scholarly journals Hypertension in Metabolic Syndrome: Vascular Pathophysiology

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Yolanda Mendizábal ◽  
Silvia Llorens ◽  
Eduardo Nava
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Signaling ◽  
Vascular Function ◽  
Historical Review ◽  
No Synthase ◽  
Perivascular Adipose Tissue ◽  
Spontaneously Hypertensive ◽  
High Release ◽  
No Release

Metabolic syndrome is a cluster of metabolic and cardiovascular symptoms: insulin resistance (IR), obesity, dyslipemia. Hypertension and vascular disorders are central to this syndrome. After a brief historical review, we discuss the role of sympathetic tone. Subsequently, we examine the link between endothelial dysfunction and IR. NO is involved in the insulin-elicited capillary vasodilatation. The insulin-signaling pathways causing NO release are different to the classical. There is a vasodilatory pathway with activation of NO synthase through Akt, and a vasoconstrictor pathway that involves the release of endothelin-1 via MAPK. IR is associated with an imbalance between both pathways in favour of the vasoconstrictor one. We also consider the link between hypertension and IR: the insulin hypothesis of hypertension. Next we discuss the importance of perivascular adipose tissue and the role of adipokines that possess vasoactive properties. Finally, animal models used in the study of vascular function of metabolic syndrome are reviewed. In particular, the Zucker fatty rat and the spontaneously hypertensive obese rat (SHROB). This one suffers macro- and microvascular malfunction due to a failure in the NO system and an abnormally high release of vasoconstrictor prostaglandins, all this alleviated with glitazones used for metabolic syndrome therapy.

Abstract 372: Upregulation of the Mineralocorticoid System in Obesity-associated Diabetes Leads to Increased Adipocyte Rho Kinase Activation and Dysregulation of Adipocytokines

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Aurelie Nguyen Dinh Cat ◽  
Glaucia E Callera ◽  
Tayze T Antunes ◽  
Augusto C Montezano ◽  
Ying He ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Vascular Function ◽  
Rho Kinase ◽  
Mrna Levels ◽  
Rock Inhibitor ◽  
Perivascular Adipose Tissue ◽  
Kinase Activation ◽  
Downstream Signaling ◽  
Protein Levels

Increased activation of the renin-angiotensin-aldosterone (RAAS) system is often associated with obesity and metabolic syndrome. We previously reported that aldosterone (aldo) produced by adipocytes regulate vascular function. Despite the fact that aldo production by adipocytes is increased in obesity, the role of aldo and its receptor, the mineralocorticoid receptor (MR), in the regulation of adipocytes biology and their downstream signaling remain elusive. Since Rho kinase (Rock) signaling has recently been implicated in the development of obesity, we tested the hypothesis that MR upregulation leads to dysregulation of adipokines through Rock-dependent mechanisms in obesity. Here we used obese db/db and lean db/+ mice, treated for 4 weeks with K canrenoate (MR antagonist, 30 mg/kg/day) and fasudil (Rock inhibitor, 30 mg/kg/day). Aldo production and Rock activation were measured by ELISA. mRNA and protein levels of adipokines and Rock signaling were assayed by real time PCR and immunoblotting. Plasma and adipocyte-derived aldo levels were increased in db/db mice (plasma: pg/mL, db/+ 310±33, db/db 567±43, p<0.05; adipocytes: pg/mL/μgRNA, db/+ 329±130, db/db 3125±494, p<0.002), an effect partially prevented by MR blockade (pg/mL/μgRNA: db/db 1278±176, p<0.01) and not by fasudil. Aldosterone synthase mRNA levels were increased (2.3 fold) as well as Nr3c2 (MR) (1.8 fold) and markers of MR activation ( Sgk1 and Ngal - 2.3 and 2.9 fold) in mature adipocytes from db/db mice. In mature adipocytes from db/db, adiponectin mRNA levels were decreased (2.6 fold; p<0.01), whereas leptin and IL-6 mRNA levels were increased (2 and 4.8 fold; p<0.01). All changes were blocked by K canrenoate. Rock activity and downstream effectors, such as activation of MYPT1 and ERM, were increased in perivascular adipose tissue from db/db mice, an effect prevented by MR blockade. In conclusion, our data demonstrate that in db/db mice adipocyte MR-dependent activation of Rock is associated with a pro-inflammatory adipose phenotype that is normalized by MR blockade. Our results implicate a potential role of adipocyte aldo/MR through RhoA/Rock in adipocyte dysfunction in obesity/diabetes, important co-morbidities often associated with metabolic syndrome and hypertension.

