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 Role of cholinergic receptors in adrenal catecholamine secretion in spontaneously hypertensive rats

1999 ◽  
Vol 277 (4) ◽  
pp. R1057-R1062 ◽  
Author(s):  
Takahiro Nagayama ◽  
Takayuki Matsumoto ◽  
Makoto Yoshida ◽  
Mizue Suzuki-Kusaba ◽  
Hiroaki Hisa ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Muscarinic Receptors ◽  
Nicotinic Receptors ◽  
Spontaneously Hypertensive Rats ◽  
Adrenal Glands ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Wistar Kyoto

We investigated the role of nicotinic and muscarinic receptors in secretion of catecholamines induced by transmural electrical stimulation (ES) from isolated perfused adrenal glands of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. ES (1–10 Hz) produced frequency-dependent increases in epinephrine (Epi) and norepinephrine (NE) output as measured in perfusate. The ES-induced increases in NE output, but not Epi output, were significantly greater in adrenal glands of SHRs than in those of WKY rats. Hexamethonium (10–100 μM) markedly inhibited the ES-induced increases in Epi and NE output from adrenal glands of SHRs and WKY rats. Atropine (0.3–3 μM) inhibited the ES-induced increases in Epi and NE output from adrenal glands of SHRs, but not from those of WKY rats. These results suggest that endogenous acetylcholine-induced secretion of adrenal catecholamines is predominantly mediated by nicotinic receptors in SHRs and WKY rats and that the contribution of muscarinic receptors may be different between these two strains.

The role of bradykinin B1 receptor on cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHR-SP)

2006 ◽  
Vol 387 (2) ◽  
pp. 203-209 ◽  
Author(s):  
Norihito Moniwa ◽  
Jun Agata ◽  
Makoto Hagiwara ◽  
Nobuyuki Ura ◽  
Kazuaki Shimamoto
Keyword(s):  
Cardiac Remodeling ◽  
Spontaneously Hypertensive Rats ◽  
Map Kinases ◽  
Expression Level ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
B1 Receptor ◽  
Tgf Β1

Abstract An angiotensin-converting enzyme inhibitor (ACE-I) reduces cardiac remodeling and a bradykinin B2 receptor (B2R) antagonist partially abolishes this ACE-I effect. However, bradykinin has two different types of receptor, the B1 receptor (B1R) and B2R. Although B1R is induced under several pathological conditions, including hypertension, the role of cardiac B1R in hypertension is not clear. We therefore investigated the role of cardiac B1R in stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto (WKY) rats. The B1R mRNA expression level in the heart was significantly higher in SHR-SP than in WKY rats. Chronic infusion of a B1R antagonist for 4 weeks significantly elevated blood pressure and left-ventricular weight of SHR-SP. Morphological analysis indicated that cardiomyocyte size and cardiac fibrosis significantly increased after administration of the B1R antagonist. The phosphorylation of mitogen-activated protein (MAP) kinases, including ERK, p38, and JNK, was significantly increased in the hearts of SHR-SP rats receiving the B1R antagonist. The TGF-β1 expression level was significantly increased in SHR-SP rats treated with the B1R antagonist compared to that in WKY rats. The B1R antagonist significantly increased phosphorylation of Thr495 in endothelial nitric oxide synthase (eNOS), which is an inhibitory site of eNOS. These results suggest that the role of B1R in the heart may be attenuation of cardiac remodeling via inhibition of the expression of MAP kinases and TGF-β1 through an increase in eNOS activity in a hypertensive condition.

scholarly journals Role of the vascular endothelial sodium channel activation in the genesis of pathologically increased cardiovascular stiffness

2020 ◽  
Author(s):  
Michael A Hill ◽  
Frederic Jaisser ◽  
James R Sowers
Keyword(s):  
Vascular Function ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Receptor Activation ◽  
Na Channel ◽  
Vascular Endothelial ◽  
Negative Consequences ◽  
Tissue Remodelling ◽  
Stimulation Of

