Open revascularization for chronic mesenteric ischemia in the endovascular era: a quaternary-center experience and management algorithm.

Background: Chronic mesenteric ischemia (CMI) is a debilitating disease with a heavy burden on quality of life. Stenting of the superior mesenteric artery (SMA) is the first option for treatment, but there is a lack of consensus defining precise indications for open revascularization (OR). Objectives: To describe a series of 4 patients with CMI treated with OR and to present an algorithm for the management of this condition. Methods: Three patients presented with typical intestinal angina and weight loss. One patient was subjected to prophylactic revascularization during open abdominal aortic aneurysm repair. Surgical techniques included: 1) Bypass from the infrarenal aorta to the SMA; 2) Bypass from an aorto-bifemoral polyester graft to the SMA; 3) Bypass from the right iliac artery to the SMA; 4) Bypass from the right graft limb of an aorto-biiliac polyester graft to the median colic artery at Riolan's arcade. PTFE was used in all surgeries. All grafts were placed in a retrograde configuration, tunneled under the left renal vein, making a smooth C-loop. A treatment algorithm was constructed based on the institution's experience and a review of recent literature. Results: All patients demonstrated resolution of symptoms and recovery of body weight. All grafts are patent after mean follow-up of two years. Conclusions: Open revascularization using the C-loop configuration is a valuable technique for CMI and may be considered in selected cases. The algorithm constructed may help decision planning in other quaternary centers.

Contexto: A isquemia mesentérica crônica (IMC) é uma doença debilitante, com grave impacto na qualidade de vida. A literatura recomenda a angioplastia com stent da artéria mesentérica superior (AMS) como primeira opção de tratamento, mas há falta de consenso que defina indicações precisas para a revascularização aberta. Objetivos: Descrever uma série de quatro pacientes com IMC, tratados com revascularização aberta, e apresentar um algoritmo para o manejo dessa condição. Métodos: Três pacientes apresentaram angina intestinal típica e perda ponderal. Uma paciente foi submetida a reparo aberto de aneurisma da aorta abdominal e apresentava obstrução da AMS, que foi revascularizada profilaticamente. As técnicas cirúrgicas incluíram: 1) enxerto entre a aorta infrarrenal e a AMS; 2) enxerto entre o dácron utilizado em um enxerto aortobifemoral e a AMS; 3) enxerto entre a artéria ilíaca comum direita e a AMS; e 4) enxerto entre o ramo direito do dácron utilizado em um enxerto aorto-biilíaco e a artéria cólica média (ao nível da arcada de Riolan). Todos os enxertos foram feitos utilizando politetrafluoretileno em uma configuração retrógrada, tunelizados abaixo da veia renal esquerda, fazendo uma alça em C. Resultados: Todos os pacientes demonstraram resolução dos sintomas e ganho ponderal. Todos os enxertos se mantiveram pérvios durante um seguimento médio de 2 anos. Conclusões: A revascularização aberta para IMC utilizando-se a alça em C é uma técnica valiosa e pode ser considerada em pacientes selecionados. O algoritmo proposto pode auxiliar na decisão terapêutica em centros quaternários.

Myoendothelial feedback in mouse mesenteric resistance arteries is similar between the sexes, dependent on nitric oxide synthase, and independent of TPRV4.

