Abstract MP57: Chronic Inhibition Of Brain Rhomboid-like Protein 2 (irhom2) Activity Decreases Arterial Blood Pressure In Salt-sensitive Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Mazher Mohammed ◽  
Mona Elgazzaz ◽  
Clara Berdasco ◽  
Eric D Lazartigues
Keyword(s):  
Blood Pressure ◽  
Neutralizing Antibody ◽  
Experimental Models ◽  
Arterial Blood ◽  
Artificial Cerebrospinal Fluid ◽  
Tnf Α ◽  
Significant Attenuation ◽  
Factor Α ◽  
Salt Sensitive Hypertension ◽  
The Brain

We previously reported that ADAM17 (aka tumor necrosis factor-α convertase) is critical for the development of hypertension in experimental models and patients. Recent studies highlighted that ADAM17’s formation of TNF-α relies on prior maturation of this sheddase, controlled by the rhomboid-like protein 2 (iRhom2) specifically in microglia. Genetic deletion of iRhom2 in mice shows significant attenuation of TNF-α and ADAM17 activity in a tissue specific manner. Here, we hypothesized that silencing iRhom2 activity specifically in the brain would decrease blood pressure (BP) in the DOCA-salt model of hypertension, in mice. Uninephrectomized mice were implanted subcutaneously (sc) with DOCA-pellets (50 mg) and provided with 1% saline in drinking water. In addition, mice were chronically implanted with an icv cannula connected to a sc osmotic minipump for delivery of: (1) iRhom2-siRNA (9.6 μg/kg/day), (2) scrambled siRNA (SCR 0.2 μg/kg/day), (3) ADAM17 antibody (ADAM17-Ab; 23.8 μg/kg/day) or (4) artificial cerebrospinal fluid (aCSF) for 2 weeks while BP was recorded by telemetry. DOCA-salt treatment led to a significant increase in BP in the control groups (SCR: 156 ±3 mmHg and aCSF: 161 ±1 mmHg; n=3/group; p<0.001) compared to baseline values (122 ±2 mmHg; n=12). ICV infusion of iRhom2-siRNA or ADAM17 neutralizing antibody for 2-weeks in DOCA-salt-treated mice resulted in a significant attenuation of BP (iRhom2-siRNA: 152 ±2 mmHg and ADAM17-Ab: 151 ±2 mmHg n=3/group, p<0.001). These data suggest that: 1) Selective silencing of iRhom2 from microglia is as potent as ADAM17 neutralization throughout the brain in lowering BP and 2) iRhom2 is a potential new therapeutic target for the treatment of salt-sensitive hypertension.

Abstract 119: Influence of Anesthetics on the Hemodynamic Response in a Rat Model of Hemorrhagic Shock

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Claudius Balzer ◽  
Franz J Baudenbacher ◽  
Susan S Eagle ◽  
Michele M Salzman ◽  
William J Cleveland ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Hemorrhagic Shock ◽  
Rat Model ◽  
Cardiovascular Response ◽  
Femoral Vein ◽  
Blood Pressure Measurement ◽  
Experimental Models ◽  
Sprague Dawley ◽  
Compensatory Mechanisms ◽  
Arterial Blood

