TP receptors regulate renal hemodynamics during angiotensin II slow pressor response

2004 ◽  
Vol 287 (4) ◽  
pp. F753-F759 ◽  
Author(s):  
Noritaka Kawada ◽  
Kathryn Dennehy ◽  
Glenn Solis ◽  
Paul Modlinger ◽  
Rebecca Hamel ◽  
...  
Keyword(s):  
Pressor Response ◽  
Thiobarbituric Acid ◽  
Ang Ii ◽  
Wild Type ◽  
Thiobarbituric Acid Reactive Substances ◽  
Filtration Fraction ◽  
Arterial Blood ◽  
Tp Receptors ◽  
Prostaglandin H ◽  
Renal Vascular

We investigated the hypothesis that thromboxane A2 (TxA2)-prostaglandin H2 receptors (TP-Rs) mediate the hemodynamic responses and increase in reactive oxygen species (ROS) to ANG II (400 ng·kg−1·min−1 sc for 14 days) using TP-R knockout (TP −/−) and wild-type (+/+) mice. TP −/− had normal basal mean arterial blood pressure (MAP) and glomerular filtration rate but reduced renal blood flow and increased filtration fraction (FF) and renal vascular resistance (RVR) and markers of ROS (thiobarbituric acid-reactive substances and 8-isoprostane PGF2α) and nitric oxide (NOx). Infusion of ANG II into TP +/+ increased ROS and thromboxane B2 (TxB2) and increased RVR and FF. ANG II infusion into TP −/− mice reduced ANG I and increased aldosterone but caused a blunted increase in MAP (TP −/−: +6 ± 2 vs. TP +/+: +15 ± 3 mmHg) and failed to increase FF, ROS, or TxB2 but increased NOx and paradoxically decreased RVR (−2.1 ± 1.7 vs. +2.6 ± 0.8 mmHg·ml−1·min−1·g−1). Blockade of AT1 receptor of TP −/− mice infused with ANG II reduced MAP (−8 mmHg) and aldosterone but did not change the RVR or ROS. In conclusion, during an ANG II slow pressor response, AT1 receptors activate TP-Rs that generate ROS and prostaglandins but inhibit NO. TP-Rs mediate all of the increase in RVR and FF, part of the increase in MAP, but are not implicated in the suppression of ANG I or increase in aldosterone. TP −/− mice have a basal increase in RVR and FF associated with ROS.

Abstract P011: Novel Roles Of Global, Intestinal, And Kidney Proximal Tubule Sodium And Hydrogen Exchanger 3 In Angiotensin Ii-induced Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Jia L Zhuo ◽  
Liang Zhang ◽  
Ana Leite ◽  
Xiao C Li
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Pressor Response ◽  
Dependent Manner ◽  
Ang Ii ◽  
Wild Type ◽  
Salt Wasting ◽  
Arterial Blood ◽  
Induced Hypertension

