scholarly journals Peroxisome Proliferator-Activated Receptor-αActivation Decreases Mean Arterial Pressure, Plasma Interleukin-6, and COX-2 While Increasing Renal CYP4A Expression in an Acute Model of DOCA-Salt Hypertension

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Dexter L. Lee ◽  
Justin L. Wilson ◽  
Rong Duan ◽  
Tamaro Hudson ◽  
Ahmed El-Marakby
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Interleukin 6 ◽  
Corn Oil ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Salt Hypertension ◽  
Cox 2

Peroxisome proliferator-activated receptor-alpha (PPAR-α) activation by fenofibrate reduces blood pressure and sodium retention during DOCA-salt hypertension. PPAR-αactivation reduces the expression of inflammatory cytokines, such as interleukin-6 (IL-6). Fenofibrate also induces cytochrome P450 4A (CYP4A) and increases 20-hydroxyeicosatetraenoic acid (20-HETE) production. This study tested whether the administration of fenofibrate would reduce blood pressure by attenuating plasma IL-6 and renal expression of cyclooxygenase-2 (COX-2), while increasing expression of renal CYP4A during 7 days of DOCA-salt hypertension. We performed uni-nephrectomy on 12–14 week old male Swiss Webster mice and implanted biotelemetry devices in control, DOCA-salt (1.5 mg/g) treated mice with or without fenofibrate (500 mg/kg/day in corn oil, intragastrically). Fenofibrate significantly decreased mean arterial pressure and plasma IL-6. In kidney homogenates, fenofibrate increased CYP4A and decreased COX-2 expression. There were no differences in renal cytochrome P450, family 2, subfamily c, polypeptide 23 (CYP2C23) and soluble expoxide hydrolase (sEH) expression between the groups. Our results suggest that the blood pressure lowering effect of PPAR-αactivation by fenofibrate involves the reduction of plasma IL-6 and COX-2, while increasing CYP4A expression during DOCA-salt hypertension. Our results may also suggest that PPAR-αactivation protects the kidney against renal injury via decreased COX-2 expression.

scholarly journals Brain Testosterone-CYP1B1 (Cytochrome P450 1B1) Generated Metabolite 6β-Hydroxytestosterone Promotes Neurogenic Hypertension and Inflammation

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 1006-1018
Author(s):  
Purnima Singh ◽  
Shubha Ranjan Dutta ◽  
Chi Young Song ◽  
SaeRam Oh ◽  
Frank J. Gonzalez ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Paraventricular Nucleus ◽  
Male Mice ◽  
Cytochrome P450 1B1 ◽  
Induced Hypertension ◽  
The Brain

Previously, we showed that peripheral administration of 6β-hydroxytestosterone, a CYP1B1 (cytochrome P450 1B1)-generated metabolite of testosterone, promotes angiotensin II-induced hypertension in male mice. However, the site of action and the underlying mechanism by which 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension is not known. Angiotensin II increases blood pressure by its central action, and CYP1B1 is expressed in the brain. This study was conducted to determine whether testosterone-CYP1B1 generated metabolite 6β-hydroxytestosterone locally in the brain promotes the effect of systemic angiotensin II to produce hypertension in male mice. Central CYP1B1 knockdown in wild-type ( Cyp1b1 +/+ ) mice by intracerebroventricular-adenovirus-GFP (green fluorescence protein)-CYP1B1-short hairpin (sh)RNA attenuated, whereas reconstitution of CYP1B1 by adenovirus-GFP-CYP1B1-DNA in the paraventricular nucleus but not in subfornical organ in Cyp1b1 −/− mice restored angiotensin II-induced increase in systolic blood pressure measured by tail-cuff. Intracerebroventricular-testosterone in orchidectomized (Orchi)- Cyp1b1 +/+ but not in Orchi- Cyp1b1 −/− , and intracerebroventricular-6β-hydroxytestosterone in the Orchi- Cyp1b1 −/− mice restored the angiotensin II-induced: (1) increase in mean arterial pressure measured by radiotelemetry, and autonomic imbalance; (2) reactive oxygen species production in the subfornical organ and paraventricular nucleus; (3) activation of microglia and astrocyte, and neuroinflammation in the paraventricular nucleus. The effect of intracerebroventricular-6β-hydroxytestosterone to restore the angiotensin II-induced increase in mean arterial pressure and autonomic imbalance in Orchi- Cyp1b1 −/− mice was inhibited by intracerebroventricular-small interfering (si)RNA-androgen receptor (AR) and GPRC6A (G protein-coupled receptor C6A). These data suggest that testosterone-CYP1B1-generated metabolite 6β-hydroxytestosterone, most likely in the paraventricular nucleus via AR and GPRC6A, contributes to angiotensin II-induced hypertension and neuroinflammation in male mice.

