Oxidative Stress and Central Cardiovascular Regulation - Pathogenesis of Hypertension and Therapeutic Aspects (original) (raw)
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Archives of …, 2007
A b s t r a c t I In nt tr ro od du uc ct ti io on n: : Intraabdominal hypertension affects the central nervous system in addition to respiratory, renal and cardiovascular systems. This effect that, investigated in detail by clinical and experimental studies, is due to the increase of intracranial pressure and decrease of cerebral perfusion pressure caused by the increase of intrathoracic pressure and increase of pressure of great veins. However, no study has been found on biochemical changes on central nervous tissue due to intraabdomial hypertension. M Ma at te er ri ia al l a an nd d m me et th ho od ds s: : Thirty rats were divided into three groups containing 10 animals: sham group, study group I and study group II. In group I, intraabdominal pressure was elevated to 20 mmHg, and in group II, it was elevated to 30 mmHg for 60 minutes. Intracranial pressures (ICP) in all animals were monitored. Values of biochemical parameters including thiobarbituric acid, nitrite oxide, xanthine oxidase, protein carbonyls and protein sulfhydryl in cortical, subcortical, cerebellar and spinal cord tissues were compared with the corresponding values in sham rats. R Re es su ul lt ts s: : Thiobarbituric acid (0.58±0.8 and 0.76±0.04 vs. 0.23±0.03, p<0.05 and p<0.001), nitrite oxide (3.11±0.10 and 8.46±0.54 vs. 1.52±0.18, p<0.05 and p<0.001), xantine oxidase (1.55±0.11 and 3.01±0.25 vs. 0.32±0.09, p<0.001) and carbonyl levels (1.41±0.01 and 1.69±0.01 vs. 1.22±0.03, p<0.001) of the various central nervous system regions and ICP were increased. SH levels (92.60±2.50 and 74.60±3.80 vs. 139.20±4.72, p<0.001) were decreased after intraabdominal hypertension, and higher IAP generally caused more detrimental effects on these parameters. The levels of spinal cord and cerebellum samples were significantly worse in the study groups for most of the markers. C Co on nc cl lu us si io on ns s: : Intraabdominal hypertension may cause biochemical changes representing oxidative stress on various regions of central nervous system even 60 minutes after increase of intraabdominal pressure, and higher IAH causes more detrimental effects. Most prominent effects were seen in spinal cord and cerebellar tissue suggesting that compression of lumbar vertebral venous pressure might have a role in addition to increase of ICP due to increase of pressure of great veins caused by increase of intrathoracic pressure.
Acute hypertension induces oxidative stress in brain tissues
Journal of Cerebral Blood Flow & Metabolism, 2006
Arterial hypertension is not only a major risk factor for cerebrovascular accidents, such as stroke and cerebral hemorrhage, but is also associated to milder forms of brain injury. One of the main causes of neurodegeneration is the increase in reactive oxygen species (ROS) that is also a common trait of hypertensive conditions, thus suggesting that such a mechanism could play a role even in the onset of hypertension-evoked brain injury. To investigate this issue, we have explored the effect of acute-induced hypertensive conditions on cerebral oxidative stress. To this aim, we have developed a mouse model of transverse aortic coarctation (TAC) between the two carotid arteries, which imposes acutely on the right brain hemisphere a dramatic increase in blood pressure. Our results show that hypertension acutely induced by aortic coarctation induces a breaking of the blood-brain barrier (BBB) and reactive astrocytosis through hyperperfusion, and evokes trigger factors of neurodegeneration such as oxidative stress and inflammation, similar to that observed in cerebral hypoperfusion. Moreover, the derived brain injury is mainly localized in selected brain areas controlling cognitive functions, such as the cortex and hippocampus, and could be a consequence of a defect in the BBB permeability. It is noteworthy to emphasize that, even if these latter events are not enough to produce ischemic/hemorrhagic injury, they are able to alter mechanisms fundamental for maintaining normal brain function, such as protein synthesis, which has a prominent role for memory formation and cortical plasticity.