The present study used global ( Nhe3 -/- ), kidney-selective (tg Nhe3 -/- ), and proximal tubule-specific Na + /H + exchanger 3 (NHE3)-deficient mice (PT- Nhe3 -/- ) to test the hypothesis that NHE3 is required for the full development of angiotensin II (Ang II)-induced hypertension in mice. Four groups of adult male, age-matched wild-type (WT), global Nhe3 -/- , kidney-selective tg Nhe3 -/- and proximal tubule-specific Nhe3 -/- mice were infused with: a) saline; b) Ang II (10 pmol/min, i.v.); Ang II via an osmotic minipump for 2 weeks (1.5 mg/kg/day, i.p.); or treated with Ang II and losartan concurrently for 2 weeks (20 mg/kg/day, p.o.). Under basal conditions, global Nhe3 -/- , kidney-selective tg Nhe3 -/- and proximal tubule-specific Nhe3 -/- mice all showed significantly lower systolic, diastolic, and mean arterial pressure than wild-type mice (~15 ± 3 mmHg, P <0.01). The hypotensive phenotype in both global Nhe3 -/- and kidney-selective tg Nhe3 -/- mice was associated with abnormal intestinal structures, diarrhea, increased 24 h fecal Na + excretion, and salt wasting ( P <0.01). By contrast, there were no differences in intestinal structures and fecal Na + excretion between wild-type and PT- Nhe3 -/- mice. PT- Nhe3 -/- mice showed significant diuretic and natriuretic responses compared with wild-type mice ( P <0.01). Acute infusion of Ang II markedly increased arterial blood pressure in a time-dependent manner in wild-type mice, as expected ( P <0.01), but the pressure response was attenuated in global Nhe3 -/- , kidney-selective tg Nhe3 -/- , and PT- Nhe3 -/- mice ( P <0.01). Furthermore, the chronic pressor response to 2-week Ang II infusion was also significantly attenuated in Nhe3 -/- , tgNhe3 -/- , and PT- Nhe3 -/- mice, compared with wild-type mice ( P <0.01). Finally, concurrent treatment with losartan completely blocked the acute and chronic pressor responses to Ang II in wild-type, Nhe3 -/- , tg Nhe3 -/- , and PT- Nhe3 -/- mice (p<0.01). Taken together, these data support the proof of concept that NHE3 in the small intestines and the proximal tubules of the kidney is required for maintaining basal blood pressure homeostasis and for the development of Ang II-induced hypertension. Supported by NIH grants, 2R01DK102429-03A1, 1R56HL130988-01, and 2R01DK067299-10A1.

Abstract P033: PRESSOR, NATRIURETIC, AND RENAL RESPONSES IN ANGIOTENSIN II-INDUCED HYPERTENSION IN MALE AND FEMALE WILD-TYPE AND PROXIMAL TUBULE-SPECIFIC AT 1A RECEPTOR KNOCKOUT MICE

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Ana Paula O Leite ◽  
Xiao C Li ◽  
Dulce E Casarini ◽  
Jia L Zhuo
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Pressor Response ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Wild Type ◽  
Tubulointerstitial Injury ◽  
Male And Female ◽  
Arterial Blood ◽  
Induced Hypertension

Dysregulation of intrarenal renin-angiotensin system is one of the key factors of human hypertension, but the mechanisms involved remain incompletely understood. To determine the roles of AT 1a receptors in the proximal tubules of the kidney, we infused angiotensin II (Ang II) for 2 weeks (40 ng / min, i.p.) in adult male and female wild-type C57BL/6J and mutant mice with deletion of AT 1a receptors in the proximal tubules (PT- Agtr1a -/- ), and treated with or without the AT 1 receptor blocker losartan (20 mg/kg/day, p.o.) (n=8 per group). The pressor response, 24 h urinary Na + excretion, glomerular and tubulointerstitial injury were compared between male and female wild-type and PT- Agtr1a -/- mice. Basal systolic, diastolic, and mean arterial blood pressure were about 13 ± 3 mmHg lower in male and female PT- Agtr1a -/- mice ( P <0.01), but no differences were observed between male and female wild-type or PT- Agtr1a -/- mice. In response to Ang II, both male and female wild-type and PT- Agtr1a -/- mice developed hypertension ( P <0.01), and the net pressor response were similar in male and female wild-type and PT- Agtr1a -/- mice (n.s.). However, absolute blood pressure was about 12 ± 3 mmHg lower in male and female PT- Agtr1a -/- mice ( P <0.01 vs. wild-type). Ang II-induced hypertension increased the natriuretic response in both male and female wild-type and PT- Agtr1a -/- mice ( P <0.01), but there were no significant differences between male and female wild-type and PT- Agtr1a -/- mice (n.s). Losartan did not increase the natriuretic responses further in all animals. Furthermore, Ang II-induced hypertension was associated with significant increases in glomerular and tubulointerstitial injury in male and female wild-type mice ( P <0.01), which were attenuated in male and female PT- Agtr1a -/- mice ( P <0.01). LOS treatment attenuated Ang II-induced hypertension and decreased Ang II-induced glomerular and tubulointerstitial injury in male and female wild-type and PT- Agtr1a -/- mice ( P <0.01). Taken together, we demonstrated that intratubular AT 1 (AT 1a ) receptors in the proximal tubules of the kidney plays a key role in maintaining basal blood pressure homeostasis and overall body salt and fluid balance, and the development of Ang II-induced hypertension and kidney injury.