Myoendothelial feedback (MEF), the endothelium-dependent vasodilation following sympathetic vasoconstriction (mediated by smooth muscle to endothelium gap junction communication), has been well studied in resistance arteries of males, but not females. We hypothesized that MEF responses would be similar between the sexes, but different in the relative contribution of the underlying nitric oxide and hyperpolarization mechanisms, given that these mechanisms differ between the sexes in agonist-induced endothelium-dependent dilation. We measured MEF responses (diameter changes) of male and female first- to second-order mouse mesenteric arteries to phenylephrine (10 µM) over 30 min using isolated pressure myography ± blinded inhibition of nitric oxide synthase (NOS) using Nω-nitro-l-arginine methyl ester (l-NAME; 0.1-1.0 mM), hyperpolarization using 35 mM KCl, or transient receptor potential vanilloid 4 (TRPV4) channels using GSK219 (0.1-1.0 µM) or RN-1734 (30 µM). MEF was similar [%dilation (means ± SE): males = 26.7 ± 2.0 and females = 26.1 ± 1.9 at 15 min] and significantly inhibited by l-NAME (1.0 mM) at 15 min [%dilation (means ± SE): males = 8.2 ± 3.3, P < 0.01; females = 6.8 ± 1.9, P < 0.001] and over time (P < 0.01) in both sexes. l-NAME (0.1 mM) + 35 mM KCl nearly eliminated MEF in both sexes (P < 0.001-0.0001). Activation of TRPV4 with GSK101 (0.1-10 µM) induced similar dilation between the sexes. Inhibition of TRPV4, which is reportedly involved in the hyperpolarization mechanism, did not inhibit MEF in either sex. Similar expression of eNOS was found between the sexes with Western blot. Thus, MEF is prominent and similar in murine first- and second-order mesenteric resistance arteries of both sexes, and reliant primarily on NOS and secondarily on hyperpolarization, but not TRPV4.NEW & NOTEWORTHY We found that female mesenteric resistance arteries have similar postconstriction dilatory responses (i.e., myoendothelial feedback) to a sympathetic neurotransmitter analog as male arteries. Both sexes use nitric oxide synthase (NOS) and hyperpolarization, but not TRPV4, in this response. Moreover, the key protein involved in this pathway (eNOS) is similarly expressed in these arteries between the sexes. These similarities are surprising given that agonist-induced endothelium-dependent dilatory mechanisms differ in these arteries between the sexes.

Open revascularization for chronic mesenteric ischemia in the endovascular era: a quaternary-center experience and management algorithm / Revascularização aberta na isquemia mesentérica crônica durante a era endovascular: experiência de um centro quaternário e um algoritmo de tratamento

Abstract Background Chronic mesenteric ischemia (CMI) is a debilitating disease with a heavy burden on quality of life. Stenting of the superior mesenteric artery (SMA) is the first option for treatment, but there is a lack of consensus defining precise indications for open revascularization (OR). Objectives To describe a series of 4 patients with CMI treated with OR and to present an algorithm for the management of this condition. Methods Three patients presented with typical intestinal angina and weight loss. One patient was subjected to prophylactic revascularization during open abdominal aortic aneurysm repair. Surgical techniques included: 1) Bypass from the infrarenal aorta to the SMA; 2) Bypass from an aorto-bifemoral polyester graft to the SMA; 3) Bypass from the right iliac artery to the SMA; 4) Bypass from the right graft limb of an aorto-biiliac polyester graft to the median colic artery at Riolan's arcade. PTFE was used in all surgeries. All grafts were placed in a retrograde configuration, tunneled under the left renal vein, making a smooth C-loop. A treatment algorithm was constructed based on the institution's experience and a review of recent literature. Results All patients demonstrated resolution of symptoms and recovery of body weight. All grafts are patent after mean follow-up of two years. Conclusions Open revascularization using the C-loop configuration is a valuable technique for CMI and may be considered in selected cases. The algorithm constructed may help decision planning in other quaternary centers.

Resumo Contexto A isquemia mesentérica crônica (IMC) é uma doença debilitante, com grave impacto na qualidade de vida. A literatura recomenda a angioplastia com stent da artéria mesentérica superior (AMS) como primeira opção de tratamento, mas há falta de consenso que defina indicações precisas para a revascularização aberta. Objetivos Descrever uma série de quatro pacientes com IMC, tratados com revascularização aberta, e apresentar um algoritmo para o manejo dessa condição. Métodos Três pacientes apresentaram angina intestinal típica e perda ponderal. Uma paciente foi submetida a reparo aberto de aneurisma da aorta abdominal e apresentava obstrução da AMS, que foi revascularizada profilaticamente. As técnicas cirúrgicas incluíram: 1) enxerto entre a aorta infrarrenal e a AMS; 2) enxerto entre o dácron utilizado em um enxerto aortobifemoral e a AMS; 3) enxerto entre a artéria ilíaca comum direita e a AMS; e 4) enxerto entre o ramo direito do dácron utilizado em um enxerto aorto-biilíaco e a artéria cólica média (ao nível da arcada de Riolan). Todos os enxertos foram feitos utilizando politetrafluoretileno em uma configuração retrógrada, tunelizados abaixo da veia renal esquerda, fazendo uma alça em C. Resultados Todos os pacientes demonstraram resolução dos sintomas e ganho ponderal. Todos os enxertos se mantiveram pérvios durante um seguimento médio de 2 anos. Conclusões A revascularização aberta para IMC utilizando-se a alça em C é uma técnica valiosa e pode ser considerada em pacientes selecionados. O algoritmo proposto pode auxiliar na decisão terapêutica em centros quaternários.