CHARACTERISTICS OF 24-HOUR BLOOD PRESSURE INDICATORS IN PATIENTS WITH HYPERTENSION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE

2020 ◽  
pp. 31-41
Author(s):  
M.A. Bubnova ◽  
O.N. Kryuchkova
Keyword(s):  
Blood Pressure ◽  
Chronic Obstructive Pulmonary Disease ◽  
Mean Arterial Pressure ◽  
High Risk ◽  
Arterial Pressure ◽  
Pulmonary Disease ◽  
Comparison Group ◽  
Cardiovascular Complications ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

Patients with hypertension (HT) and chronic obstructive pulmonary disease (COPD) have a high risk of cardiovascular complications. Up to now, there is no optimal strategy for combined antihypertensive therapy. Still, the data of 24-hour blood pressure monitoring (BPM) are important while choosing treatment tactics. The aim of the paper is to study the features of indicators in patients with arterial hypertension (AH) and COPD. Materials and methods. 130 patients with HT were included in the study. The main group (n=90) included comorbid patients with HT and COPD, their average age was 61.30±1.01; the comparison group (n=40) consisted of patients with HT, their average age was 59.10±1.53. All patients underwent 24-hour BPM. Results. Comorbid patients revealed an increase in the mean 24-hour and night systolic and mean arterial pressure values as well as a significant increase in the load index of systolic, diastolic and mean arterial pressure. Also, comorbid patients demonstrated higher blood pressure in contrast to the patients of the comparison group. They had increased systolic, diastolic and mean blood pressure variability and a quicker rate of morning blood pressure rise. According to 24-hour blood pressure dynamics, pathological types of the 24-hour blood pressure curve, a higher frequency of the night-peaker profile dominated in patients with COPD if compared to patients with HT. Conclusion. The obtained data indicated a high risk of cardiovascular complications in comorbid patients, early target organ damage and an unfavorable disease prognosis. It means that both further study of hypertension clinical course in such patients and personalization of antihypertensive therapy are relevant. Keywords: hypertension, chronic obstructive pulmonary disease, 24-hour monitoring, blood pressure. Пациенты с артериальной гипертензией (АГ) и хронической обструктивной болезнью легких (ХОБЛ) имеют высокий риск возникновения кардиоваскулярных осложнений. В настоящее время в лечении не определена наиболее оптимальная стратегия комбинированной антигипертензивной терапии. Для выбора тактики терапии важную роль играют показатели суточного мониторирования артериального давления (СМАД). Цель. Изучить особенности показателей СМАД у пациентов с АГ на фоне ХОБЛ. Материалы и методы. В исследование включено 130 пациентов с АГ. В основную группу (n=90) вошли пациенты с АГ и ХОБЛ (средний возраст – 61,30±1,01 года), в группу сравнения (n=40) – больные только АГ (средний возраст – 59,10±1,53 года). Всем пациентам проведено СМАД. Результаты. У пациентов с коморбидностью выявлены следующие особенности суточных показателей артериального давления: увеличение значений среднесуточных и средненочных показателей систолического и среднего артериального давления; существенное повышение индекса нагрузки систолическим, диастолическим и средним артериальным давлением. Также эти больные отличались от пациентов группы сравнения более высокими значениями пульсового давления, имели повышенную вариабельность систолического, диастолического и среднего артериального давления, у них наблюдалось увеличение скорости утреннего подъема артериального давления. Суточная динамика артериального давления у пациентов с ХОБЛ характеризовалась преобладанием патологических типов суточной кривой АД, более высокой частотой профиля night-peaker по сравнению с больными только АГ. Выводы. Выявленные особенности свидетельствуют о высоком риске сердечно-сосудистых осложнений у пациентов с коморбидностью, раннем поражении органов-мишеней и неблагоприятном прогнозе заболевания, что требует дальнейшего изучения особенностей клинического течения АГ у таких больных и индивидуализации антигипертензивной терапии. Ключевые слова: артериальная гипертензия, хроническая обструктивная болезнь легких, суточное мониторирование, артериальное давление.

