed models to account for multilevel repeated measurements. Results - 27 pigs (75-85 kg) were studied. Total ischemic times were significantly longer for open grafts than SPIDER grafts for all branch vessels (p<0.0001). Branch vessel flows were not present in the OSR group during crossclamping, but recovered at clamp release and 6H postoperatively. Perfusion of the visceral organs measured by fluorescent microsphere varied significantly between baseline, post-implant and 6H postoperatively in all groups (p<0.0001). Between graft types, highly significant time-by-group interactions were observed for liver and bowel (all p<0.015). Hierarchical modeling demonstrated significant multilevel correlational influence of macro-hemodynamic changes (celiac or SMA flow and ischemic time) on microcirculation (end-organ perfusion) of hepatic and mesenteric beds (multilevel R2 0.61). Lactate levels were strongly correlated with bowel but not liver perfusion. Conclusion - Hybrid grafts significantly reduce intraoperative ischemia, end-organ perfusion abnormalities and metabolic derangements during thoracoabdominal aortic repair.

Vascular effects of aqueous Crocus sativus petals’ extract in the hypertensive rats

Background and Aim: Crocus sativus (C. sativus) petals attenuates smooth muscle tension and blood pressure in control animals. However the antihypertensive effect and its mechanisms haven’t been recognized. This study investigates the antihypertensive effects of C. sativus petals’ aqueous extract in hypertensive rats and also responses of the rat isolated perfused mesenteric bed. Materials and Methods: The interventional experimental study was performed on 20 male rats (divided to 5 and 15 rats for in vivo and in vitro studies respectively). Hypertension was induced by DOCA-salt injection (20 mg/kg, twice weekly, for 5 weeks, S.C) and water was replaced by NaCl (1%). Five weeks later, animals were anaesthetized with sodium thiopental (30 mg intraperitoneal). Then systemic arterial blood pressure was measured by cannulation of carotid artery following administration of different doses of aqueous extract of C. sativus. Isolated mesenteric beds precontracted with KCl (40 mM), and the tension was measured in presence of different concentrations of the aqueous extract. Finally, various doses of C. sativus extract were applied after incubation by L-NAME or indomethacin. The mesentry was perfused with pump and the recordings were done by physiograph. Results: Mean arterial blood pressure in hypertensive rats was 231±6 mmHg. Administration of aqueous extracts of C. sativus reduced the blood pressure in a dose–dependent manner. In mesenteric beds preparation, addition of C. sativus reduced the contractile effects of KCl. Incubation with L-NAME but not indomethacin abolished hypotension effect of the extract. Conclusion: It was proposed that the antihypertensive effects of C. sativus petals’ extract are through the reduction in total peripheral resistance following nitric oxide production.

Perivascular Adipose Tissue Contributes to the Modulation of Vascular Tone in vivo

Background: Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte β₃-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. Objective: We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of β₃-adrenoceptors and adiponectin. Method: In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). Results: We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using β₃-adrenoceptor inhibition, and activation of β₃-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The β₃-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon β₃-adrenoceptor activation. Conclusions: These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte β₃-adrenoceptors, which may trigger release of the vasodilator adiponectin.

Mesenchymal stem cells promote mesenteric vasodilation through hydrogen sulfide and endothelial nitric oxide.

Mesenteric ischemia is a devastating process that can result in intestinal necrosis. Mesenchymal stem cells (MSCs) are becoming a promising treatment modality. We hypothesized that 1) MSCs would promote vasodilation of mesenteric arterioles, 2) hydrogen sulfide (H2S) would be a critical paracrine factor of stem cell-mediated vasodilation, 3) mesenteric vasodilation would be impaired in the absence of endothelial nitric oxide synthase (eNOS) within the host tissue, and 4) MSCs would improve the resistin-to-adiponectin ratio in mesenteric vessels. H2S was measured with a specific fluorophore (7-azido-3-methylcoumarin) in intact MSCs and in cells with the H2S-producing enzyme cystathionine β synthase (CBS) knocked down with siRNA. Mechanical responses of isolated second- and third-order mesenteric arteries (MAs) from wild-type and eNOS knockout (eNOSKO) mice were monitored with pressure myography, after which the vessels were snap frozen and later analyzed for resistin and adiponectin via multiplex beaded assay. Addition of MSCs to the myograph bath significantly increased vasodilation of norepinephrine-precontracted MAs. Knockdown of CBS in MSCs decreased H2S production by MSCs and also decreased MSC-initiated MA dilation. MSC-initiated vasodilation was further reduced in eNOSKO vessels. The MA resistin-to-adiponectin ratio was higher in eNOSKO vessels compared with wild-type. These results show that MSC treatment promotes dilation of MAs by an H2S-dependent mechanism. Furthermore, functional eNOS within the host mesenteric bed appears to be essential for maximum stem cell therapeutic benefit, which may be attributable, in part, to modifications in the resistin-to-adiponectin ratio.NEW & NOTEWORTHY Stem cells have been shown to improve survival, mesenteric perfusion, and histological injury scores following intestinal ischemia. These benefits may be due to the paracrine release of hydrogen sulfide. In an ex vivo pressure myography model, we observed that mesenteric arterial dilation improved with stem cell treatment. Hydrogen sulfide release from stem cells and endothelial nitric oxide synthase within the vessels were critical components of optimizing stem cell-mediated mesenteric artery dilation.