American journal of …, 2009
Background Based on previous data, we hypothesized that an increase of angiotensin II (ang II)-via the ang II type 1 (aT-1) receptor-in the rostral ventrolateral medulla (RVLm) and the paraventricular nucleus (PVN) of the hypothalamus could activate NaD(P)H oxidase that will produce superoxides resulting in increased sympathetic activity and hypertension. Methods The mRNa expression of aT-1 receptors, NaD(P)H oxidase subunits (p47phox and gp91phox), and CuZnSOD were analyzed in the RVLm and PVN of male Wistar rats (Goldblatt hypertension model, 2K-1C). In addition, we administered Tempol 1 and 5 nmol into the RVLm, PVN, or systemically. The mean arterial pressure (maP) and renal sympathetic nerve activity (RSNa) were analyzed. results The aT-1 mRNa expression and NaD(P)H oxidase subunits was greater in the RVLm and PVN in 2K-1C compared to the control group. Furthermore, the CuZnSOD expression was similar in both groups. Tempol 1 nmol into the RVLm reduced maP (15 ± 1%) and RSNa (11 ± 2%) only in 2K-1C rats. Tempol (5 nmol) in the same region decreased the maP (12 ± 4%) and RSNa (20 ± 7%), respectively, only in 2K-1C. In the PVN, Tempol 5 nmol resulted in a significant fall in the maP (24 ± 1%) and in the RSNa (7.9 ± 2%) only in the 2K-1C. acute intravenous (IV) infusion of Tempol decreased maP and RSNa in the 2K-1C but not in the control rats. conclusions The data suggest that the hypertension and sympathoexcitation in 2K-1C rats were associated with an increase in oxidative stress within the RVLm, the PVN and systemically.
The role of oxidative stress in renovascular hypertension
Clinical and Experimental Pharmacology and Physiology, 2011
1. There is mounting evidence that increased oxidative stress and sympathetic nerve activity play important roles in renovascular hypertension. In the present review, we focus on the importance of oxidative stress in two distinct populations of neurons involved with cardiovascular regulation: those of the rostral ventrolateral medulla (RVLM) and those of the paraventricular nucleus of the hypothalamus (PVN) in the maintenance of sympathoexcitation and hypertension in two kidney-one clip (2K1C) hypertensive rats. Furthermore, the role of oxidative stress in the clipped kidney is also discussed. 2. In the studies reviewed in this article, it was found that hypertension and renal sympathoexcitation in 2K1C rats were associated with an increase in Angiotensin II type one receptor (AT 1) expression and in oxidative markers within the RVLM, PVN and in the clipped kidneys of 2K1C rats. Furthermore, acute or chronic anti-oxidant treatment decreased blood pressure and sympathetic activity, and improved the baroreflex control of heart rate and renal sympathetic nerve activity in 2K1C rats. Tempol or vitamin C administration in the RVLM, PVN or systemically all reduced blood pressure and renal sympathetic activity. Cardiovascular improvement in response to chronic anti-oxidant treatment was associated with a downregulation of AT 1 receptors, as well as oxidative markers in the central nuclei and clipped kidney. 3. The data discussed in the present review support the idea that an increase in oxidative stress within the RVLM, PVN and in the ischaemic kidney plays a major role in the maintenance of sympathoexcitation and hypertension in 2K1C rats.
Frontiers in Physiology
Chronic intermittent hypoxia (CIH), the hallmark of obstructive sleep apnea, is the main risk factor to develop systemic hypertension. Oxidative stress, inflammation, and sympathetic overflow have been proposed as possible mechanisms underlying the CIH-induced hypertension. CIH potentiates the carotid body (CB) chemosensory discharge leading to sympathetic overflow, autonomic dysfunction, and hypertension. Oxidative stress and pro-inflammatory molecules are involved in neurogenic models of hypertension, acting on brainstem and hypothalamic nuclei related to the cardiorespiratory control, such as the nucleus of the solitary tract, which is the primary site for the afferent inputs from the CB. Oxidative stress and pro-inflammatory molecules contribute to the activation of the CB chemoreflex pathway in CIHinduced hypertension. In this brief review, we will discuss new evidence for a critical role of oxidative stress and neuro-inflammation in development of the CIH-induced hypertension through activation of the CB chemoreflex pathway.
Oxidative stress contributes to renovascular hypertension
American journal of hypertension, 2008
Oxidative stress is a state in which excess reactive oxygen species (ROS) overwhelm endogenous antioxidant systems. It is known that this state has been involved in the development of hypertension. On the basis of previous data, we hypothesized that overactivity of NAD(P)H oxidase-derived ROS and the lowered activity of CuZnSOD, an endogenous antioxidant within the rostral ventrolateral medulla (RVLM), could contribute to 2K-1C (two-kidney one-clip) hypertension. Moreover, to test the functional significance of whether oxidative stress was involved in the maintenance of sympathetic vasomotor tone and blood pressure in 2K-1C hypertension, we administered Ascorbic Acid (Vit C), an antioxidant, into the RVLM or systemically. Experiments were performed in male Wistar rats (6 weeks after renal surgery--Goldblatt hypertension model--2K-1C). The mRNA expression of NAD(P)H oxidase subunits (p47phox and gp91phox) and CuZnSOD were analyzed in the RVLM using real-time PCR technique. The mean a...
