scholarly journals Endothelial ATP-Sensitive Potassium Channel Protects Against the Development of Hypertension and Atherosclerosis

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 776-784
Author(s):  
Yiwen Li ◽  
Qadeer Aziz ◽  
Naomi Anderson ◽  
Leona Ojake ◽  
Andrew Tinker
Keyword(s):  
Blood Pressure ◽  
High Fat Diet ◽  
Vascular Reactivity ◽  
High Salt ◽  
Mesenteric Arteries ◽  
Membrane Excitability ◽  
High Fat ◽  
Basal Blood Pressure ◽  
Endothelial Integrity

In the endothelium, ATP-sensitive potassium (K ATP ) channels are thought to couple cellular metabolism with membrane excitability, calcium entry, and endothelial mediator release. We hypothesized that endothelial K ATP channels have a broad role protecting against high blood pressure and atherosclerosis. Endothelial-specific Kir6.1 KO mice (eKO) and eKO mice on an apolipoprotein E KO background were generated (A-eKO) to investigate the role of K ATP channels in the endothelium. Basal blood pressure was not elevated in eKO mice. However, when challenged with a high-salt diet and the eNOS inhibitor L-NAME, eKO mice became more hypertensive than their littermate controls. In aorta, NO release at least partly contributes to the endothelium-dependent vasorelaxation induced by pinacidil. In A-eKO mice atherosclerotic plaque density was significantly greater than in their littermate controls when challenged with a high-fat diet, particularly in the aortic arch region. Levels of endothelial dysfunction markers were higher in eKO compared with WT mice; however, these were not significant for A-eKO mice compared with their littermate controls. Furthermore, decreased vascular reactivity was observed in the mesenteric arteries of A-eKO mice, but not in aorta when on a high-fat diet. Our data support a role for endothelial Kir6.1-containing K ATP channels in the endothelial protection against environmental stressors: the maintenance of blood pressure homeostasis in response to high salt and endothelial integrity when challenged with a high-fat diet.

Abstract P212: Sphingolipid De Novo Pathway is a Novel Regulator of Blood Pressure Homeostasis

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Anna Cantalupo ◽  
Yi Zhang ◽  
Xian-Cheng Jiang ◽  
Annarita Di Lorenzo
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
High Blood Pressure ◽  
Vascular Reactivity ◽  
De Novo ◽  
Ex Vivo ◽  
Mesenteric Arteries ◽  
Serine Palmitoyltransferase ◽  
Sphingosine 1 Phosphate

Background and objectives: Sphingolipids, particularly sphingosine 1-phosphate (S1P), play an important role in the cardiovascular homeostasis. Recently, we revealed that endothelial de novo biosynthesis of sphingolipids is very important to control vascular functions and blood pressure. We discovered that in blood vessels, particularly in endothelial cells, Nogo-B, a membrane protein of the endoplasmic reticulum, inhibits serine palmitoyltransferase (SPT), the first and rate-limiting enzyme of de novo production of sphingolipids, to impact vascular tone and blood pressure. Indeed, mice lacking Nogo-B are protected from angiotensin II-induced hypertension, and pharmacological inhibition of SPT by myriocin reinstates high blood pressure in absence of Nogo-B, suggesting that the upregulation of SPT activity exerts anti-hypertensive functions. Thus, the goal of this study is to investigate the role of SPT in vascular functions and blood pressure regulation by using novel genetic mouse models. Methods: The SBP was evaluated in 14 weeks old mice heterozygous for Sptlc2 ( Sptlc2 +/- ) or lacking Sptlc2 specifically in endothelial cells (ECKO Sptlc2 ) and smooth muscle cells (SMCKO Sptlc2 ) by using tail-cuff system. Vascular reactivity of isolated mesenteric arteries was assessed ex-vivo by using the pressure myograph system. Results: Sptlc2 +/- , ECKO Sptlc2 and SMCKO Sptlc2 mice were hypertensive compared to their respective controls ( Sptlc2 +/- 128.9±2.6 vs. WT 112.1±2.6 mmHg; ECKO Sptlc2 125.5±1.8, SMCKO Sptlc2 127.2±0.6 vs. Sptlc2 f/f 106±0.84 mmHg) and developed endothelial dysfunction as shown by the impaired vasodilation in response to acetylcholine (EC 50 Sptlc2 +/- 1.48x10 -6 M vs. WT 4.46x10 -7 M; Emax ECKO Sptlc2 73.2±3.3% vs. Sptlc2 f/f 95.3±1.1%), as well as to flow (Emax: Sptlc2 +/- 23.3±1.4 μm vs. WT 42.9±4.4 μm; ECKO Sptlc2 19.9±0.9 μm vs. Sptlc2 f/f 41.3±3.1 μm). Conclusion: This study demonstrates the important role of SPT, thus the de novo production of sphingolipids, in controlling blood flow and pressure homeostasis, and provides the ground for the development of alternative therapeutic strategies to manage high blood pressure.