The emerging role of COX-2, 15-LOX, and PPARγ in metabolic diseases and cancer: An introduction to novel multi-target directed ligands (MTDLs)

2020 ◽  
Vol 27 ◽  
Author(s):  
Rana A. Alaaeddine ◽  
Perihan A. Elzahhar ◽  
Ibrahim AlZaim ◽  
Wassim Abou-Kheir ◽  
Ahmed S.F. Belal ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Biological Effects ◽  
Arachidonic Acid Metabolism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cellular Targets ◽  
Design And Synthesis ◽  
Early Results ◽  
Cox 2

: Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro-and anti-tumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarize the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

scholarly journals Plasticity in breathing and arterial blood pressure following acute intermittent hypercapnic hypoxia in infant rat pups with a partial loss of 5-HT neurons

2015 ◽  
Vol 309 (10) ◽  
pp. R1273-R1284 ◽  
Author(s):  
Jennifer Magnusson ◽  
Kevin J. Cummings
Keyword(s):  
Blood Pressure ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Arterial Blood Pressure ◽  
Cardiovascular Responses ◽  
Partial Loss ◽  
Rat Pups ◽  
Arterial Blood ◽  
Hypercapnic Hypoxia ◽  
Long Term Facilitation

The role of serotonin (5-HT) neurons in cardiovascular responses to acute intermittent hypoxia (AIH) has not been studied in the neonatal period. We hypothesized that a partial loss of 5-HT neurons would reduce arterial blood pressure (BP) at rest, increase the fall in BP during hypoxia, and reduce the long-term facilitation of breathing (vLTF) and BP following AIH. We exposed 2-wk-old, 5,7-dihydroxytryptamine-treated and controls to AIH (10% O2; n = 13 control, 14 treated), acute intermittent hypercapnia (5% CO2; n = 12 and 11), or acute intermittent hypercapnic hypoxia (AIHH; 10% O2, 5% CO2; n = 15 and 17). We gave five 5-min challenges of AIH and acute intermittent hypercapnia, and twenty ∼20-s challenges of AIHH to mimic sleep apnea. Systolic BP (sBP), diastolic BP, mean arterial pressure, heart rate (HR), ventilation (V̇e), and metabolic rate (V̇o2) were continuously monitored. 5,7-Dihydroxytryptamine induced an ∼35% loss of 5-HT neurons from the medullary raphe. Compared with controls, pups deficient in 5-HT neurons had reduced resting sBP (∼6 mmHg), mean arterial pressure (∼5 mmHg), and HR (56 beats/min), and experienced a reduced drop in BP during hypoxia. AIHH induced vLTF in both groups, reflected in increased V̇e and V̇e/V̇o2, and decreased arterial Pco2. The sBP of pups deficient in 5-HT neurons, but not controls, was increased 1 h following AIHH. Our data suggest that a relatively small loss of 5-HT neurons compromises resting BP and HR, but has no influence on ventilatory plasticity induced by AIHH. AIHH may be useful for reversing cardiorespiratory defects related to partial 5-HT system dysfunction.