Emerging Concepts in Hypertension
Antioxidants & Redox Signaling, 2014
Cellular redox balance is vital in health and disease. In this Forum, we highlight the importance of reactive oxygen species (ROS) in the regulation of redox balance in different organ systems of the body and ROS contribution to the development of hypertension. The Forum examines interactions between oxidative and nitrosative stress in the brain, vasculature, and kidney, and redox effect on end-organ damage and hypertension. Furthermore, the Forum examines the role of immune cells in the modulation of hypertension. We also introduce a new role for endoplasmic reticulum stress in the induction of ROS and its possible contribution to the development of hypertension. Finally, we explore the clinical relevance of increased ROS in the setting of human hypertension. Antioxid. Redox Signal. 20, 69-73.
American Journal of Nephrology, 2009
lation of MnSOD with little change in CuZnSOD. Conclusions: Chronic hypertension in phenol-injected rats is associated with upregulation of NAD(P)H oxidase and hence increased O 2-ؒ production capacity in the key regions of the brain involved in regulation of blood pressure. Since reactive oxygen species can intensify central noradrenergic activity, the observed maladaptive changes may contribute to the genesis and maintenance of the associated hypertension.
Oxidative-Nitrosative Stress In Hypertension
Current Vascular Pharmacology, 2005
Reactive oxygen species (ROS) are important signaling molecules in the vasculature. However, when there is imbalance between their occurrence and antioxidant defense mechanisms, ROS can contribute to the vascular abnormalities that lead to hypertension. Evidence accumulated in the last decade strongly supports the notion that ROS are generated in the vasculature mainly by NAD(P)H oxidase in a mechanism that is angiotensin II-dependent. Activation of this enzyme leads to superoxide production and uncouples endothedial NO synthase (eNOS), which sustains oxidative stress while increasing the levels of tissue-damaging peroxynitrite. The latter can result in vascular dysfunction. NAD(P)Hdependent ROS formation, in particular H 2 O 2 , could also contribute to vascular injury by sustaining NAD(P)H oxidase activation, promoting inflammatory gene expression, extracellular matrix reorganization, and growth (hypertrophy/hyperplasia) of vascular smooth muscle cells. The effect of ROS appears to be mediated by redox-sensitive targets such as tyrosine kinases and phosphatases, mitogen-activated protein kinases, transcription factors, matrix metalloproteinases, peroxisome proliferator activated receptor-α, poly(ADP-ribose)polymerase-1, Ca 2+ signaling mechanisms and secreted factors such as cyclophilin A and heat shock protein 90-α. Redox-sensitive targets appear to play a central role in normal vascular function, but can also lead to remodeling of the vascular wall, increasing vascular reactivity and hypertension. Polymorphisms in the p22phox gene promoter could determine susceptibility to NAD(P)H-mediated oxidative stress in humans and animals with hypertension. Although ROS are strongly implicated in the etiology of hypertension, clinical trials with antioxidants are inconclusive regarding their effectiveness in treating the disease. New drugs with both antihypertensive action and antioxidant properties (Celiprolol, Carvedilol) offer promising results in the management of hypertension.
The Continuing Saga of Neuronal Oxidative Stress in Hypertension: Nox, Nox Who's There, and Where?
Hypertension, 2007
N umerous studies have demonstrated increased production of reactive oxygen species (ROS) in blood vessels and kidneys in hypertension and provided evidence that the oxidative stress in these organs causes or contributes to the elevated blood pressure. 1,2 Recently, the nervous system has emerged as an additional site and target of oxidative stress in hypertension. The vast majority of these studies have focused on the central nervous system, where activation of reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase has been shown to contribute to sympatho-excitation and increases in blood pressure. 3 NAD(P)H oxidase is a major source of ROS in hypertension, in both peripheral tissues and brain 1-3 ; and homologues of NAD(P)H oxidase (Nox) are differentially expressed in diverse cell types including neurons. 3,4 NAD(P)H oxidase consists of 2 membrane-bound subunits (p22 phox and Nox) and cytosolic components that are recruited to the membrane during activation (p47 phox , p67 phox , p40 phox , and GTPase Rac). 4 Nox homologues include Nox1, Nox2 (gp91 phox), Nox3, Nox4, Nox5, Duox1, and Duox2. 4