Introduction: Experimental models of hemorrhagic shock (HS) in rats are important to test new treatments that may improve outcomes in humans, and general anesthesia is required during these experiments. The volatile anesthetic Isoflurane is known for its beneficial effects in rat HS models. Focusing on cardiovascular compensatory mechanisms, we wanted to evaluate Isoflurane versus the injectable anesthetic Pentobarbital in our rat model of mild HS (class 2). We hypothesize that Isoflurane during development of HS improves hemodynamics compared to Pentobarbital. Methods: Twelve Sprague-Dawley rats were initially anesthetized with an intraperitoneal (IP) injection of Pentobarbital (45 mg/kg) and intubated (1 L/min, FiO 2 0.25); heart rate (HR) was monitored by subcutaneous ECG needles. Femoral artery and vein were cannulated for continuous blood pressure measurement and delivery of fluids, respectively. In one group (n=7), anesthesia was continued with repeated IP injections of Pentobarbital (dose mg/kg), the other group (n=5) received continuous Isoflurane (1%). After 30 min of stabilization and administration of Heparin (100 IU/kg), HS was induced by removal of 1 ml of blood over 1 min via the femoral vein, repeated every 3 min until a volume of 5 ml of blood was removed. Mean arterial blood pressure (MAP) and HR were recorded and analyzed in LabChart. Results: During baseline, rats showed no significant differences in HR and MAP between both groups. After 5 ml of hemorrhage, both groups showed significant changes compared to baseline, with significantly higher MAP and HR in rats given only Pentobarbital. Conclusions: In our rat model of HS, Isoflurane dampens the physiologic response to compensate for mild hemorrhage. The cardiovascular response of rats in the Isoflurane group was a decrease of HR and MAP to every ml of hemorrhage, while rats given only Pentobarbital were able to maintain their MAP by raising their HR until decompensation.

Vasodilation of cat cerebral arterioles by prostaglandins D2, E2, G2, and I2

1979 ◽  
Vol 237 (3) ◽  
pp. H381-H385 ◽  
Author(s):  
E. F. Ellis ◽  
E. P. Wei ◽  
H. A. Kontos
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Arterial Blood Pressure ◽  
Standard Error ◽  
Arterial Blood ◽  
Cerebral Arterioles ◽  
The Mean ◽  
Dose Dependent ◽  
The Brain

To determine the possible role that endogenously produced prostaglandins may play in the regulation of cerebral blood flow, the responses of cerebral precapillary vessels to prostaglandins (PG) D2, E2, G2, and I2 (8.1 X 10(-8) to 2.7 X 10(-5) M) were studied in cats equipped with cranial windows for direct observation of the microvasculature. Local application of PGs induced a dose-dependent dilation of large (greater than or equal to 100 microns) and small (less than 100 microns) arterioles with no effect on arterial blood pressure. The relative vasodilator potency was PGG2 greater than PGE2 greater than PGI2 greater than PGD2. With all PGs, except D2, the percent dilation of small arterioles was greater than the dilation of large arterioles. After application of prostaglandins in a concentration of 2.7 X 10(-5) M, the mean +/- standard error of the percent dilation of large and small arterioles was, respectively, 47.6 +/- 2.7 and 65.3 +/- 6.1 for G2, 34.1 +/- 2.0, and 53.6 +/- 5.5 for E2, 25.4 +/- 1.8, and 40.2 +/- 4.6 for I2, and 20.3 +/- 2.5 and 11.0 +/- 2.2 for D2. Because brain arterioles are strongly responsive to prostaglandins and the brain can synthesize prostaglandins from its large endogenous pool of prostaglandin precursor, prostaglandins may be important mediators of changes in cerebral blood flow under normal and abnormal conditions.

Insights into Dahl salt-sensitive hypertension revealed by temporal patterns of renal medullary gene expression

2003 ◽  
Vol 12 (3) ◽  
pp. 229-237 ◽  
Author(s):  
Mingyu Liang ◽  
Baozhi Yuan ◽  
Elizabeth Rute ◽  
Andrew S. Greene ◽  
Michael Olivier ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Injury ◽  
Time Course ◽  
Expression Patterns ◽  
Renal Medulla ◽  
Temporal Patterns ◽  
Reference Distribution ◽  
Arterial Blood ◽  
Renal Tubular ◽  
Salt Sensitive Hypertension