Sexual dimorphism in regional blood flow responses to vasopressin in conscious rats

1997 ◽  
Vol 273 (3) ◽  
pp. R1126-R1131 ◽  
Author(s):  
Y. X. Wang ◽  
J. T. Crofton ◽  
S. L. Bealer ◽  
L. Share
Keyword(s):  
Blood Flow ◽  
Vascular Resistance ◽  
Regional Blood Flow ◽  
Pressor Response ◽  
Peripheral Resistance ◽  
Female Rats ◽  
Sexually Dimorphic ◽  
Arterial Blood ◽  
Vasoconstrictor Response ◽  
Renal Vascular

The greater pressor response to vasopressin in male than in nonestrous female rats results from a greater increase in total peripheral resistance in males. The present study was performed to identify the vascular beds that contribute to this difference. Mean arterial blood pressure (MABP) and changes in blood flow in the mesenteric and renal arteries and terminal aorta were measured in conscious male and nonestrous female rats 3 h after surgery. Graded intravenous infusions of vasopressin induced greater increases in MABP and mesenteric vascular resistance and a greater decrease in mesenteric blood flow in males. Vasopressin also increased renal vascular resistance to a greater extent in males. Because renal blood flow remained unchanged, this difference may be due to autoregulation. The vasopressin-induced reduction in blood flow and increased resistance in the hindquarters were moderate and did not differ between sexes. Thus the greater vasoconstrictor response to vasopressin in the mesenteric vascular bed of male than nonestrous females contributed importantly to the sexually dimorphic pressor response to vasopressin in these experiments.

scholarly journals Oxidative stress in patients on mechanical ventilation

2009 ◽  
Vol 62 (11-12) ◽  
pp. 578-581
Author(s):  
Vesna Marjanovic ◽  
Vidosava Djordjevic ◽  
Goran Marjanovic
Keyword(s):  
Oxidative Stress ◽  
Mechanical Ventilation ◽  
Head Injuries ◽  
Lipid Peroxide ◽  
Thiobarbituric Acid ◽  
Lactic Dehydrogenase ◽  
Lung Damage ◽  
Thiobarbituric Acid Reactive Substances ◽  
Acid Base Balance ◽  
Arterial Blood

Introduction. The appearance and intensity of oxidative stress were analyzed in the course of mechanical ventilation and parameters that could point toward potential lung damage. Material and methods. In three time intervals on day 1, 3 and 7 of mechanical ventilation, parameters such as: triglycerides, cholesterol, lactate, serum lactic dehydrogenase, acid-base balance and lipid peroxidation products - thiobarbituric acid reactive substances, were followed in 30 patients with head injuries. Results. A decrease in the level of partial oxygen pressure (PaO2) (p<0.01) and PaO2/FiO2 index (p<0.05) in arterial blood was recorded on day 3 of mechanical ventilation. This was accompanied with an increase in alveolar-arterial difference (AaDO2) (p<0.05), thiobarbituric acid reactive substances (p<0.001) and lactic dehydrogenase (p<0.001) comparing to day 1 of mechanical ventilation. The patients with initial PaO2>120 mmHg, had significant increase of thiobarbituric acid reactive substances and AaDO2 (p<0.05) and fall of PaO2 (p<0.001) on day 3 of mechanical ventilation. Conclusion. Oxidative stress and lipid peroxide production are increased during third day of mechanical ventilation leading to disruption of oxygen diffusion through alveolar-capillary membrane and reduction of parameters of oxygenation.