Hypotensive and Regional Haemodynamic Effects of Exercise, Fasted and after Food, in Human Sympathetic Denervation

1998 ◽  
Vol 94 (1) ◽  
pp. 49-55 ◽  
Author(s):  
Sharmini Puvi-Rajasingham ◽  
Gareth D. P. Smith ◽  
Adeola Akinola ◽  
Christopher J. Mathias
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Superior Mesenteric Artery ◽  
Vascular Resistance ◽  
Mesenteric Artery ◽  
Autonomic Failure ◽  
Sympathetic Denervation ◽  
Stroke Distance

1. In human sympathetic denervation due to primary autonomic failure, food and exercise in combination may produce a cumulative blood pressure lowering effect due to simultaneous splanchnic and skeletal muscle dilatation unopposed by corrective cardiovascular reflexes. We studied 12 patients with autonomic failure during and after 9 min of supine exercise, when fasted and after a liquid meal. Standing blood pressure was also measured before and after exercise. 2. When fasted, blood pressure fell during exercise from 162 ± 7/92 ± 4 to 129 ± 9/70 ± 5 mmHg (mean arterial pressure by 22 ± 5%), P < 0.0005. After the meal, blood pressure fell from 159 ± 8/88 ± 6 to 129 ± 6/70 ± 4 mmHg (mean arterial pressure by 22 ± 3%), P < 0.0001, and further during exercise to 123 ± 6/61 ± 3 mmHg (mean arterial pressure by 9 ± 3%), P < 0.01. The stroke distance—heart rate product, an index of cardiac output, did not change after the meal. During exercise, changes in the stroke distance—heart rate product were greater when fasted. 3. Resting forearm and calf vascular resistance were higher when fasted. Calf vascular resistance fell further after exercise when fasted. Resting superior mesenteric artery vascular resistance was lower when fed; 0.19 ± 0.02 compared with 032 ± 0.06, P < 0.05. After exercise, superior mesenteric artery vascular resistance had risen by 82%, to 0.53 ± 0.12, P < 0.05 (fasted) and by 47%, to 0.29 ± 0.05, P < 0.05 (fed). 4. On standing, absolute levels of blood pressure were higher when fasted [83 ± 7/52 ± 7 compared with 71 ± 2/41 ± 3 (fed), each P < 0.05]. Subjects were more symptomatic on standing post-exercise when fed. 5. In human sympathetic denervation, exercise in the fed state lowered blood pressure further than when fasted and worsened symptoms of postural hypotension.

Increased vascular resistance in paralyzed legs after spinal cord injury is reversible by training

2002 ◽  
Vol 93 (6) ◽  
pp. 1966-1972 ◽  
Author(s):  
Maria T. E. Hopman ◽  
Jan T. Groothuis ◽  
Marcel Flendrie ◽  
Karin H. L. Gerrits ◽  
Sibrand Houtman
Keyword(s):  
Blood Pressure ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Blood Flow ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Vascular Resistance ◽  
Arterial Blood Flow ◽  
Arterial Blood ◽  
Cord Injury

The purpose of the present study was to determine the effect of a spinal cord injury (SCI) on resting vascular resistance in paralyzed legs in humans. To accomplish this goal, we measured blood pressure and resting flow above and below the lesion (by using venous occlusion plethysmography) in 11 patients with SCI and in 10 healthy controls (C). Relative vascular resistance was calculated as mean arterial pressure in millimeters of mercury divided by the arterial blood flow in milliliters per minute per 100 milliliters of tissue. Arterial blood flow in the sympathetically deprived and paralyzed legs of SCI was significantly lower than leg blood flow in C. Because mean arterial pressure showed no differences between both groups, leg vascular resistance in SCI was significantly higher than in C. Within the SCI group, arterial blood flow was significantly higher and vascular resistance significantly lower in the arms than in the legs. To distinguish between the effect of loss of central neural control vs. deconditioning, a group of nine SCI patients was trained for 6 wk and showed a 30% increase in leg blood flow with unchanged blood pressure levels, indicating a marked reduction in vascular resistance. In conclusion, vascular resistance is increased in the paralyzed legs of individuals with SCI and is reversible by training.

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