Dahl salt-sensitive SS and consomic, salt-resistant SS-13BN/Mcw rats possess a highly similar genetic background but exhibit substantial differences in blood pressure salt sensitivity. We used cDNA microarrays to examine sequential changes of mRNA expression of ∼2,000 currently known rat genes in the renal medulla (a tissue critical for long-term blood pressure regulation) in SS and SS-13BN/Mcw rats in response to a high-salt diet (16 h, 3 days, or 2 wk). Differentially expressed genes in each between-group comparison were identified based on a threshold determined experimentally using a reference distribution that was constructed by comparing rats within the same group. A difference analysis of 54 microarrays identified 50 genes that exhibited the most distinct temporal patterns of expression between SS and SS-13BN/Mcw rats over the entire time course. Thirty of these genes could be linked to the regulation of arterial blood pressure or renal injury based on their known involvement in functional pathways such as renal tubular transport, metabolism of vasoactive substances, extracellular matrix formation, and apoptosis. Importantly, the majority of the 30 genes exhibited temporal expression patterns that would be expected to lower arterial pressure and reduce renal injury in SS-13BN/Mcw compared with SS rats. The phenotypic impact of the other 20 genes was less clear. These 50 genes are widely distributed on chromosome 13 and several other chromosomes. This suggested that primary genetic defects, although important, are unlikely to be solely responsible for the full manifestation of this type of hypertension and associated injury phenotypes. In summary, the results of this study identified a number of pathways potentially important for the amelioration of hypertension and renal injury in SS-13BN/Mcw rats, and these results generated a series of testable hypotheses related to the role of the renal medulla in the complex mechanism of salt-sensitive hypertension.

Abstract 081: Reporter Mouse Strain Provides a Novel Look at Angiotensin Type-2 Receptor Distribution in Central Nervous System Cardiovascular Control Centers

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Annette D de Kloet ◽  
Lei Wang ◽  
Jacob A Ludin ◽  
Helmut Hiller ◽  
Justin A Smith ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Fluid Balance ◽  
Hypothalamic Nucleus ◽  
Reporter Mouse ◽  
Arterial Blood ◽  
Egfp Reporter ◽  
Angiotensin Type 2 Receptor ◽  
The Brain ◽  
Angiotensin Type

It is established that angiotensin-II acts at its type-1 receptor (AT1R) in the brain to increase sympathetic outflow and blood pressure, and modulate fluid balance. However, the role of the angiotensin type-2 receptor (AT2R) in the neural control of these processes has received far less attention, largely because of an inability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-eGFP reporter mouse with recent advances in in situ hybridization (ISH) to circumvent this obstacle. Dual IHC/ ISH studies validated the AT2R-eGFP reporter mice by determining that eGFP and AT2R mRNA were highly co-localized within the nucleus of the solitary tract (NTS; 98.0 ± 0.18 %; 125 ± 3.6 of 127 ± 3.9 cells; n = 4). Analysis of eGFP immunoreactivity in the brain revealed localization to neurons within nuclei that regulate blood pressure and fluid balance (e.g., NTS and median preoptic nucleus [MnPO]). Additional IHC/ISH studies uncovered the phenotype of specific AT2R-eGFP cells. For example, within the NTS, AT2R-eGFP neurons primarily express glutamic acid decarboxylase-67 (GABAergic; 80 ± 2.8 %; 225 ± 12.5 of 280 ± 8.4 cells; n = 4), while only a subset express vesicular glutamate transporter-2 (glutamatergic; 18.2 ± 2.9 %; 50.8 ± 7.7 of 280 ± 8.4 cells) or AT1R (8.7 ± 1.0 %; 22 ± 2.2 of 256 ± 11.7 cells). No co-localization was observed with tyrosine hydroxylase in the NTS. Although AT2R-eGFP neurons were not observed within the paraventricular hypothalamic nucleus (PVN), eGFP was localized to efferents terminating in the PVN and to GABAergic neurons surrounding this nucleus. Retrograde neuronal tract tracing studies revealed that many eGFP-positive efferents to the PVN arise from neurons in the MnPO. Based on these neuroanatomical results, we hypothesized that activation of central AT2R would decrease blood pressure. Consistent with this hypothesis, chronic administration of the selective AT2R agonist, compound 21 (7.5 ng/h into the lateral cerebral ventricle) reduced baseline mean arterial blood pressure relative to control mice (103 ± 1.65 v. 110 ± 1.70 mmHg; n = 16; p = 0.02). These studies demonstrate that central AT2R are positioned to regulate blood pressure.