Abstract 2474: Rho-Kinase Inhibition Improves Endothelium-Dependent Vasodilation during Hyperinsulinemia in Patients with Metabolic Syndrome

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Francesca Schinzari ◽  
Manfredi Tesauro ◽  
Valentina Rovella ◽  
Augusto Veneziani ◽  
Nadia Mores ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Vascular Function ◽  
Vascular Reactivity ◽  
Rho Kinase ◽  
Serine Phosphorylation ◽  
No Donor ◽  
Kinase Inhibition ◽  
Impaired Insulin

Impaired insulin-mediated vasodilation in the skeletal muscle may be involved in the development of hypertension in patients with metabolic syndrome (MetS) and contribute to insulin resistance by diminishing the glucose uptake. Rho-kinase, an effector of the small G protein Rho A, plays an important role in hypertension and is reported to interfere with insulin signaling through serine phosphorylation of insulin receptor substrate-1 in blood vessels. We therefore examined the role of Rho-kinase in the pathophysiology of impaired vascular reactivity in patients with MetS by evaluating the effect of Rho-kinase inhibition on NO-dependent vasodilation during hyperinsulinemia. Forearm blood flow (FBF) responses to acetylcholine (ACh), a stimulus for endothelial release of NO, and sodium nitroprusside (SNP), an exogenous NO donor, were assessed during insulin administration (0.1 mU/Kg/min) using the forearm perfusion technique in patients with MetS (n=10) and matched controls (n=10). Patients with MetS were then randomized to intra-arterial infusion of either fasudil (inhibitor of Rho-kinase, 200 μg/min) or placebo and reactivity to ACh and SNP was reassessed. During hyperinsulinemia, vasodilator responses to both ACh and SNP were blunted in patients with MetS (both P>0.001 vs. controls). In patients who received fasudil, its administration did not change unstimulated FBF (P=0.75 vs. insulin alone); the vasodilator response to ACh, however, was significantly enhanced by fasudil (P=0.009 vs. insulin alone), while the response to SNP was not significantly changed (P=0.56). In patients with MetS who received placebo, vascular reactivity to both ACh and SNP was not different than before (both P>0.05). In conclusion, Rho-kinase inhibition during hyperinsulinemia improves endothelium-dependent vasodilator responsiveness in patients with MetS. This suggests that, under those conditions, intravascular activation of Rho-kinase is involved in the pathophysiology of endothelial dysfunction and may constitute a critical mediator linking metabolic and hemodynamic abnormalities in insulin resistance. As a consequence, targeting Rho-kinase might beneficially impact both vascular function and insulin sensitivity in patients with MetS.

Increased coronary perfusion augments cardiac contractility in the rat through stretch-activated ion channels

2002 ◽  
Vol 282 (4) ◽  
pp. H1334-H1340 ◽  
Author(s):  
R. R. Lamberts ◽  
M. H. P. van Rijen ◽  
P. Sipkema ◽  
P. Fransen ◽  
S. U. Sys ◽  
...  
Keyword(s):  
Ion Channels ◽  
Perfusion Pressure ◽  
Cardiac Contractility ◽  
No Synthase ◽  
Coronary Perfusion ◽  
Channel Blockade ◽  
No Release ◽  
Sustained Increase ◽  
Stretch Activated Ion Channels

