Different Models Of Hypertension Research Articles

Chemical Characterization of Phoenix dactylifera L. Seeds and their Beneficial Effects on the Vascular Response in Hypertensive Rats.

Although Phoenix dactylifera dates are traditionally consumed for their health benefits, no research has been done on the vascular response in hypertensive animals. This study evaluated the vascular relaxation of hydroalcoholic extracts from seeds of three varieties of P. dactylifera; Sukkari seed (SS), Ajwa seed (AS), and Mabroom seed (MS) on L-NAME-induced hypertension and spontaneously hypertensive rats (SHR). Results showed that all extracts (10µg/mL) caused relaxations higher than 60% in the aortic rings precontracted with 10- 6 M phenylephrine in normotensive rats, the SS extract was the most potent. Endothelial nitric oxide (NO) pathway is involved as significantly reduced vascular relaxation in denuded-endothelium rat aorta and with an inhibitor (10- 4 M L-Nω-Nitro arginine methyl ester; L-NAME) of endothelial nitric oxide synthase (eNOS). Confocal microscopy confirmed that 10µg/mL SS extract increases NO generation as detected by DAF-FM fluorescence in intact aortic rings. Consistent with these findings, vascular relaxation in intact aortic rings at 10µg/mL SS extract was significantly decreased in L-NAME-induced hypertensive rats (endothelial dysfunction model), but not in SHR. In both hypertensive models, the denuded endothelium blunted the vascular relaxation. In conclusion, the hydroalcoholic extract of the seed of P. dactylifera (Sukkari, Ajwa and Mabroom varieties) presents a potent endothelium-dependent vascular relaxation, via NO, in normotensive rats as well as in two different models of hypertension. This effect could be mediated by the presence of phenolic compounds identified by UHPLC-ESI-MS/MS, such as protocatechuic acid, and caftaric acid.

Contribution of Fat‐derived Sensory Signals to Sympathetic Activation During Obesity‐hypertension

Blood pressure regulation in health and disease involves a balance between afferent and efferent signals from multiple organs and tissues. Numerous studies have addressed the role of sympathetic nerves in different models of hypertension; however, few have focused on the contribution of afferent nerves innervating the adipose tissue and their role in the development of obesity‐induced hypertension. Thus, the aim of this study was to determine the changes in blood pressure in response to sensory stimulation of the fat pads and the subsequent neuronal activation in brain areas that receive afferent signals from white adipose tissue (WAT). Male C57BL/6J mice were fed low fat diet (LF), regular chow, or high fat diet (HF) for 16 weeks (10%, 18% and 60% Kcal from fat, respectively). First, using radiotelemetry, we determined that mice fed HF display increased mean arterial pressure (MAP), heart rate and sympathetic index compared with LF‐fed mice (p<0.05). The selective afferent denervation of visceral fat using resiniferotoxin (RTX, 20 pmol/ul, 6 sites, 1 ul per site; bilateral) reduced mean arterial pressure (MAP). In addition, capsaicin‐induced increases in MAP were measured in anesthetized mice via carotid catheter. Capsaicin was infused in the intravascular space or skeletal muscle (2 nmol/μl, 8 μl/2 min), and subcutaneous WAT or epidydimal WAT (2 nmol/μl, 8 μl/2 min, 4 sites, bilateral). MAP did not change from baseline after capsaicin infusion into the blood stream via the jugular vein, adjacent skeletal muscle or subcutaneous WAT; whereas the infusion induced a significant increase on MAP in response to epidydimal WAT stimulation (p<0.05). Subcutaneous or epidydimal WAT stimulation with saline solution (0.9% NaCl, 8 μl/2 minutes, 4 sites, bilateral) did not influence baseline MAP in either fat depots. In a different set of mice not subjected to catheter implantation, epidydimal WAT was infused with 0.9% saline (resting, n=4) or capsaicin (n=3–5) for Fos+ cells quantification by immunohistochemistry. We quantified the posterior paraventricular nucleus of the hypothalamus (PVN), magnocellular subdivision of PVN (PaLM), supraoptic nucleus (SON), organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO) and subfornical organ (SFO). HF increased the number of Fos+ cells in the SFO and SON at resting when compared with LF‐fed mice (p<0.05). However, no changes in nonendocrine neurons in the posterior PVN, PaLM, SON, OVLT and MnPO were observed in response to HF at resting. Capsaicin stimulation in epidydimal WAT significantly decreased Fos expression in OVLT and MnPO in HF fed males compared to LF‐fed mice (p<0.05). However, no significant changes were observed in nonendocrine neurons in the posterior PVN, PaLM, SON and SFO in response to diet. Thus, this data shows that adipose tissue‐blood pressure axis response is fat depot‐specific and exacerbated in HF. In addition, although several brain areas are overactivated in response to acute stimulation with capsaicin, the OVLT and MnPO decreased its activation in mice fed a chronic HF.Support or Funding InformationR01 HL135158