Role of superoxide anion in regulating pressor and vascular hypertrophic response to angiotensin II

2002 ◽  
Vol 282 (5) ◽  
pp. H1697-H1702 ◽  
Author(s):  
Hui Di Wang ◽  
Douglas G. Johns ◽  
Shanqin Xu ◽  
Richard A. Cohen
Keyword(s):  
Superoxide Anion ◽  
Pressor Response ◽  
Cross Sectional Area ◽  
Ang Ii ◽  
Sectional Area ◽  
Wild Type ◽  
Cross Sectional ◽  
Hypertrophic Response

Our purpose was to address the role of NAPDH oxidase-derived superoxide anion in the vascular response to ANG II. Blood pressure, aortic superoxide anion, 3-nitrotyrosine, and medial cross-sectional area were compared in wild-type mice and in mice that overexpress human superoxide dismutase (hSOD). The pressor response to ANG II was significantly less in hSOD mice. Superoxide anion levels were increased twofold in ANG II-treated wild-type mice but not in hSOD mice. 3-Nitrotyrosine increased in aortic endothelium and adventitia in wild-type but not hSOD mice. In contrast, aortic medial cross-sectional area increased 50% with ANG II in hSOD mice, comparable to wild-type mice. The lower pressor response to ANG II in the mice expressing hSOD is consistent with a pressor role of superoxide anion in wild-type mice, most likely because it reacts with nitric oxide. Despite preventing the increase in superoxide anion and 3-nitrotyrosine, the aortic hypertrophic response to ANG II in vivo was unaffected by hSOD.

Changes in angiotensin type 1 receptor binding and angiotensin-induced pressor responses in the rostral ventrolateral medulla of angiotensinogen knockout mice

2010 ◽  
Vol 298 (2) ◽  
pp. R411-R418 ◽  
Author(s):  
Daian Chen ◽  
Lisa Hazelwood ◽  
Lesley L. Walker ◽  
Brian J. Oldfield ◽  
Michael J. McKinley ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Receptor Binding ◽  
Knockout Mice ◽  
Pressor Response ◽  
Ventrolateral Medulla ◽  
Ang Ii ◽  
Wild Type ◽  
Intravenous Injections ◽  
Angiotensin Type

ANG II, the main circulating effector hormone of the renin-angiotensin system, is produced by enzymatic cleavage of angiotensinogen. The present study aimed to examine whether targeted deletion of the angiotensinogen gene ( Agt) altered brain ANG II receptor density or responsiveness to ANG II. In vitro autoradiography was used to examine the distribution and density of angiotensin type 1 (AT1) and type 2 receptors. In most brain regions, the distribution and density of angiotensin receptors were similar in brains of Agt knockout mice ( Agt −/− ) and wild-type mice. In Agt −/− mice, a small increase in AT1 receptor binding was observed in the rostral ventrolateral medulla (RVLM), a region that plays a critical role in blood pressure regulation. To examine whether Agt −/− mice showed altered responses to ANG II, blood pressure responses to intravenous injection (0.01–0.1 μg/kg) or RVLM microinjection (50 pmol in 50 nl) of ANG II were recorded in anesthetized Agt −/− and wild-type mice. Intravenous injections of phenylephrine (4 μg/kg and 2 μg/kg) were also made in both groups. The magnitude of the pressor response to intravenous injections of ANG II or phenylephrine was not different between Agt −/− and wild-type mice. Microinjection of ANG II into the RVLM induced a pressor response, which was significantly smaller in Agt −/− compared with wild-type mice (+10 ± 1 vs. +23 ± 4 mmHg, respectively, P = 0.004). Microinjection of glutamate into the RVLM (100 pmol in 10 nl) produced a robust pressor response, which was not different between Agt −/− and wild-type mice. A diminished response to ANG II microinjection in the RVLM of Agt −/− mice, despite an increased density of AT1 receptors suggests that signal transduction pathways may be altered in RVLM neurons of Agt −/− mice, resulting in attenuated cellular excitation.

scholarly journals D-α-tocopherol reduces renal damage in hypertensive rats

2012 ◽  
Vol 48 (2) ◽  
pp. 291-298 ◽  
Author(s):  
Thaís Maria da Fonseca Pletiskaitz ◽  
Guiomar Nascimento Gomes
Keyword(s):  
Renal Damage ◽  
Thiobarbituric Acid ◽  
Thiobarbituric Acid Reactive Substances ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Functional Changes ◽  
Beneficial Effects ◽  
Renal Vascular ◽  
Volume Retention ◽  
Normotensive Control