The role of stretch-activated ion channels (SACs) in coronary perfusion-induced increase in cardiac contractility was investigated in isolated isometrically contracting perfused papillary muscles from Wistar rats. A brief increase in perfusion pressure (3–4 s, perfusion pulse, n = 7), 10 repetitive perfusion pulses ( n = 4), or a sustained increase in perfusion pressure (150–200 s, perfusion step, n = 7) increase developed force by 2.7 ± 1.1, 7.7 ± 2.2, and 8.3 ± 2.5 mN/mm2 (means ± SE, P < 0.05), respectively. The increase in developed force after a perfusion pulse is transient, whereas developed force during a perfusion step remains increased by 5.1 ± 2.5 mN/mm2 ( P < 0.05) in the steady state. Inhibition of SACs by addition of gadolinium (10 μmol/l) or streptomycin (40 and 100 μmol/l) blunts the perfusion-induced increase in developed force. Incubation with 100 μmol/l N ω-nitro-l-arginine [nitric oxide (NO) synthase inhibition], 10 μmol/l sodium nitroprusside (NO donation) and 0.1 μmol/l verapamil (L-type Ca2+ channel blockade) are without effect on the perfusion-induced increase of developed force. We conclude that brief, repetitive, or sustained increases in coronary perfusion augment cardiac contractility through activation of stretch-activated ion channels, whereas endothelial NO release and L-type Ca2+channels are not involved.

Abstract 13: Cholic Acid Supplementation Attenuates Hypertension In Spontaneously Hypertensive Stroke Prone Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Bojun Zhang ◽  
Sriram Ayyaswamy ◽  
Robert M Bryan ◽  
David J Durgan
Keyword(s):  
Cholic Acid ◽  
Vascular Function ◽  
Vascular Endothelial ◽  
Spontaneously Hypertensive ◽  
Gut Dysbiosis ◽  
Wky Rats ◽  
Hyocholic Acid ◽  
Control Plasma ◽  
Number Of Bacteria

Recent studies have demonstrated a causal role of gut dysbiosis in the development of hypertension in several animal models. However, our understanding of the mechanisms linking gut dysbiosis to blood pressure (BP) regulation of the host is still lacking. One key mechanism by which the microbiota influences the host is through the generation/modification of metabolites, such as bile acids (BAs). BA signaling has been shown to influence many pathways involved in BP regulation, including systemic inflammation and vascular function. We previously observed that spontaneously hypertensive stroke prone rat (SHRSP) exhibited dysbiotic cecal microbiome, which included a significant increase in the genus Lactobacillus , known to sequester BAs within its cytosol and reduce BAs availability, when compared to WKY. Thus, we hypothesized that gut dysbiosis contributes to the development of hypertension by reducing bile acid signaling. We observed a significant reduction in 9 of 18 plasma BAs in SHRSPs, as compared to WKY. This included a 72% reduction in cholic acid (CA), a primary BA (n=7-8, p<0.05). We next examined the effects of CA supplementation (0.5% CA diet for 16 weeks) on systolic BP (SBP) in WKY and SHRSP. Within the 9 BAs that were reduced in SHRSP, CA and hyocholic acid were restored by CA treatment in SHRSP plasma to similar levels of that observed in WKY control plasma. Furthermore, CA treatment decreased SBP by 18 ±7mmHg at 20 weeks in SHRSP (n=7-8, p<0.05), but had no effect on SBP in WKY rats. Acetylcholine-induced vasodilation of the aorta was significantly impaired in SHRSP control by 40% (10 -6 μM ACh, 59.5% vs. 99.3%) as compared to WKY control (n=3-4, p<0.01). CA treatment significantly improved endothelium-dependent vasodilation in the aorta of SHRSP rats similar to that in WKY rats (n=3-4, p<0.05). CA treatment also altered a number of bacteria in the gut including restoration of relative abundance of Lactobacillus in SHRSP to the level of WKY controls. We conclude that reduced BA signaling contributes to the development of hypertension in SHRSP, and that CA treatment may be a potential therapeutic approach to attenuate vascular endothelial dysfunction and associated hypertension.

scholarly journals Perivascular Adipose Tissue and Mesenteric Vascular Function in Spontaneously Hypertensive Rats

2006 ◽  
Vol 26 (6) ◽  
pp. 1297-1302 ◽  
Author(s):  
Beatriz Gálvez ◽  
Javier de Castro ◽  
Diana Herold ◽  
Galyna Dubrovska ◽  
Silvia Arribas ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Vascular Function ◽  
Spontaneously Hypertensive Rats ◽  
Hypertensive Rats ◽  
Perivascular Adipose Tissue ◽  
Spontaneously Hypertensive

scholarly journals The role of the endothelium in the hyperemic response to passive leg movement: looking beyond nitric oxide