Abstract Cardiovascular (CV) stiffening represents a complex series of events evolving from pathological changes in individual cells of the vasculature and heart which leads to overt tissue fibrosis. While vascular stiffening occurs naturally with ageing it is accelerated in states of insulin (INS) resistance, such as obesity and type 2 diabetes. CV stiffening is clinically manifested as increased arterial pulse wave velocity and myocardial fibrosis-induced diastolic dysfunction. A key question that remains is how are these events mechanistically linked. In this regard, heightened activation of vascular mineralocorticoid receptors (MR) and hyperinsulinaemia occur in obesity and INS resistance states. Further, a downstream mediator of MR and INS receptor activation, the endothelial cell Na+ channel (EnNaC), has recently been identified as a key molecular determinant of endothelial dysfunction and CV fibrosis and stiffening. Increased activity of the EnNaC results in a number of negative consequences including stiffening of the cortical actin cytoskeleton in endothelial cells, impaired endothelial NO release, increased oxidative stress-meditated NO destruction, increased vascular permeability, and stimulation of an inflammatory environment. Such endothelial alterations impact vascular function and stiffening through regulation of vascular tone and stimulation of tissue remodelling including fibrosis. In the case of the heart, obesity and INS resistance are associated with coronary vascular endothelial stiffening and associated reductions in bioavailable NO leading to heart failure with preserved systolic function (HFpEF). After a brief discussion on mechanisms leading to vascular stiffness per se, this review then focuses on recent findings regarding the role of INS and aldosterone to enhance EnNaC activity and associated CV stiffness in obesity/INS resistance states. Finally, we discuss how coronary artery-mediated EnNaC activation may lead to cardiac fibrosis and HFpEF, a condition that is especially pronounced in obese and diabetic females.

Tetrahydroxystilbene Glucoside Inhibits Excessive Autophagy and Improves Microvascular Endothelial Dysfunction in Prehypertensive Spontaneously Hypertensive Rats

2016 ◽  
Vol 44 (07) ◽  
pp. 1393-1412 ◽  
Author(s):  
Qianqian Dong ◽  
Wenjuan Xing ◽  
Feng Fu ◽  
Zhenghua Liu ◽  
Jie Wang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Mesenteric Artery ◽  
Spontaneously Hypertensive Rats ◽  
Vascular Endothelial ◽  
Vascular Endothelial Function ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Tetrahydroxystilbene Glucoside

Autophagy exists in vascular endothelial cells, but the relationship between autophagy and blood vessel dysfunction in hypertension remains elusive. This study aimed to investigate role of autophagy in vascular endothelial dysfunction in prehypertension and hypertension and the underlying mechanisms involved. Furthermore, we sought to determine if and how tetrahydroxystilbene glucoside (TSG), a resveratrol analogue and active ingredient of Polygonum multiflorum Thunb used for its cardiovascular protective properties in traditional Chinese medicine, influences vascular endothelial function. Male spontaneously hypertensive rats (SHRs) aged 4 weeks (young) and 12 weeks (adult) were studied and the vascular function of isolated aorta and mesenteric artery was assessed in vitro. Compared with Wistar Kyoto rats (WKY), young and adult SHRs showed endothelial dysfunction of the aorta and mesenteric artery, along with decreased pAkt, pmTOR, and autophagic marker protein p62 and increased LC3 II/I in microvascular but not aortic tissues. TSG administration for 14 days significantly improved mesenteric vascular endothelial function, increased levels of pAkt and pmTOR, and decreased autophagy. Pretreatment of young SHRs with the mTOR inhibitor rapamycin blocked the antiautophagic and vasodilative effects of TSG. Moreover, TSG significantly activated Akt-mTOR signaling in HUVECs and reduced the autophagic levels in vitro, which were almost completely blocked by rapamycin. In summary, mesenteric endothelial dysfunction in prehypertensive SHRs was at least partly attributable to excessive autophagy in vascular tissues. TSG partly restored microvascular endothelial dysfunction through activating the Akt/mTOR pathway, which consequently suppressed autophagy, indicating that TSG could be potentially applied to protect vascular function against subclinical changes in prehypertension.