scholarly journals Adiponectin improves endothelial function in mesenteric arteries of rats fed a high-fat diet: role of perivascular adipose tissue

2017 ◽  
Vol 174 (20) ◽  
pp. 3514-3526 ◽  
Author(s):  
Cristina M Sena ◽  
Ana Pereira ◽  
Rosa Fernandes ◽  
Liliana Letra ◽  
Raquel M Seiça
Keyword(s):  
Adipose Tissue ◽  
Endothelial Function ◽  
High Fat Diet ◽  
Mesenteric Arteries ◽  
High Fat ◽  
Perivascular Adipose Tissue

scholarly journals High Salt Intake Increases Blood Pressure in Normal Rats: Putative Role of 20-HETE and No Evidence on Changes in Renal Vascular Reactivity

2015 ◽  
Vol 40 (3) ◽  
pp. 323-334 ◽  
Author(s):  
A. Walkowska ◽  
M. Kuczeriszka ◽  
J. Sadowski ◽  
K.H. Olszyñski ◽  
L. Dobrowolski ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Reactivity ◽  
Salt Intake ◽  
High Salt ◽  
Putative Role ◽  
High Salt Intake ◽  
Renal Vascular

Resistance of mice lacking the serum- and glucocorticoid-inducible kinase SGK1 against salt-sensitive hypertension induced by a high-fat diet

2006 ◽  
Vol 291 (6) ◽  
pp. F1264-F1273 ◽  
Author(s):  
Dan Yang Huang ◽  
Krishna M. Boini ◽  
Hartmut Osswald ◽  
Björn Friedrich ◽  
Ferruh Artunc ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Flow Rate ◽  
High Fat Diet ◽  
Fluid Intake ◽  
Salt Intake ◽  
High Salt ◽  
Urinary Flow Rate ◽  
Urinary Flow ◽  
High Fat

Mineralocorticoids enhance expression and insulin stimulates activity of the serum- and glucocorticoid-inducible kinase SGK1, which activates the renal epithelial Na+ channel (ENaC). Under a salt-deficient diet, SGK1 knockout mice ( sgk1−/−) excrete significantly more NaCl than their wild-type littermates ( sgk1 +/+) and become hypotensive. The present experiments explored whether SGK1 participates in the hypertensive effects of a high-fat diet and high-salt intake. Renal SGK1 protein abundance of sgk1 +/+ mice was significantly elevated after a high-fat diet. Under a control diet, fluid intake, blood pressure, urinary flow rate, and urinary Na+, K+, and Cl− excretion were similar in sgk1−/− and sgk1 +/+ mice. Under a standard diet, high salt (1% NaCl in the drinking water for 25 days) increased fluid intake, urinary flow rate, and urinary Na+, K+, and Cl− excretion similarly in sgk1−/− and sgk1 +/+ mice without significantly altering blood pressure. A high-fat diet alone (17 wk) did not significantly alter fluid intake, urinary flow rate, urinary Na+, K+, or Cl− excretion, or plasma aldosterone levels but increased plasma insulin, total cholesterol, triglyceride concentrations, and systolic blood pressure to the same extent in both genotypes. Additional salt intake (1% NaCl in the drinking water for 25 days) on top of a high-fat diet did not affect hyperinsulinemia or hyperlipidemia but increased fluid intake, urinary flow rate, and urinary NaCl excretion significantly more in sgk1−/− than in sgk1 +/+mice. Furthermore, in animals receiving a high-fat diet, additional salt intake increased blood pressure only in sgk1 +/+ mice (to 132 ± 3 mmHg) but not in sgk1−/− mice (120 ± 4 mmHg). Thus lack of SGK1 protects against the hypertensive effects of a combined high-fat/high-salt diet.