Central effect of endothelin on blood pressure in conscious rats

1989 ◽  
Vol 256 (6) ◽  
pp. H1747-H1751 ◽  
Author(s):  
Y. Ouchi ◽  
S. Kim ◽  
A. C. Souza ◽  
S. Iijima ◽  
A. Hattori ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Conscious Rats ◽  
Arterial Blood ◽  
Norepinephrine Concentration ◽  
Artificial Cerebrospinal Fluid ◽  
Male Wistar Rats ◽  
The Mean ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Lateral Cerebral Ventricle

This study was conducted to investigate the effect of intracerebroventricular administration of endothelin (EDT), a novel potent vasoconstricting peptide, on blood pressure in conscious rats. The lateral cerebral ventricle of male Wistar rats was cannulated, and the femoral artery was also cannulated to measure the mean arterial blood pressure (MABP) and heart rate (HR). EDT dissolved in 10 microliters of artificial cerebrospinal fluid (ACSF) (8.25-66 pmol icv) provoked a dose-dependent increase in MABP. EDT also increased HR, although the effect of 66 pmol was variable. Intracerebroventricular ACSF did not provoke any effects on MABP and HR. Intracerebroventricular EDT also provoked contralateral rotational behavior. Pretreatment with 2 mg/kg iv phenoxybenzamine significantly suppressed the 16.5 pmol icv EDT-induced increase in MABP. Moreover, 16.5 pmol icv EDT markedly increased plasma epinephrine and norepinephrine concentration. These results indicate that EDT has a central pressor action, and the action might be mediated, at least in part, by catecholamine release to the periphery. EDT might play a role in the central control of blood pressure, although the physiological implications have not yet been determined.

Is the renal production of erythropoietin controlled by the brain stem?

2005 ◽  
Vol 289 (1) ◽  
pp. E82-E86 ◽  
Author(s):  
Ursula von Wussow ◽  
Janina Klaus ◽  
Horst Pagel
Keyword(s):  
Blood Pressure ◽  
Brain Stem ◽  
Structure And Function ◽  
Humoral Factors ◽  
Arterial Blood ◽  
Arterial Ph ◽  
Sensitive Sensor ◽  
Releasing Factors ◽  
And Function ◽  
The Brain

Although the structure and function of erythropoietin (Epo) are well documented, the mechanisms of the regulation of the renal synthesis of Epo are still poorly understood. Especially, the description of the localization and function of the O2-sensitive sensor regulating the renal synthesis of Epo is insufficient. A body of evidence suggests that extrarenal O2-sensitive sensors, localized particularly in the brain stem, play an important role in this connection. To support this concept, high cerebral pressure with consecutive hypoxia of the brain stem was generated by insufflation of synthetic cerebrospinal fluid into the catheterized cisterna magna of rats. When the cerebral pressure of the rats was above the level of their mean arterial blood pressure or the high cerebral pressure persisted for a longer period (≥10 min), the Epo plasma concentration increased significantly. Bilateral nephrectomy or hypophysectomy before initiation of high intracranial pressure abolished this effect. Systemic parameters (heart rate, blood pressure, PaO2, PaCO2, arterial pH, renal blood flow, glucose concentration in blood) were not affected. Other stressors, like restricting the mobility of the rats, had no effect on Epo production. Hence, the effect of high cerebral pressure on renal synthesis of Epo seems to be specific. Increasing cerebral hydrostatic pressure leads to increased renal synthesis of Epo. Obviously, during hypoxia, cerebral O2-sensitive sensors release humoral factors, triggering the renal synthesis of Epo. The structure and function of these “Epo-releasing-factors” will have to be characterized in future experiments.