Role of renal nerves in onset and maintenance of spontaneous hypertension

1982 ◽  
Vol 243 (2) ◽  
pp. H284-H288 ◽  
Author(s):  
R. A. Norman ◽  
D. J. Dzielak
Keyword(s):  
Arterial Pressure ◽  
Renal Denervation ◽  
Indirect Measurement ◽  
Renal Nerves ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Norepinephrine Content ◽  
Wistar Kyoto

Renal denervation has been reported to delay development of hypertension in Okamoto spontaneously hypertensive rats (SHR) but to have no effect on the final hypertensive state. However, functional reinnervation begins to occur about 1 mo after renal denervation. The arterial pressure of SHR undergoing repeated bilateral renal denervations at the age of 4, 7, 10, 13, and 16 wk was compared with that in sham-operated SHR. In addition, the effect of successive renal denervations at 4, 7, and 10 wk of age in Wistar-Kyoto (WKY) control rats was determined. Both indirect measurement of pressure by the tail-cuff technique and mean arterial pressure (MAP) measurement indicated that renal denervation prevents full expression of hypertension in SHR. MAP in 19-wk-old renal-denervation SHR averaged 159 +/- 5.1 mmHg (SE) vs. 178 +/-0 4.2 mmHg in sham-operated SHR. Renal denervation had no effect on arterial pressure of WKY rats. Renal norepinephrine content in the renal-denervated WKY rats and SHR was less than 20% of that in the sham-operated groups. Successive bilateral renal denervations every 3 wk blocks 30-40% of the expected progressive elevation of arterial pressure in aging SHR.

scholarly journals Differential Mechanisms of Ang (1-7)-Mediated Vasodepressor Effect in Adult and Aged Candesartan-Treated Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
S. Bosnyak ◽  
R. E. Widdop ◽  
K. M. Denton ◽  
E. S. Jones
Keyword(s):  
Blood Pressure ◽  
Angiotensin Receptor ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Receptor Localization ◽  
Wistar Kyoto ◽  
Depressor Effect ◽  
Stimulation Of

Angiotensin (1-7) (Ang (1-7)) causes vasodilator effects in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) via angiotensin type 2 receptors (AT2R). However, the role of vascular AT2R in aging is not known. Therefore, we examined the effect of aging on Ang (1-7)-mediated vasodepressor effects and vascular angiotensin receptor localization in aging. Blood pressure was measured in conscious adult (~17 weeks) and aged (~19 months) normotensive rats that received drug combinations in a randomised fashion over a 4-day protocol: (i) Ang (1-7) alone, (ii) AT1R antagonist, candesartan, alone, (iii) Ang (1-7) and candesartan, or (iv) Ang-(1-7), candesartan, and the AT2R antagonist, PD123319. In a separate group of animals, the specificMasR antagonist, A779, was administered in place of PD123319. Receptor localisation was also assessed in aortic sections from adult and aged WKY rats by immunofluorescence. Ang (1-7) reduced blood pressure (~15 mmHg) in adult normotensive rats although this effect was dependant on the background dose of candesartan. This depressor effect was reversed by AT2R blockade. In aged rats, the depressor effect of Ang (1-7) was evident but was now inhibited by either AT2R blockade orMasR blockade. At the same time, AT2R,MasR, and ACE2 immunoreactivity was markedly elevated in aortic sections from aged animals. These results indicate that the Ang (1-7)-mediated depressor effect was preserved in aged animals. Whereas Ang (1-7) effects were mediated exclusively via stimulation of AT2R in adult WKY, with aging the vasodepressor effect of Ang (1-7) involved both AT2R andMasR.

Abstract 097: Vascular Aging in Aldosterone Associated Hypertension: Role of NADPH Oxidase 1

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Adam Harvey ◽  
Augusto C Montezano ◽  
Katie Y Hood ◽  
Rheure A Lopes ◽  
Delyth Graham ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Mrna Levels ◽  
Vascular Aging ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Vascular Phenotype ◽  
Gene Level ◽  
Nadph Oxidase 1 ◽  
Cell Cycle Inhibitors