[Indications and techniques for endovascular revascularization of visceral arteries in mesenteric ischemia]. / Indikation und Technik der endovaskulären Revaskularisation der Viszeralarterien bei mesenterialer Ischämie.

Endovascular revascularization of visceral arteries is an important cornerstone of an interdisciplinary treatment concept for both acute and chronic forms of mesenteric ischemia. The advantages lie in the minimally invasive procedure and the speed of restoration of perfusion. This article provides an overview of the indications, techniques and current state of the clinical literature with respect to endovascular revascularization.

Ezetimibe Induces Vasodilation in Rat Mesenteric Resistance Arteries through Inhibition of Extracellular Ca2+ Influx.

Ezetimibe is a lipid-lowering agent that selectively inhibits cholesterol absorption by binding to the Niemann-Pick C1-like 1 (NPC1L1) protein. Although it is well known that administration of ezetimibe in hypercholesterolemia patients reduces the risk of cardiovascular events through attenuation of atherosclerosis, studies on the direct effect of ezetimibe on vascular function are not sufficient. The aim of the present study was to investigate the vascular effects of ezetimibe in rat mesenteric arteries. In the present study, 12-week-old male Sprague Dawley rats were used. After the rats were sacrificed, the second branches of the mesenteric arteries were isolated and cut into 2-3 mm segments and mounted in a multi-wire myography system to measure isometric tension. Ezetimibe reduced vasoconstriction induced by U46619 (500 nM) in endothelium-intact and endothelium-denuded arteries. Ezetimibe-induced vasodilation was not affected by the endothelial nitric oxide synthase (eNOS) inhibitor Nω-Nitro-L-arginine (L-NNA, 300 µM) or the non-selective potassium channel blocker, tetraethylammonium (TEA, 10 mM). Moreover, ezetimibe also completely blocked the contraction induced by an increase in external calcium concentration. Ezetimibe significantly reduced vascular contraction induced by L-type Ca2+ channel activator (Bay K 8644, 30 nM). Treatment with ezetimibe decreased the phosphorylation level of 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that ezetimibe has a significant vasodilatory effect in rat mesenteric resistance arteries. These results suggest that ezetimibe may have beneficial cardiovascular effects beyond its cholesterol-lowering properties.

Evaluación angiográfica de la distribución anatómica de la irrigación sanguínea del ángulo esplénico del colon en población chilena

Objetivo: Identificar los patrones de distribución vascular del ángulo esplénico del colon (AEC) en la población chilena para su comparación con la literatura oriental (Fukuoka). Materiales y Métodos: Estudio descriptivo, transversal. Se caracterizó la irrigación del AEC de imágenes con protocolo Urotac realizadas en Clínica INDISA entre el año 2020 y 2021 (n = 127), clasificándolas dentro de 6 tipos descritos por Fukuoka. Se evaluaron características demográficas y comorbilidades. Las variables fueron analizadas utilizando estadística descriptiva y la significancia mediante la prueba Chi2. Resultados: Existen diferencias en los tipos irrigación del AEC entre la serie local y Fukuoka, la irrigación tipo 3 fue la que presentó mayor variación (p < 0,05). El tipo 1 es la más frecuente (34,7%), sin casos del Tipo 4. No se identificó diferencia entre los distintos tipos de irrigación con relación a las variables demográficas y comorbilidades. Discusión: Al comparar nuestra serie con la oriental se evidenció similar frecuencia en tipos 1 y 6, mayor en tipos 3 y 5, y tipos 2 y 4 con menor representación. Se identificó un mayor aporte en la irrigación del AEC por la arteria cólica izquierda (ACI) en la población estudiada (64,6%). Conclusión: Nuestra población tiene mayor participación de ACI en irrigación del AEC que orientales (64,6% vs 49,6%), los tipos más frecuentes son 1, 3 y 6, el Tipo 1 es la forma más frecuente de irrigación, similar a Fukuoka (34,7% vs 39,7%), Tipo 3 tiene mayor representación en nuestra población que en la oriental (29,9% vs 9,9%).