Regulation of intracellular polyamine biosynthesis and transport by NO and cytokines TNF-α and IFN-γ

1999 ◽  
Vol 276 (4) ◽  
pp. C892-C899 ◽  
Author(s):  
Joseph Satriano ◽  
Shunji Ishizuka ◽  
D. Clay Archer ◽  
Roland C. Blantz ◽  
Carolyn J. Kelly
Keyword(s):  
Cellular Proliferation ◽  
Interferon Γ ◽  
Experimental Models ◽  
Proximal Tubule Cell ◽  
Polyamine Biosynthesis ◽  
No Donors ◽  
Temporal Regulation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α

Nitric oxide (NO) has been described to exert cytostatic effects on cellular proliferation; however the mechanisms responsible for these effects have yet to be fully resolved. Polyamines, conversely, are required components of cellular proliferation. In experimental models of inflammation, a relationship between these two pathways has been suggested by the temporal regulation of a common precursor, arginine. This study was undertaken to determine the effects NO and the NO synthase (NOS)-inducing cytokines, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), exert on polyamine regulation. The transformed kidney proximal tubule cell line, MCT, maintains high constitutive levels of the first polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). NO donors markedly suppressed ODC activity in MCT and all other cell lines examined. TNF-α and IFN-γ induction of NO generation resulted in suppressed ODC activity, an effect prevented by the inducible NOS inhibitorl- N 6-(1-iminoethyl)lysine (l-NIL). Dithiothreitol reversal of NO-mediated ODC suppression supports nitrosylation as the mechanism of inactivation. We also evaluated polyamine uptake, inasmuch as inhibition of ODC can result in a compensatory induction of polyamine transporters. Administration of NO donors, or TNF-α and IFN-γ, suppressed [3H]putrescine uptake, thereby preventing transport-mediated reestablishment of intracellular polyamine levels. This study demonstrates the capacity of NO and inflammatory cytokines to regulate both polyamine biosynthesis and transport.

Sodium-, potassium-, chloride-, and bicarbonate-related effects on blood pressure and electrolyte homeostasis in deoxycorticosterone acetate-treated rats

2008 ◽  
Vol 295 (6) ◽  
pp. F1752-F1763 ◽  
Author(s):  
Agata Ziomber ◽  
Agnes Machnik ◽  
Anke Dahlmann ◽  
Peter Dietsch ◽  
Franz-Xaver Beck ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Male Rats ◽  
Sodium Potassium ◽  
Arterial Blood ◽  
Electrolyte Homeostasis ◽  
Water Mass Balance ◽  
Group 2 ◽  
Total Body ◽  
Salt Sensitive Hypertension ◽  
Volume Retention

Na+ loading without Cl− fails to increase blood pressure in the DOCA model. We compared the changes in the total body (TB) effective Na+, K+, Cl−, and water (TBW) content as well as in intracellular (ICV) or extracellular (ECV) volume in rats receiving DOCA-NaCl, DOCA-NaHCO3, or DOCA-KHCO3. We divided 42 male rats into 5 groups. Group 1 was untreated, group 2 received 1% NaCl, and groups 3, 4, and 5 were treated with DOCA and received 1% NaCl, 1.44% NaHCO3, or 1.7% KHCO3 to drink. We measured mean arterial blood pressure (MAP) directly after 3 wk. Tissue electrolyte and water content was measured by chemical analysis. Compared with control rats, DOCA-NaCl increased MAP while DOCA-NaHCO3 and DOCA-KHCO3 did not. DOCA-NaCl increased TBNa+ 26% but only moderately increased TBW. DOCA-NaHCO3 led to similar TBNa+ excess, while TBW and ICV, but not ECV, were increased more than in DOCA-NaCl rats. DOCA-KHCO3 did not affect TBNa+ or volume. At a given TB(Na++K+) and TBW, MAP in DOCA-NaCl rats was higher than in control, DOCA-NaHCO3, and DOCA-KHCO3 rats, indicating that hypertension in DOCA-NaCl rats was not dependent on TB(Na++K+) and water mass balance. Skin volume retention was hypertonic compared with serum and paralleled hypertension in DOCA-NaCl rats. These rats had higher TB(Na++K+)-to-TBW ratio in accumulated fluid than DOCA-NaHCO3 rats. DOCA-NaCl rats also had increased intracellular Cl− concentrations in skeletal muscle. We conclude that excessive cellular electrolyte redistribution and/or intracellular Na+ or Cl− accumulation may play an important role in the pathogenesis of salt-sensitive hypertension.