The vascular phenotype in hypertension is characterised by features typically observed in the ageing vasculature. Pathophysiological processes underlying premature vascular aging in hypertension remains unclear but aldosterone (aldo) and oxidative stress may be important. We postulated that physiological aging is amplified in hypertension due to increased aldo-induced Nox activation and redox signalling. We used arteries from adult WKY (18 weeks), aged WKY (52 weeks) and adult stroke-prone spontaneously hypertensive (SHRSP) rats. Blood pressure was measured by tail-cuff. Vascular function/structure was analysed by myography. Gene level was assessed by qPCR and protein by immunoblotting. BP was increased in SHRSP (180.7±2.5 vs. 127±2.7 mmHg, p<0.05). Endothelial dysfunction was observed in vessels from SHRSP. Increased vascular contraction in aged WKY rats was similar to SHRSP rats (p<0.05 vs WKY). Increased vascular stiffness was observed in arteries from aged WKY and SHRSP compared to WKY rats. Nox2 (0.82±0.4/2.4±0.9 vs 0.22±0.2), NoxA1 (4.9±2/9.5±5 vs 1±0.3) and NoxO1 (1.9±0.6/4.1±1 vs 1±0.4) mRNA was increased (p<0.05; SHRSP/aged WKY vs WKY). Nox1 mRNA (2.3±0.8 vs 1.1±0.4) was only increased in SHRSP rats (p<0.05; vs WKY). Similarly, mRNA levels of MCP-1 (2.3±0.5/3.9±1.9 vs 0.3±0.1) and RANTES (7.4±2/6.3±1.7 vs 1.1±0.2), aging-related inflammatory markers, and cell cycle inhibitors, p21 (3.2±1.1/3.1±0.7 vs 1±0.1) and p27 (2.2±0.7/2±0.8 vs 0.4±0.1), were increased in SHRSP and aged WKY rats (p<0.05; SHRSP/aged WKY vs WKY). ROS production (VSMC: 1.74±0.4 AU/protein), H2AX (DNA damage; 1.3±0.1) and aldosterone (plasma; 99.5±19 pg/mL) levels were increased in SHRSP rats (p<0.05; vs WKY). Aldo-induced Nox1 mRNA expression and p66SHC activation was exacerbated in VSMCs from SHRSP rats; an effect blocked by ML171 (a Nox1 inhibitor) and blunted in VSMCs from Nox1 KO mice. In conclusion, endothelial dysfunction and vascular remodelling in hypertension are associated with increased aldo-mediated activation of pro-inflammatory and redox-sensitive pathways. These processes involve Nox1. Our findings identify an important role for aldo/Nox1/ROS in molecular processes underlying vascular changes of ageing in hypertension.

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.

Effect of sodium chloride and sodium bicarbonate on blood pressure in stroke-prone spontaneously hypertensive rats

1988 ◽  
Vol 74 (6) ◽  
pp. 577-585 ◽  
Author(s):  
F. C. Luft ◽  
H. Steinberg ◽  
U. Ganten ◽  
D. Meyer ◽  
K. H. Gless ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mineral Water ◽  
Sodium Reabsorption ◽  
Sodium Potassium ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Ph Values ◽  
Wistar Kyoto ◽  
Renal Sodium Reabsorption

1. To test the hypothesis that NaCl increases blood pressure, while NaHCO3 does not, we measured the effect of an NaHCO3-containing mineral water on blood pressure in stroke-prone spontaneously hypertensive (SHR-SP) and Wistar–Kyoto (WKY) rats. We compared mineral water with equimolar amounts of NaCl and demineralized drinking water in six groups of 20 rats each over 24 weeks. 2. NaCl consistently increased blood pressure in both SHR-SP and WKY compared with demineralized water, while mineral water did not. 3. We studied the possible role of sodium-regulating hormones. Sodium, potassium-dependent adenosine triphosphatase activity was decreased by NaCl and by age, but not by mineral water. The concentration of atrial natriuretic peptide was greater in SHR-SP, but was not influenced by the two regimens. Components of the renin–angiotensin–aldosterone system and 18-hydroxy-deoxycorticosterone tended to decrease with NaCl, but not with mineral water. 4. Plasma pH values in the six groups of rats were not different; however, SHR-SP had consistently lower Pco2 and HCO−3 values and higher anion gap values than WKY rats. These values were not influence by the two regimens. 5. NaCl elevates blood pressure in SHR-SP while NaHCO3 does not. The changes in hormones regulating sodium homoeostasis suggest that NaCl induces volume expansion while NaHCO3 does not. The effect may be related to influences on renal sodium reabsorption by chloride and bicarbonate. The possible role of increased proton excretory activity in SHR-SP remains to be determined.

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