Objective: To identify the vascular distribution patterns of the splenic flexure of the colon (AEC) in the Chilean population for comparison with the oriental literature (Fukuoka). Methods: Descriptive, cross-sectional study. The irrigation of the AEC of images with the Urotac protocol performed at the INDISA Clinic between 2020 and 2021 (n = 127) was characterized, classifying them into 6 types described by Fukuoka. Demographic characteristics and comorbidities were evaluated. Variables were analyzed using descriptive statistics and significance using the Chi2 test. Results: There are differences in the types of irrigation of the AEC between the local series and Fukuoka, irrigation type 3 was the one that presented the greatest variation (p < 0.05). Type 1 is the most frequent (34.7%), with no cases of Type 4. No difference was identified between the different types of irrigation in relation to demographic variables and comorbidities. Discussion: When comparing our series with the eastern one, a similar frequency was found in types 1 and 6, higher in types 3 and 5, and types 2 and 4 with less representation. A greater contribution was identified in the irrigation of the AEC by the left colic artery (ICA) in the population studied (64.6%). Conclusion: Our population has a greater participation of ICA in AEC irrigation than Orientals (64.6% vs 49.6%), the most frequent types are 1, 3 and 6, Type 1 is the most frequent form of irrigation, similar to Fukuoka (34.7% vs 39.7%), Type 3 is more represented in our population than in the eastern one (29.9% vs 9.9%).

Aberrant Left Colic Artery and Accessory Right Colic Artery: A Case Report and Surgical Implications.

During a routine dissection of the abdominal region in our department of anatomy's dissection laboratory, we found two variations of the vasculature of the gastrointestinal tract within the greater peritoneal and retroperitoneal compartments: an aberrant left colic artery (LCA) and an accessory right colic artery (RCA). The aberrant LCA originates from a common trunk (CT) that arises from the superior mesenteric artery instead of the inferior mesenteric artery. The CT continues for a short distance and terminates by dividing into a middle colic artery and an accessory RCA. The aberrant LCA and accessory RCA had abnormal courses; therefore, they are vulnerable to injury during surgical procedures of the region. Hence, a thorough knowledge of vascular variations is required to avoid potential complications.

[Features of the upper gastrointestinal tract mucous membrane state in patients with atherosclerosis of the mesenteric arteries].

AIM: To evaluate the clinical and endoscopic features of diseases of the upper gastrointestinal tract (GIT) in patients with atherosclerosis of the mesenteric arteries (MA). MATERIALS AND METHODS: The study included 48 patients with atherosclerosis of MA and 43 patients without atherosclerosis of MA, who were hospitalized in the department of vascular surgery of the Chelyabinsk Regional Clinical Hospital in the period from 2019 to 2021. All patients underwent multispiral computed tomoangiography of the visceral and lower limb arteries, esophagogastroduodenoscopy. RESULTS: Assessment of lesions of the upper gastrointestinal tract revealed a higher incidence of erosive and ulcerative gastroduodenopathies among patients with atherosclerosis of MA (60.4%), compared with patients without atherosclerosis MA (39.5%); p=0.047. Signs of severe atrophy according to the data of histological examination were statistically significantly more frequent among patients with atherosclerosis of MA (29.2 and 11.6%; p=0.031). According to the results of logistic regression, the following predictors of erosions and ulcers of the upper gastrointestinal tract were revealed: the severity of stenosis of the superior mesenteric artery (SMA) is more than 35%, the body mass index (BMI) is less than 25.9 and the total score on the HADS scale is more than 6.5 points for depression (p=0.008). CONCLUSION: Erosive-ulcerative gastroduodenopathies and atrophy of the gastric mucosa are significantly more common in the group of patients with MA atherosclerosis. The main risk factors for erosions and ulcers of the upper gastrointestinal tract in patients with MA atherosclerosis are: the severity of SMA stenosis is more than 35%, a decrease in BMI is less than 25.9 and an increase in the HADS score is more than 6.5 points.

Management of spontaneous isolated mesenteric artery dissection.

