scholarly journals The absence of sympathoexcitation during the development of hypertension in Cyp1a1 Ren-2 transgenic rats

2019 ◽  
pp. 329-334
Author(s):  
J. Zicha ◽  
J. Hojná ◽  
L. Kopkan ◽  
L. Červenka ◽  
I. Vaněčková
Keyword(s):  
Blood Pressure ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Calcium Sensitization ◽  
Sympathetic Vasoconstriction ◽  
Rho Kinase Inhibitor ◽  
Dependent Form

The insertion of mouse renin gene (Ren-2) into the genome of normotensive rats causes a spontaneous rise of blood pressure (BP), leading to an angiotensin II (Ang II)-dependent form of hypertension in transgenic (mRen-2)27 rats (TGR). However, enhanced sympathetic BP component was demonstrated in heterozygous TGR aged 20 weeks. In the present study we used another model, i.e. Cyp1a1-Ren-2 transgenic rats (iTGR) in which hypertension can be induced by natural xenobiotic indole-3 carbinol (I3C) added to the diet. We investigated whether the development of high blood pressure (BP) in 5-month-old iTGR animals fed I3C diet for 10 days is solely due to enhanced Ang II-dependent vasoconstriction or whether enhanced sympathetic vasoconstriction also participates in BP maintenance in this form of hypertension. Using acute sequential blockade of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and NO synthase (NOS) we have demonstrated that the observed gradual increase of BP in iTGR fed I3C diet was entirely due to the augmentation of Ang II-dependent BP component without significant changes of sympathetic BP component. Thus, the hypertension in iTGR resembles to that of homozygous TGR in which high BP was entirely dependent on Ang II-dependent vasoconstriction. Moreover, our measurements of acute BP response to Rho kinase inhibitor fasudil in animals subjected to a combined blockade of RAS, SNS and NOS indicated the attenuation of basal calcium sensitization in both iTGR and homozygous TGR.

scholarly journals Basal and Activated Calcium Sensitization Mediated by RhoA/Rho Kinase Pathway in Rats with Genetic and Salt Hypertension

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Michal Behuliak ◽  
Michal Bencze ◽  
Ivana Vaněčková ◽  
Jaroslav Kuneš ◽  
Josef Zicha
Keyword(s):  
Blood Pressure ◽  
Kinase Inhibitor ◽  
Blood Pressure Response ◽  
Blood Pressure Reduction ◽  
Rho Kinase ◽  
Experimental Hypertension ◽  
Acute Administration ◽  
Calcium Sensitization ◽  
Rho Kinase Inhibitor ◽  
Kinase Pathway

Calcium sensitization mediated by RhoA/Rho kinase pathway can be evaluated either in the absence (basal calcium sensitization) or in the presence of endogenous vasoconstrictor systems (activated calcium sensitization). Our aim was to compare basal and activated calcium sensitization in three forms of experimental hypertension with increased sympathetic tone and enhanced calcium entry—spontaneously hypertensive rats (SHR), heterozygous Ren-2 transgenic rats (TGR), and salt hypertensive Dahl rats. Activated calcium sensitization was determined as blood pressure reduction induced by acute administration of Rho kinase inhibitor fasudil in conscious rats with intact sympathetic nervous system (SNS) and renin-angiotensin system (RAS). Basal calcium sensitization was studied as fasudil-dependent difference in blood pressure response to calcium channel opener BAY K8644 in rats subjected to RAS and SNS blockade. Calcium sensitization was also estimated from reduced development of isolated artery contraction by Rho kinase inhibitor Y-27632. Activated calcium sensitization was enhanced in all three hypertensive models (due to the hyperactivity of vasoconstrictor systems). In contrast, basal calcium sensitization was reduced in SHR and TGR relative to their controls, whereas it was augmented in salt-sensitive Dahl rats relative to their salt-resistant controls. Similar differences in calcium sensitization were seen in femoral arteries of SHR and Dahl rats.

scholarly journals Sex differences in the enhanced responsiveness to acute angiotensin II in growth-restricted rats: role of fasudil, a Rho kinase inhibitor

2013 ◽  
Vol 304 (7) ◽  
pp. F900-F907 ◽  
Author(s):  
Norma B. Ojeda ◽  
Thomas P. Royals ◽  
Barbara T. Alexander
Keyword(s):  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Angiotensin Ii ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Ang Ii ◽  
Intact Male ◽  
Rho Kinase Inhibitor