Abstract P291: High Fat Diet Promotes Hypertension and Vascular Remodeling but Not Vascular Fibrosis or Altered Contractility in Dahl Salt Sensitive Rats

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Roxanne Fernandes ◽  
Patricia A Perez Bonilla ◽  
Hannah Garver ◽  
James J Galligan ◽  
Gregory D Fink ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Vascular Remodeling ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Mesenteric Arteries ◽  
High Fat ◽  
Perivascular Adipose Tissue ◽  
Morphological Studies

Obesity associated hypertension in rodent models is commonly associated with altered vascular reactivity to sympathetic neurotransmitters and inflammation-induced vascular remodeling/fibrosis. Dahl salt-sensitive (SS) rats exhibit elevated sympathetic activity and vascular remodeling. We hypothesized that diet-induced obesity in Dahl SS rats would promote hypertension, vascular dysfunction and remodeling/fibrosis. Male Dahl SS rats were placed on high fat diet (HFD, 60% kcal from fat with final concentrations of 0.33% NaCl and 1% K + , n=5) or normal-fat diet (NFD; 10% kcal from fat, 0.24% NaCl, 0.36% K + , n=5) for 24-26 weeks after weaning (3 weeks of age). Compared with NFD rats, HFD rats displayed severe hypertension (MAP, 165±4 mmHg vs 133±6 mmHg, P<0.05), higher body-weight (470±6g vs 433±7g, P<0.05), and hyperlipidemia (cholesterol, 211±22 mg/dl vs 138±23 mg/dl, P=0.05). HFD rats did not show significant changes in plasma levels of fasting glucose (85±5 mg/dl vs 75±5 mg/dl), insulin (2.6±0.8 ng/ml vs 2.2±1.1 ng/ml), leptin (0.77±0.18 ng/ml vs 0.44±0.06 ng/ml), or aldosterone (249±3 pg/ml vs 234±3 pg/ml) (all P>0.05). HFD did not affect pressurized mesenteric arterial (~300 μm inner diameter, 60 mmHg) reactivity to norepinephrine or ATP in vitro . Pressurized mesenteric arteries from HFD rats displayed thicker walls (Ca 2+ free buffer, 40±1 μm vs 36±1 μm, P<0.05), but showed slightly increased distensibility. Morphological studies did not reveal greater fibrosis in adventitia of mesenteric, intrarenal and coronary arteries from HFD rats. However, HFD induced inflammation in mesenteric perivascular adipose tissue, as shown by increased CD3 positive cell infiltration and histological evidence of fibrosis and angiogenesis. Our studies indicate that HFD in male Dahl SS rats promotes hypertension, perivascular adipose tissue inflammation and vascular remodeling, but not vascular fibrosis. Alteration of vascular contractility to sympathetic neurotransmitters, however, is not required for obesity associated hypertension in Dahl SS rats.

scholarly journals A low-carbohydrate/high-fat diet reduces blood pressure in spontaneously hypertensive rats without deleterious changes in insulin resistance

2013 ◽  
Vol 304 (12) ◽  
pp. H1733-H1742 ◽  
Author(s):  
John D. Bosse ◽  
Han Yi Lin ◽  
Crystal Sloan ◽  
Quan-Jiang Zhang ◽  
E. Dale Abel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
High Fat Diet ◽  
Spontaneously Hypertensive Rats ◽  
Mesenteric Arteries ◽  
Heart Weight ◽  
High Fat ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Low Carbohydrate