scholarly journals Tumor necrosis factor-α: regulation of renal function and blood pressure

2013 ◽  
Vol 304 (10) ◽  
pp. F1231-F1242 ◽  
Author(s):  
Vanesa D. Ramseyer ◽  
Jeffrey L. Garvin
Keyword(s):  
Blood Pressure ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Immune Cell ◽  
Organ Damage ◽  
Physiological Status ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that becomes elevated in chronic inflammatory states such as hypertension and diabetes and has been found to mediate both increases and decreases in blood pressure. High levels of TNF-α decrease blood pressure, whereas moderate increases in TNF-α have been associated with increased NaCl retention and hypertension. The explanation for these disparate effects is not clear but could simply be due to different concentrations of TNF-α within the kidney, the physiological status of the subject, or the type of stimulus initiating the inflammatory response. TNF-α alters renal hemodynamics and nephron transport, affecting both activity and expression of transporters. It also mediates organ damage by stimulating immune cell infiltration and cell death. Here we will summarize the available findings and attempt to provide plausible explanations for such discrepancies.

scholarly journals Clerodendrum Chinensis Extracts; AeC and EeC Exerts Rapid Antihypertensive Effects in L-NAME Hypertensive Experimental Models

2020 ◽  
Author(s):  
Joy I. Odimegwu ◽  
Tolulope F. Okanlawon ◽  
Obumneme Noel ◽  
Ismail Ishola
Keyword(s):  
Blood Pressure ◽  
Communicable Disease ◽  
Scientific Basis ◽  
Experimental Models ◽  
Dependent Manner ◽  
Arterial Blood ◽  
High Doses ◽  
Mean Differences ◽  
Antihypertensive Properties ◽  
Dose Dependent

ABSTRACTBackgroundThe rise in occurrence of hypertension, a non-communicable disease and a major factor for chronic renal failure, cardiovascular disease, and stroke, which most times lead to sudden death is worrisome. Resistant hypertension is more common and may have no symptoms at all for months or years, but then can cause heart attack, stroke, and vision and kidney damage. Prevention and quick management of hypertension are therefore essential in reducing the risk of these debilitating ailments. Aqueous and ethanolic extracts of the leaves of Clerodendrum chinensis (AeC and EeC) are used by local communities of West Africa as medicine for rapid antihypertensive actions. We aim to discover the scientific basis for the use of the herb as medicine.MethodsThis work investigates the antihypertensive effects of AeC and EeC in L-Arginine Methyl Ester Hydrochloride (L-NAME)-induced hypertensive rats Acetylcholine, L-Arginine and Sodium Nitroprusside were used as standards. All results were expressed as means ± standard error of mean. Differences were considered significant at p <0.05.ResultsIntravenous administration of the extracts caused a significant decrease in the Mean Arterial Blood Pressure (MABP) in a dose-dependent manner. AeC at 100mg/kg caused a significant decline in blood pressure in a dose-related manner. Likewise at 100mg/kg, EeC reduced MABP steadily from 103.9± 2.55 to 34.1± 0.95mmHg. The two extracts; possess significant antihypertensive properties.ConclusionsBoth extracts show significant antihypertensive effects and at high doses could lead to hypotension and so should be used with care. Further research is necessary to determine safe dosage forms.

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