This study tested the hypothesis that Rho kinase contributes to the enhanced pressor response to acute angiotensin II in intact male growth-restricted and gonadectomized female growth-restricted rats. Mean arterial pressure (MAP) and renal function were determined in conscious animals pretreated with enalapril (250 mg/l in drinking water) for 1 wk to block the endogenous renin-angiotensin system and normalize blood pressure (baseline). Blood pressure and renal hemodynamics did not differ at baseline. Acute Ang II (100 ng·kg−1·min−1) induced a greater increase in MAP and renal vascular resistance and enhanced reduction in glomerular filtration rate in intact male growth-restricted rats compared with intact male controls ( P < 0.05). Cotreatment with the Rho kinase inhibitor fasudil (33 μg·kg−1·min−1) significantly attenuated these hemodynamic changes ( P < 0.05), but it did not abolish the differential increase in blood pressure above baseline, suggesting that the impact of intrauterine growth restriction on blood pressure in intact male growth-restricted rats is independent of Rho kinase. Gonadectomy in conjunction with fasudil returned blood pressure back to baseline in male growth-restricted rats, and yet glomerular filtration rate remained significantly reduced ( P < 0.05). Thus, these data suggest a role for enhanced renal sensitivity to acute Ang II in the developmental programming of hypertension in male growth-restricted rats. However, inhibition of Rho kinase had no effect on the basal or enhanced increase in blood pressure induced by acute Ang II in the gonadectomized female growth-restricted rat. Therefore, these studies suggest that Rho kinase inhibition exerts a sex-specific effect on blood pressure sensitivity to acute Ang II in growth-restricted rats.

Animal model for angiotensin II effects in the internal anal sphincter smooth muscle: mechanism of action

2002 ◽  
Vol 282 (3) ◽  
pp. G461-G469 ◽  
Author(s):  
Ya-Ping Fan ◽  
Rajinder N. Puri ◽  
Satish Rattan
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Ang Ii ◽  
Kinase C ◽  
Rho Kinase Inhibitor ◽  
Isolated Smooth Muscle Cells

Effect of ANG II was investigated in in vitro smooth muscle strips and in isolated smooth muscle cells (SMC). Among different species, rat internal and sphincter (IAS) smooth muscle showed significant and reproducible contraction that remained unmodified by different neurohumoral inhibitors. The AT1antagonist losartan but not AT2 antagonist PD-123319 antagonized ANG II-induced contraction of the IAS smooth muscle and SMC. ANG II-induced contraction of rat IAS smooth muscle and SMC was attenuated by tyrosine kinase inhibitors genistein and tyrphostin, protein kinase C (PKC) inhibitor H-7, Ca2+ channel blocker nicardipine, Rho kinase inhibitor Y-27632 or p44/42mitogen-activating protein kinase (MAPK44/42) inhibitor PD-98059. Combinations of nicardipine and H-7, Y-27632, and PD-98059 caused further attenuation of the ANG II effects. Western blot analyses revealed the presence of both AT1 and AT2receptors. We conclude that ANG II causes contraction of rat IAS smooth muscle by the activation of AT1 receptors at the SMC and involves multiple intracellular pathways, influx of Ca2+, and activation of PKC, Rho kinase, and MAPK44/42.

scholarly journals Crucial role of Rho-nuclear factor-κB axis in angiotensin II-induced renal injury

2007 ◽  
Vol 293 (1) ◽  
pp. F100-F109 ◽  
Author(s):  
Yuri Ozawa ◽  
Hiroyuki Kobori
Keyword(s):  
Renal Injury ◽  
Kinase Inhibitor ◽  
Urinary Albumin Excretion ◽  
Rho Kinase ◽  
Urinary Albumin ◽  
Ang Ii ◽  
Kinase Activation ◽  
Protein Excretion ◽  
Rho Kinase Inhibitor ◽  
Tgf Β1