Spontaneous isolated mesenteric arterial dissection (SIMAD) is an uncommon subset of non-traumatic dissection of the mesenteric arteries without concurrent aortic dissection. Due to the widespread use of computer tomography angiography, SIMAD cases have been increasingly reported in the past 20 years. Common risk factors associated with SIMAD include male gender, age 50-60 years, hypertension and smoking. This review summarises the diagnostic pathway and management of SIMAD based on contemporary literature and proposes a treatment algorithm for SIMAD. The presentation of SIMAD can be divided into symptomatic and asymptomatic cases. Symptomatic patients should be carefully assessed to detect the development of complications, particularly bowel ischemia or vessel rupture. Although these complications are rare, they necessitate urgent surgical management. The vast majority of symptomatic SIMAD cases are uncomplicated and can be managed safely with conservative treatment that includes antihypertensive therapy, bowel rest, with or without antithrombotic therapy. For asymptomatic SIMAD cases, expectant management with outpatient surveillance imaging appears to be a safe strategy.

Tetrodotoxin Decreases the Contractility of Mesenteric Arteries, Revealing the Contribution of Voltage-Gated Na+ Channels in Vascular Tone Regulation.

Tetrodotoxin (TTX) poisoning through the consumption of contaminated fish leads to lethal symptoms, including severe hypotension. This TTX-induced hypotension is likely due to the downfall of peripheral arterial resistance through direct or indirect effects on adrenergic signaling. TTX is a high-affinity blocker of voltage-gated Na+ (NaV) channels. In arteries, NaV channels are expressed in sympathetic nerve endings, both in the intima and media. In this present work, we aimed to decipher the role of NaV channels in vascular tone using TTX. We first characterized the expression of NaV channels in the aorta, a model of conduction arteries, and in mesenteric arteries (MA), a model of resistance arteries, in C57Bl/6J mice, by Western blot, immunochemistry, and absolute RT-qPCR. Our data showed that these channels are expressed in both endothelium and media of aorta and MA, in which scn2a and scn1b were the most abundant transcripts, suggesting that murine vascular NaV channels consist of NaV1.2 channel subtype with NaVß1 auxiliary subunit. Using myography, we showed that TTX (1 µM) induced complete vasorelaxation in MA in the presence of veratridine and cocktails of antagonists (prazosin and atropine with or without suramin) that suppressed the effects of neurotransmitter release. In addition, TTX (1 µM) strongly potentiated the flow-mediated dilation response of isolated MA. Altogether, our data showed that TTX blocks NaV channels in resistance arteries and consecutively decreases vascular tone. This could explain the drop in total peripheral resistance observed during mammal tetrodotoxications.

The pig is a better model than the rabbit or rat for studying the pathophysiology of human mesenteric arteries.

AIMS: Animal models are essential to investigate cardiovascular pathophysiology and pharmacology, but phylogenetic diversity makes it necessary to identify the model with vasculature most similar to that of humans. METHODS AND RESULTS: In this study, we compared the mesenteric arteries of humans, pigs, rabbits and rats in terms of the i) evolutionary changes in the amino acid sequences of α1 and ß2 adrenoceptors; M1, M2, and M3 muscarinic receptors; and bradykinin (BKR) and thromboxane-prostanoid (TP) receptors, through bioinformatics tools; ii) expression of α1, ß2, M1, M3 and TP receptors in each tunica, as assessed by immunofluorescence; and iii) reactivity to receptor-dependent and independent contractile agonists and relaxants, by performing organ bath assays. Phylogenetically, pigs showed the highest degree of evolutionary closeness to humans for all receptors, and with the exception of BKR, rabbits presented the greatest evolutionary difference compared to humans, pigs and rats. The expression of the measured receptors in the three vascular tunica in pigs was most similar to that in humans. Using a one-way ANOVA to determine the differences in vascular reactivity, we found that the reactivity of pigs was the most similar to that of humans in terms of sensitivity (pD2) and maximum effect of vascular reactivity (Emax) to KCl, phenylephrine, isoproterenol and carbachol. CONCLUSIONS: The pig is a better vascular model than the rabbit or rat to extrapolate results to human mesenteric arteries. Comparative vascular studies have implications for understanding the evolutionary history of different species. TRANSLATIONAL PERSPECTIVE: The presented findings are useful for identifying an animal model with a vasculature that is similar to that of humans. This information is important to extrapolate, with greater precision, the findings in arterial pathophysiology or pharmacology from animal models to the healthy or diseased human being.

An Update on Acute Mesenteric Ischemia.