2020 ◽  
Author(s):  
Joel D. Trinity ◽  
Oh Sung Kwon ◽  
Ryan M. Broxterman ◽  
Jayson R. Gifford ◽  
Andrew C. Kithas ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Vascular Function ◽  
No Synthase ◽  
Ketorolac Tromethamine ◽  
Arterial Infusion ◽  
Healthy Men ◽  
Leg Movement ◽  
Hyperemic Response

Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite NO synthase (NOS) inhibition. Therefore, in 9 young healthy men (25±4 yrs), this investigation aimed to determine if the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement) when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of NG-monomethyl L-arginine (L-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P450 (CYP450) by L-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF (LBFAUC) response to both PLM (control: 456±194, L-NMMA: 168±127 ml, p<0.01) and sPLM (control: 185±171, L-NMMA: 62±31 ml, p=0.03). The combined inhibition of NOS, COX, and CYP450 (i.e. L-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBFAUC: 271±97 ml, p>0.05) or sPLM (LBFAUC: 72±45 ml, p>0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent, hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests.

scholarly journals Potential role of perivascular adipose tissue in modulating atherosclerosis

2020 ◽  
Vol 134 (1) ◽  
pp. 3-13 ◽  
Author(s):  
Samah Ahmadieh ◽  
Ha Won Kim ◽  
Neal L. Weintraub
Keyword(s):  
Adipose Tissue ◽  
Vascular Function ◽  
Vessel Wall ◽  
Potential Role ◽  
Inflammatory Cells ◽  
Protective Role ◽  
Clinical Implications ◽  
Blood Vessel Wall ◽  
Perivascular Adipose Tissue

Abstract Perivascular adipose tissue (PVAT) directly juxtaposes the vascular adventitia and contains a distinct mixture of mature adipocytes, preadipocytes, stem cells, and inflammatory cells that communicate via adipocytokines and other signaling mediators with the nearby vessel wall to regulate vascular function. Cross-talk between perivascular adipocytes and the cells in the blood vessel wall is vital for normal vascular function and becomes perturbed in diseases such as atherosclerosis. Perivascular adipocytes surrounding coronary arteries may be primed to promote inflammation and angiogenesis, and PVAT phenotypic changes occurring in the setting of obesity, hyperlipidemia etc., are fundamentally important in determining a pathogenic versus protective role of PVAT in vascular disease. Recent discoveries have advanced our understanding of the role of perivascular adipocytes in modulating vascular function. However, their impact on cardiovascular disease (CVD), particularly in humans, is yet to be fully elucidated. This review will highlight the complex mechanisms whereby PVAT regulates atherosclerosis, with an emphasis on clinical implications of PVAT and emerging strategies for evaluation and treatment of CVD based on PVAT biology.

scholarly journals Erratum to: Di-peptidyl peptidase-4 inhibitor sitagliptin protects vascular function in metabolic syndrome: possible role of epigenetic regulation

2014 ◽  
Vol 41 (9) ◽  
pp. 6327-6327 ◽  
Author(s):  
Figen Amber Cicek ◽  
Zeynep Tokcaer-Keskin ◽  
Evren Ozcinar ◽  
Yusuf Bozkus ◽  
Kamil Can Akcali ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Epigenetic Regulation ◽  
Vascular Function

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives

2011 ◽  
Vol 300 (6) ◽  
pp. R1288-R1295 ◽  
Author(s):  
Stephane L. Bourque ◽  
Sandra T. Davidge ◽  
Michael A. Adams
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Disease ◽  
Vascular Remodeling ◽  
Vascular Function ◽  
No Synthase ◽  
Endothelin 1 ◽  
No Signaling ◽  
No Bioavailability

Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease. Here, we review classical and more recent data that suggest that ET-1 should be regarded as an essential component of NO signaling. In particular, we review evidence of the role of ET-1 in models of acute and chronic NO synthase blockade. Furthermore, we discuss the possible mechanisms by which NO modulates ET-1 activity. On the basis of these studies, we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.

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