This study was performed to determine the effectiveness of the Rho kinase inhibitor and NF-κB inhibitor in renal injury of ANG II-infused hypertensive rats. Male Sprague-Dawley rats, maintained on a normal diet, received either a sham operation ( n = 7) or continuous ANG II infusion (120 ng/min) subcutaneously via minipumps. The ANG II-infused rats were further subdivided into three subgroups ( n = 7 each) to receive one of the following treatments during the entire period: vehicle, Rho kinase inhibitor (fasudil; 3 mg·kg−1·day−1 ip), or NF-κB inhibitor (parthenolide; 1 mg·kg−1·day−1 ip). After 12 days of ANG II infusion, systolic blood pressure (BP; 208 ± 7 vs. 136 ± 3 mmHg), Rho kinase activity, NF-κB activity, renal ANG II contents (160 ± 25 vs. 84 ± 14 pg/g), monocytic chemotactic protein (MCP) 1 mRNA, interstitial macrophage infiltration, transforming growth factor-β1 (TGF-β1) mRNA, interstitial collagen-positive area, urinary protein excretion (43 ± 6 vs. 11 ± 2 mg/day), and urinary albumin excretion were significantly enhanced compared with the Sham group. While fasudil or parthenolide did not alter systolic BP (222 ± and 190 ± 21, respectively), both treatments completely blocked ANG II-induced enhancement of NF-κB activity, renal ANG II contents (103 ± 11 and 116 ± 21 pg/g, respectively), MCP1 mRNA, interstitial macrophage infiltration, TGF-β1 mRNA, interstitial collagen-positive area, urinary protein excretion (28 ± 6 and 23 ± 3 mg/day, respectively), and urinary albumin excretion. Importantly, parthenolide did not alter ANG II-induced Rho kinase activation although fasudil abolished ANG II-induced Rho kinase activation. These data indicate that the Rho-NF-κB axis plays crucial roles in the development of ANG IIinduced renal injury independently from BP regulation.

scholarly journals Combined Suppression of the Intrarenal and Circulating Vasoconstrictor Renin-ACE-ANG II Axis and Augmentation of the Vasodilator ACE2-ANG 1-7-Mas Axis Attenuates the Systemic Hypertension in Ren-2 Transgenic Rats Exposed to Chronic Hypoxia

2015 ◽  
pp. 11-24 ◽  
Author(s):  
L. ČERVENKA ◽  
J. BÍBOVÁ ◽  
Z. HUSKOVÁ ◽  
Z. VAŇOURKOVÁ ◽  
H. J. KRAMER ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Hypoxia ◽  
Substantial Reduction ◽  
Kidney Tissue ◽  
Renin Angiotensin System ◽  
Systemic Hypertension ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Pressure Lowering

The aim of the present study was to test the hypothesis that chronic hypoxia would aggravate hypertension in Ren-2 transgenic rats (TGR), a well-defined monogenetic model of hypertension with increased activity of endogenous renin-angiotensin system (RAS). Systolic blood pressure (SBP) in conscious rats and mean arterial pressure (MAP) in anesthetized TGR and normotensive Hannover Sprague-Dawley (HanSD) rats were determined under normoxia that was either continuous or interrupted by two weeks´ hypoxia. Expression, activities and concentrations of individual components of RAS were studied in plasma and kidney of TGR and HanSD rats under normoxic conditions and after exposure to chronic hypoxia. In HanSD rats two weeks´ exposure to chronic hypoxia did not alter SBP and MAP. Surprisingly, in TGR it decreased markedly SBP and MAP; this was associated with substantial reduction in plasma and kidney renin activities and also of angiotensin II (ANG II) levels, without altering angiotensin-converting enzyme (ACE) activities. Simultaneously, in TGR the exposure to hypoxia increased kidney ACE type 2 (ACE2) activity and angiotensin 1-7 (ANG 1-7) concentrations as compared with TGR under continuous normoxia. Based on these results, we propose that suppression of the hypertensiogenic ACE-ANG II axis in the circulation and kidney tissue, combined with augmentation of the intrarenal vasodilator ACE2-ANG 1-7 axis, is the main mechanism responsible for the blood pressure-lowering effects of chronic hypoxia in TGR.

Abstract P127: Angiotensin II Priming Enhances Prostaglandin E2 Vasoconstrictor Effects

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Maria P Kraemer ◽  
Fred Lamb ◽  
Richard M Breyer
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Area Under The Curve ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Ang Ii ◽  
Concentration Dependent Manner ◽  
Femoral Arteries