Acute mesenteric ischemia (AMI) is an uncommon yet highly lethal cause of acute abdomen in the emergency setting. Computed tomography (CT) imaging, in particular a biphasic protocol consisting of angiographic and venous phase scans, is widely used to corroborate non-specific clinical findings when suspicions of AMI are high. Techniques such as low kilovoltage peak scanning, dual energy acquisition, or a combined arterial/enteric phase can improve iodine conspicuity and evaluation of bowel enhancement. Biphasic CT with CT angiography is mandatory to directly assess for the 3 primary etiologies of AMI-arterial, venous, and non-occlusive mesenteric ischemia (NOMI), and the CT angiographic findings may be the first visible in the disease. In addition, numerous non-vascular CT findings have also been reported. Bowel wall thickening, mesenteric stranding, and ascites are common but non-specific findings that correlate poorly with disease severity. Pneumatosis intestinalis and portomesenteric venous gas, while not pathognomonic for ischemia, are highly specific in cases of high clinical suspicion. Bowel wall hypoenhancement is an early and specific sign but requires a protocol optimizing iodine conspicuity to confidently identify. Finally, intraperitoneal free air and solid organ infarcts are also highly specific ancillary findings in AMI. AMI occurs as a complication in 10% of small bowel obstruction (SBO) patients, and understanding imaging findings of ischemia in the context of SBO is necessary to aid in treatment planning and reduce over- and under-diagnosis of strangulation. Familiarity with the imaging features of ischemia by radiologists is vital to establish an early diagnosis before irreversible necrosis occurs.

Functional Role of STIM-1 and Orai1 in Human Microvascular Aging.

The impact of aging on vascular function is heterogeneous depending on the vascular territories. Calcium regulation plays a key role in vascular function and has been implicated in aging-related hypercontractility of corpus cavernosum. We aimed to evaluate stromal interaction molecule (STIM)/Orai system involvement in aging-related vascular alterations in the human macro and microvasculature. Aortae specimens and mesenteric arteries (MA), obtained from 45 organ donors, were functionally evaluated in organ chambers and wire myographs. Subjects were divided into groups either younger or older than 65-years old. The expressions of STIM-1, Orai1, and Orai3 were determined by immunofluorescence in the aorta and MA, and by Western blot in the aorta homogenates. The inhibition of STIM/Orai with YM-58483 (20 µM) reversed adrenergic hypercontractility in MA from older subjects but did not modify aging-related hypercontractility in the aortic strips. Aging was related to an increased expression of Orai1 in human aorta, while Orai1 and STIM-1 were upregulated in MA. STIM-1 and Orai1 protein expressions were inversely correlated to endothelial function in MA. Circulating levels of Orai1 were correlated with the inflammatory factor TNF-α and with the endothelial dysfunction marker asymmetric dimethylarginine. Aging is associated with an increased expression of the STIM/Orai system in human vessels with functional relevance only in the microvascular territory, suggesting its role in aging-related microvascular dysfunction.

Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure.

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is reported to produce beneficial cardiovascular effects including a reduction in arterial contractility, and blood pressure. However, whether canagliflozin could directly relax resistance mesenteric arteries, underlying molecular mechanism and its role in regulating systemic blood pressure remain unclear. Here, we investigated the mechanism of regulation of small mesenteric artery contractility and its relevance for blood pressure regulation. Our pressure myography data showed that canagliflozin application rapidly produces a concentration-dependent vasodilation in mesenteric arteries. Such vasodilation was inhibited by concurrent inhibition of smooth muscle cell voltage-gated K+ channels KV1.5 (by 1 µM DPO-1), KV2.1 (by 100 nM guangxitoxin), and KV7 (by 10 µM linopirdine) but not by the inhibition of small-, intermediate-, and large-conductance Ca2+-activated K+ channels (SKCa by 1 µM apamin, IKCa 10 µM TRAM-34, and BKCa by 10 µM paxilline, respectively), ATP-sensitive (KATP) channels (by 10 µM glibenclamide), or SERCA pump (by 0.1 µM thapsigargin). Inhibition of SGLTs (by 1 µM phlorizin or the inhibition of endothelial signaling did not alter canagliflozin-evoked vasodilation. Consistently, acute canagliflozin treatment (4 mg/kg body weight) lowered systemic blood pressure in vivo. Overall, our data suggests that canagliflozin stimulates KV1.5, KV2.1, and KV7 channels, leading to vasodilation and a reduction of systemic blood pressure.