This study investigated the beneficial effects of D-α-tocopherol supplementation in protecting against the renal morphological and functional changes caused by hypertension. Spontaneously hypertensive (SHR) and normotensive control (WKY) rats received D-α-tocopherol (80 mg/kg by gavage) or vehicle (mineral oil) every other day for 60 days, from the age of 2 months. After this treatment period, all animals were assessed for renal morphological and functional parameters. The glomerular hypertrophy, increased interlobular wall thickness and enlarged renal vascular resistance found in SHR were reduced by D-α-tocopherol treatment. Sodium and volume retention observed in SHR were also decreased by D-α-tocopherol treatment. Moreover, D-α-tocopherol supplementation significantly reduced arterial pressure in SHR but not in WKY. D-α-tocopherol also reduced the excretion of thiobarbituric acid-reactive substances (TBARS), a marker of oxidative stress, in SHR. These results suggest that D-α-tocopherol supplementation can reduce kidney damage induced by hypertension.

Contribution of endothelin to renal vascular tone and autoregulation in the conscious dog

1999 ◽  
Vol 276 (3) ◽  
pp. F417-F424 ◽  
Author(s):  
Heike Berthold ◽  
Klaus Münter ◽  
Armin Just ◽  
Hartmut R. Kirchheim ◽  
Heimo Ehmke
Keyword(s):  
Time Course ◽  
Vascular Tone ◽  
Ace Inhibition ◽  
Renal Hemodynamics ◽  
Receptor Subtype ◽  
Ang Ii ◽  
Renal Autoregulation ◽  
Arterial Blood ◽  
Renal Vascular ◽  
Renal Vascular Tone

Exogenous endothelin-1 (ET-1) is a strong vasoconstrictor in the canine kidney and causes a decrease in renal blood flow (RBF) by stimulating the ETA receptor subtype. The aim of the present study was to investigate the role of endogenously generated ET-1 in renal hemodynamics under physiological conditions. In six conscious foxhounds, the time course of the effects of the selective ETA receptor antagonist LU-135252 (10 mg/kg iv) on mean arterial blood pressure (MAP), heart rate (HR), RBF, and glomerular filtration rate (GFR), as well as its effects on renal autoregulation, were examined. LU-135252 increased RBF by 20% (from 270 ± 21 to 323 ± 41 ml/min, P < 0.05) and HR from 76 ± 5 to 97 ± 8 beats/min ( P< 0.05), but did not alter MAP, GFR, or autoregulation of RBF and GFR. Since a number of interactions between ET-1 and the renin-angiotensin system have been reported previously, experiments were repeated during angiotensin converting enzyme (ACE) inhibition by trandolaprilat (2 mg/kg iv). When ETA receptor blockade was combined with ACE inhibition, which by itself had no effects on renal hemodynamics, marked changes were observed: MAP decreased from 91 ± 4 to 80 ± 5 mmHg ( P < 0.05), HR increased from 85 ± 5 to 102 ± 11 beats/min ( P < 0.05), and RBF increased from 278 ± 23 to 412 ± 45 ml/min ( P< 0.05). Despite a pronounced decrease in renal vascular resistance over the entire pressure range investigated (40–100 mmHg), the capacity of the kidneys to autoregulate RBF was not impaired. The GFR remained completely unaffected at all pressure levels. These results demonstrate that endogenously generated ET-1 contributes significantly to renal vascular tone but does not interfere with the mechanisms of renal autoregulation. If ETAreceptors are blocked, then the vasoconstrictor effects of ET-1 in the kidney are compensated for to a large extent by an augmented influence of ANG II. Thus ET-1 and ANG II appear to constitute a major interrelated vasoconstrictor system in the control of RBF.