Prostaglandins are key modulators of blood pressure and arterial tone. Prostaglandin E 2 (PGE 2 ), is a prostanoid that has vasodepressor effects; however, under certain circumstances PGE 2 can induce vasopressor responses. Recent reports demonstrated that sub-threshold concentrations of vasoconstrictors augment PGE 2 -mediated constriction in rat femoral arteries. However, whether angiotensin II (Ang II) could affect PGE 2 -mediated contraction is not known. Using a wire myograph, we demonstrated that PGE 2 had no significant effect on mouse femoral arterial rings at doses up to 1 μM. However, priming of arterial rings with 1 nM Ang II potentiated PGE 2 -evoked constriction in a concentration dependent manner (Area Under the Curve, AUC untreated 1.784 ± 0.353, AUC Ang II 23.27± 9.820, P<0.05). We tested femoral arteries from EP1, EP2, and EP3 receptor knockout mice. Only the EP3-/- arteries were unable to respond to PGE 2 after Ang II priming (figure below). Pretreatment of arterial rings with 1 μM losartan, an angiotensin receptor antagonist, blocked PGE 2 -induced constrictor effects primed with Ang II (% of KCl, Ang II 21.72 ± 5.296, Ang II + losartan 3.025 ± 1.046, n=3). We have determined that re-addition of extracellular Ca 2+ to a Ca 2+ -free artery restores PGE 2 -induced contractions (n=5) and that the Rho-kinase inhibitor Y-27632 blocks contraction (n=3). Taken together these data are consistent with angiotensin AT1 and prostaglandin EP3 receptors mediating a synergistic Rho-kinase-dependent contractile response. We are continuing to investigate the relationship between Ang II and PGE 2 to determine the physiological relevance this may have in modulating blood pressure.

Abstract 057: Nox5 Induces Vascular Dysfunction and Arterial Remodelling Independently of Blood Pressure Elevation in Ang II-infused Nox5-expressing Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Augusto C Montezano ◽  
Adam P Harvey ◽  
Francisco J Rios ◽  
Maria Dulak-Lis ◽  
Wendy Beatie ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Kinase Inhibitor ◽  
Vascular Dysfunction ◽  
Rho Kinase ◽  
Lumen Diameter ◽  
Ang Ii ◽  
Cross Sectional ◽  
Blood Pressure Elevation ◽  
Endothelium Dependent Relaxation

Nox5 is a unique Ca 2+ -sensitive Nox isoform that is expressed in human vascular smooth muscle cells (VSMC). Although Nox5 has been implicated in diabetic nephropathy, its role in vascular function and development of hypertension remain unclear. Nox5 is not expressed in rodents, and accordingly we generated humanised Nox5 mice with Nox5 expressed in a VSMC-specific manner (Nox5SM22). Control (wild-type) and Nox5SM22 mice were infused with Ang II (600 ng/Kg/day). Blood pressure (BP) was assessed by tail-cuff. Vascular function and structure of resistance arteries were measured by myography. Ang II increased BP in WT (182.5±10 mmHg) and Nox5SM22 mice (173.1±5 mmHg) with no significant differences. Arteries from Nox5SM22 mice exhibited reduced endothelium-dependent relaxation versus WT controls (%ACh relaxation: 55.1±4 vs ctl: 81.6±7%). Fasudil (Rho kinase inhibitor)-induced relaxation was reduced in Nox5SM22 mice versus controls (%Fas: 111.3±11 vs ctl: 166.6±8%) (p<0.05). Ang II increased the maximal contraction to U46619 (thromboxane A2 mimetic) in WT (115.8±2 vs untreated: 101.4±2%) and Nox5SM22 (121.3±3 vs untreated: 99.1±2) (p<0.05) and induced endothelial dysfunction in all groups. Fasudil-induced relaxation was impaired by Ang II in WT (102.7±6 vs untreated: 166.6±8%, p<0.05) but not further impaired in Nox5SM22 mice (114.9±6 vs untreated: 111.3±11%). Ang II increased cross-sectional area (CSA) and lumen diameter; while in Nox5SM22 mice, Ang II increased wall thickness, wall-to-lumen ratio, CSA and decreased lumen diameter, with associated increased vascular stiffness. Our findings indicate that in mice expressing human Nox5 in VSMCs, endothelium-dependent relaxation is impaired, fasudil-mediated vasodilation is attenuated and vessels undergo exaggerated hypertrophic inward remodelling with increased stiffness; processes that occur independently of BP elevation. These data suggest an important role for Nox5 in Ang II-induced vascular dysfunction and remodeling, but not in the development of hypertension. Moreover, we identify Rho kinase as a putative target for Nox5-induced vascular injury. We provide novel insights into Nox5 vascular biology and demonstrate that vascular Nox5 actions are dissociated from BP effects.

scholarly journals Rho-kinase inhibitor reduces hypersensitivity to ANG II in human mesenteric arteries retrieved and conserved under the same conditions as transplanted organs

2014 ◽  
Vol 68 ◽  
pp. 1022-1027 ◽  
Author(s):  
Rafal Szadujkis-Szadurski ◽  
Maciej Slupski ◽  
Katarzyna Szadujkis-Szadurska ◽  
Leszek Szadujkis-Szadurski ◽  
Milosz Jasinski ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Rho Kinase Inhibitor ◽  
Transplanted Organs
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