Previous studies reported that diets high in simple carbohydrates could increase blood pressure in rodents. We hypothesized that the converse, a low-carbohydrate/high-fat diet, might reduce blood pressure. Six-week-old spontaneously hypertensive rats (SHR; n = 54) and Wistar-Kyoto rats (WKY; n = 53, normotensive control) were fed either a control diet (C; 10% fat, 70% carbohydrate, 20% protein) or a low-carbohydrate/high-fat diet (HF; 20% carbohydrate, 60% fat, 20% protein). After 10 wk, SHR-HF had lower ( P < 0.05) mean arterial pressure than SHR-C (148 ± 3 vs. 159 ± 3 mmHg) but a similar degree of cardiac hypertrophy (33.4 ± 0.4 vs. 33.1 ± 0.4 heart weight/tibia length, mg/mm). Mesenteric arteries and the entire aorta were used to assess vascular function and endothelial nitric oxide synthase (eNOS) signaling, respectively. Endothelium-dependent (acetylcholine) relaxation of mesenteric arteries was improved ( P < 0.05) in SHR-HF vs. SHR-C, whereas contraction (potassium chloride, phenylephrine) was reduced ( P < 0.05). Phosphorylation of eNOSSer1177 increased ( P < 0.05) in arteries from SHR-HF vs. SHR-C. Plasma glucose, insulin, and homoeostatic model of insulin assessment were lower ( P < 0.05) in SHR-HF vs. SHR-C, whereas peripheral insulin sensitivity (insulin tolerance test) was similar. After a 10-h fast, insulin stimulation (2 U/kg ip) increased ( P < 0.05) phosphorylation of AktSer473 and S6 in heart and gastrocnemius similarly in SHR-C vs. SHR-HF. In conclusion, a low-carbohydrate/high-fat diet reduced blood pressure and improved arterial function in SHR without producing signs of insulin resistance or altering insulin-mediated signaling in the heart, skeletal muscle, or vasculature.

scholarly journals Glomerulosclerosis in the diet-induced obesity model correlates with sensitivity to nitric oxide inhibition but not glomerular hyperfiltration or hypertrophy

2015 ◽  
Vol 309 (9) ◽  
pp. F791-F799 ◽  
Author(s):  
Aaron J. Polichnowski ◽  
Hector Licea-Vargas ◽  
Maria Picken ◽  
Jianrui Long ◽  
Rashmi Bisla ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Renal Blood Flow ◽  
High Fat Diet ◽  
High Fat ◽  
Renal Hypertrophy ◽  
Diet Induced Obesity ◽  
Renal Vascular ◽  
Oxide Inhibition

The diet-induced obesity (DIO) model is frequently used to examine the pathogenesis of obesity-related pathologies; however, only minimal glomerulosclerosis (GS) has been reported after 3 mo. We investigated if GS develops over longer periods of DIO and examined the potential role of hemodynamic mechanisms in its pathogenesis. Eight-week-old male obesity-prone (OP) and obesity-resistant (OR) rats (Charles River) were administered a moderately high-fat diet for 5 mo. Radiotelemetrically measured blood pressure, proteinuria, and GS were assessed. OP ( n = 10) rats developed modest hypertension (142 ± 3 vs. 128 ± 2 mmHg, P < 0.05) and substantial levels of proteinuria (63 ± 12 vs. 12 ± 1 mg/day, P < 0.05) and GS (7.7 ± 1.4% vs. 0.4 ± 0.2%) compared with OR rats ( n = 8). Potential hemodynamic mechanisms of renal injury were assessed in additional groups of OP and OR rats fed a moderately high-fat diet for 3 mo. Kidney weight (4.3 ± 0.2 vs. 4.3 ± 0.1 g), glomerular filtration rate (3.3 ± 0.3 vs. 3.1 ± 0.1 ml/min), and glomerular volume (1.9 ± 0.1 vs. 2.0 ± 0.1 μm3 × 10−6) were similar between OP ( n = 6) and OR ( n = 9) rats. Renal blood flow autoregulation was preserved in both OP ( n = 7) and OR ( n = 7) rats. In contrast, Nω-nitro-l-arginine methyl ester (l-NAME) administration in conscious, chronically instrumented OP ( n = 11) rats resulted in 15% and 39% increases in blood pressure and renal vascular resistance, respectively, and a 16% decrease in renal blood flow. Minimal effects of l-NAME were seen in OR ( n = 9) rats. In summary, DIO-associated GS is preceded by an increased hemodynamic sensitivity to l-NAME but not renal hypertrophy or hyperfiltration.

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