Abstract 37: Deletion of Notch3 Gene Impairs Contractility of Renal Resistance Vessels

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Frank Helle ◽  
Panagiotis Kavvadas ◽  
Michael Hultström ◽  
Bjarne Iversen ◽  
Christos Chatziantoniou
Keyword(s):  
Vascular Reactivity ◽  
Channel Blocker ◽  
Chelating Agent ◽  
Dependent Manner ◽  
Ang Ii ◽  
Wild Type ◽  
Renal Vasculature ◽  
Resistance Vessels ◽  
And Function ◽  
Renal Vascular

Background: Notch3 plays an important role in the differentiation and development of vascular smooth muscle cells. In previous studies we showed that mice lacking Notch3 display deficient renal autoregulation. Objective: Our aim was to study the mechanisms involved in the Notch3-mediated control of renal vascular response. Methods and Results: To this end, renal afferent arterioles were isolated from Notch3-/- and wild type littermates and stimulated with ANG II. Contractions and intracellular Ca2+ concentrations were blunted in Notch3-/- vessels in a dose-dependent manner (diameter decrease: 15±3 vs. 38±5%, p<0.01; change of fura 2 ratio: 0.18±0.02 vs. 0.39±0.05, p<0.001, at 10-7Ang II for Notch3-/- and wt vessels, respectively). Differential transcriptomic analysis of 47 genes known to participate in vasoreactivity indicated an important downregultion of the cacna1h gene expressing the α1H subunit of the T-type Ca2+ channel in the renal vessels of Notch3-/- mice. This finding was confirmed by real-time qPCR and western blotting. In subsequent experiments, addition of EGTA (Ca2+ chelating agent), nifedipine (L-type channel blocker) or mibefradil (T-type channel blocker) blunted as expected the response to ANG II in wild-type vessels. In sharp contrast, these agents did not affect vessel responsiveness in Notch3-/- indicating dysfunctional extracellular Ca2+-entry. Abolishing stored Ca2+ with thapsigargine, reduced Ca2+ responses equally in both strains, signifying intact Ca2+-mobilization in Notch3-/- vessels. In contrast to renal resistance vessels, pre-capillary muscle arterioles of Notch3-/- mice reacted normally to ANG II, suggesting a focal role of Notch3 in the renal vasculature. Conclusions: Notch3-/- mice display deficient renal vascular reactivity because of blunted expression and function of calcium channels. Consequently, intact Notch3 expression is necessary for proper regulation of renal vascular tone in the kidney, whereas dysfunction of Notch3 can have important physiopathological consequences by impairing regulation of renal hemodynamics

Role of thromboxane receptors in the dipsogenic response to central angiotensin II

2002 ◽  
Vol 282 (3) ◽  
pp. R865-R869 ◽  
Author(s):  
Chagriya Kitiyakara ◽  
William J. Welch ◽  
Joseph G. Verbalis ◽  
Christopher S. Wilcox
Keyword(s):  
Angiotensin Ii ◽  
Water Intake ◽  
Ang Ii ◽  
Tp Receptor ◽  
Drinking Response ◽  
Tp Receptors ◽  
Thromboxane Receptors ◽  
Prostaglandin H ◽  
The Brain

Central angiotensin II (ANG II) regulates thirst. Because thromboxane A2-prostaglandin H2 (TP) receptors are expressed in the brain and mediate some of the effects of ANG II in the vasculature, we investigated the hypothesis that TP receptors mediate the drinking response to intracerebroventricular (icv) injections of ANG II. Pretreatment with the specific TP-receptor antagonist ifetroban (Ifet) decreased water intake with 50 ng/kg icv ANG II (ANG II + Veh, 7.2 ± 0.7 ml vs. ANG II + Ifet, 2.8 ± 0.8 ml; n = 5 rats; P < 0.001) but had no effect on water intake induced by hypertonic saline (NaCl + Veh, 8.4 ± 1.1 ml vs. NaCl + Ifet, 8.9 ± 1.8 ml; n = 5 rats; P = not significant). Administration of 0.6 μg/kg icv of the TP-receptor agonist U-46,619 did not induce drinking when given alone but did increase the dipsogenic response to a near-threshold dose of 15 ng/kg icv ANG II (ANG II + Veh, 1.1 ± 0.7 vs. ANG II + U-46,619, 4.5 ± 0.9 ml; n = 5 rats; P < 0.01). We conclude that central TP receptors contribute to the dipsogenic response to ANG II.

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