Role of adropin in arterial stiffening associated with obesity and type 2 diabetes.

Adropin is a peptide largely secreted by the liver and known to regulate energy homeostasis; however, it also exerts cardiovascular effects. Herein, we tested the hypothesis that low circulating levels of adropin in obesity and type 2 diabetes (T2D) contribute to arterial stiffening. In support of this hypothesis, we report that obesity and T2D are associated with reduced levels of adropin (in liver and plasma) and increased arterial stiffness in mice and humans. Establishing causation, we show that mesenteric arteries from adropin knockout mice are also stiffer, relative to arteries from wild-type counterparts, thus recapitulating the stiffening phenotype observed in T2D db/db mice. Given the above, we performed a set of follow-up experiments, in which we found that 1) exposure of endothelial cells or isolated mesenteric arteries from db/db mice to adropin reduces filamentous actin (F-actin) stress fibers and stiffness, 2) adropin-induced reduction of F-actin and stiffness in endothelial cells and db/db mesenteric arteries is abrogated by inhibition of nitric oxide (NO) synthase, and 3) stimulation of smooth muscle cells or db/db mesenteric arteries with a NO mimetic reduces stiffness. Lastly, we demonstrated that in vivo treatment of db/db mice with adropin for 4 wk reduces stiffness in mesenteric arteries. Collectively, these findings indicate that adropin can regulate arterial stiffness, likely via endothelium-derived NO, and thus support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D.NEW & NOTEWORTHY Arterial stiffening, a characteristic feature of obesity and type 2 diabetes (T2D), contributes to the development and progression of cardiovascular diseases. Herein we establish that adropin is decreased in obese and T2D models and furthermore provide evidence that reduced adropin may directly contribute to arterial stiffening. Collectively, findings from this work support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D.

Dynein Coordinates ß2-Adrenoceptor-Mediated Relaxation in Normotensive and Hypertensive Rat Mesenteric Arteries.

BACKGROUND: The voltage-gated potassium channel (Kv)7.4 and Kv7.5 channels contribute to the ß-adrenoceptor-mediated vasodilatation. In arteries from hypertensive rodents, the Kv7.4 channel is downregulated and function attenuated, which contributes to the reduced ß-adrenoceptor-mediated vasodilatation observed in these arteries. Recently, we showed that disruption of the microtubule network, with colchicine, or inhibition of the microtubule motor protein, dynein, with ciliobrevin D, enhanced the membrane abundance and function of Kv7.4 channels in rat mesenteric arteries. This study aimed to determine whether these pharmacological compounds can improve Kv7.4 function in third-order mesenteric arteries from the spontaneously hypertensive rat, thereby restoring the ß-adrenoceptor-mediated vasodilatation. METHODS: Wire and intravital myography was performed on normotensive and hypertensive male rat mesenteric arteries and immunostaining was performed on isolated smooth muscle cells from the same arteries. RESULTS: Using wire and intravital microscopy, we show that ciliobrevin D enhanced the ß-adrenoceptor-mediated vasodilatation by isoprenaline. This effect was inhibited partially by the Kv7 channel blocker linopirdine and was dependent on an increased functional contribution of the ß2-adrenoceptor to the isoprenaline-mediated relaxation. In mesenteric arteries from the spontaneously hypertensive rat, ciliobrevin D and colchicine both improved the isoprenaline-mediated vasorelaxation and relaxation to the Kv7.2 -7.5 activator, ML213. Immunostaining confirmed ciliobrevin D enhanced the membrane abundance of Kv7.4. As well as an increase in the function of Kv7.4, the functional changes were associated with an increase in the contribution of ß2-adrenoceptor following isoprenaline treatment. Immunostaining experiments showed ciliobrevin D prevented isoprenaline-mediated internalizationof the ß2-adrenoceptor. CONCLUSIONS: Overall, these data show that colchicine and ciliobrevin D can induce a ß2-adrenoceptor-mediated vasodilatation in arteries from the spontaneously hypertensive rat as well as reinstating Kv7.4 channel function.

Dapagliflozin induces vasodilation in resistance-size mesenteric arteries by stimulating smooth muscle cell KV7 ion channels.

Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that, in addition to glucose reduction, lowers systemic blood pressure. Here, we investigated if dapagliflozin could directly relax small mesenteric arteries that control peripheral vascular resistance and blood pressure, and the underlying molecular mechanism. We used pressurized arterial myography, pharmacological inhibition and Western blotting to investigate the direct effect of dapagliflozin on the contractility of freshly isolated, resistance-size rat mesenteric arteries. Our pressure myography data unveiled that dapagliflozin relaxed small mesenteric arteries in a concentration-dependent manner. Non-selective inhibition of KV channels and selective inhibition of smooth muscle cell voltage-gated K+ channels KV7 attenuated dapagliflozin-induced vasorelaxation. Inhibition of other major KV isoforms such as KV1.3, KV1.5 channels as well as large-conductance Ca2+-activated K+ (BKCa) channels, ATP-sensitive (KATP) channels did not abolish vasodilation. Dapagliflozin-evoked vasodilation remained unaltered by pharmacological inhibition of endothelium-derived nitric oxide (NO) signaling, prostacyclin (PGI2), as well as by endothelium denudation. Our Western blotting data revealed that SGLT2 protein is expressed in rat mesenteric arteries. However, non-selective inhibition of SGLTs did not induce vasodilation, demonstrating that the vasodilatory action is independent of SGLT2 inhibition. Overall, our data suggests that dapagliflozin directly and selectively stimulates arterial smooth muscle cells KV7 channels, leading to vasodilation in resistance-size mesenteric arteries. These findings are significant as it uncovers for the first time a direct vasodilatory action of dapagliflozin in resistance mesenteric arteries, which may lower systemic blood pressure.

MRI-based pre- and postprandial flow in the mesenteric vasculature of patients with suspected chronic mesenteric ischemia.

PURPOSE: The physiological increase of mesenteric blood flow after a meal is impaired in patients with occlusive chronic mesenteric ischemia (CMI). This principle could be used to develop a highly desired diagnostic test assessing the sufficiency of the collateral mesenteric circulation. This study assesses the potential to identify CMI patients using two-dimensional time-resolved phase-contrast magnetic resonance imaging (2D PC-MRI) flow measurements. METHOD: This prospective cohort study included patients with suspected CMI, based on: typical history, imaging, and functional testing. Cardiac gated 2D PC-MRI flow measurements (expressed as ml/min/kg) were performed in mesenteric arteries and veins during inspiration and expiration, after six hours of fasting and 20, 30, and 40 min after a meal challenge with a high caloric drink. RESULTS: Flow measurements were obtained in 19 patients: 8 CMI and 11 non-CMI. CMI patients showed a significantly smaller increase in postprandial blood flow in the superior mesenteric artery (SMA) at 30 and 40 min (30 min CMI 1.27(0.12-2.44) vs. non-CMI 7.82(6.28-10.90); 40 min CMI 0.30(-0.26-3.16) vs. non-CMI 7.94(6.32-10.90)) and a lower total arterial flow at 40 min (CMI 3.21(-0.72-5.05) vs. non-CMI 9.31(5.58-13.83)). Repeated flow measurements showed normalization of impaired postprandial venous flow after mesenteric artery stenting in one patient. CONCLUSIONS: The significantly lower increase in postprandial mesenteric blood flow in CMI patients confirms the promise of mesenteric blood flow measurements, before and 30-40 min after a meal, as a future diagnostic test to identify CMI patients among patients with a high clinical suspicion of CMI and mesenteric artery stenosis.

Abdominal apoplexy due to rupture of inferior pancreaticoduodenal artery: A rare case of acute abdomen.

BACKGROUND: Abdominal apoplexy is one of the rare causes of non-traumatic intra-abdominal bleeding. This condition is usually seen in male patients in their 50s with history of hypertension. As soon as abdominal apoplexy is suspected, immediate resuscitation should be performed followed by emergent surgery. The patient's outcome depends entirely on the clinical condition and the time interval between diagnosis and treatment. CASE PRESENTATION: Herein we present a 63-year-old man with idiopathic spontaneous intraperitoneal hemorrhage (ISIH) caused by spontaneous rupture of non-aneurysmal inferior pancreaticoduodenalartery (IPDA). CONCLUSION: In this report, a case of abdominal apoplexy has been presented caused by spontaneous rupture of non-aneurysmal inferior pancreaticoduodenalartery (IPDA) in a patient without any significant past medical history.