Sensory signals mediating high blood pressure via sympathetic activation: role of adipose afferent reflex

Blood pressure regulation in health and disease involves a balance between afferent and efferent signals from multiple organs and tissues. Although there are numerous reviews focused on the role of sympathetic nerves in different models of hypertension, few have revised the contribution of afferent nerves innervating adipose tissue and their role in the development of obesity-induced hypertension. Both clinical and basic research support the beneficial effects of bilateral renal denervation in lowering blood pressure. However, recent studies revealed that afferent signals from adipose tissue, in an adipose-brain-peripheral pathway, could contribute to the increased sympathetic activation and blood pressure during obesity. This review focuses on the role of adipose tissue afferent reflexes and briefly describes a number of other afferent reflexes modulating blood pressure. A comprehensive understanding of how multiple afferent reflexes contribute to the pathophysiology of essential and/or obesity-induced hypertension may provide significant insights into improving antihypertensive therapeutic approaches.

Abstract P166: Identification of Cyr61 and Tfgbi as Hypertensive Renal LEC Genes

Increased renal lymphatic density is observed in various experimental models of hypertension. To identify differentially expressed genes in lymphatic endothelial cells (LECs) from hypertensive kidneys, we utilized Gene Expression Omnibus (GEO) which was developed by the NIH NCBI. GEO is an international public repository that archives and distributes high-throughput functional genomic data sets such as microarray and next-generation sequencing data. GEO2R is an interactive web tool that allows users to compare samples across experimental conditions in a GEO Series in order to identify genes that are differentially expressed. Results are presented as a table of genes ordered by significance. Using GEO2R, the search terms “lymphatic” and “hypertensive kidney” were used to identify studies of LEC-associated genes and renal hypertension-associated genes. Among the search results for LEC genes, 4 studies were chosen that were done in mice comparing: a) murine primary LECs vs. murine endothelial SVEC4-10 cell line, b) collecting lymphatic endothelium of mice with 293EBNA xenografts with and without overexpression of VEGFD, c) LECs from afferent and efferent lymphatic vessels, and d) LECs and blood vascular endothelial cells from mouse intestine. For renal hypertensive genes, we chose a study that reported differentially expressed genes in kidneys of mice treated with angiotensin II for 1, 3 or 7 days compared to controls. From all of these lists, the top 250 differentially expressed genes were chosen. The list of renal genes was crossed with a combined list of LEC genes to obtain potential “LEC genes differentially expressed in hypertensive kidneys”. This yielded a list of 40 genes for which mRNA expression was tested in the kidneys of mice from 3 different models of hypertension: nitric oxide inhibition-induced, salt-sensitive, and angiotensin II-induced. Among the differentially expressed genes, Cyr61 and Tgfbi were elevated significantly in all 3 hypertensive models. Cyr61 is a well-known inducer of angiogenesis. Tfgbi is involved in LEC adhesion to extracellular matrix under hypoxic conditions. The upregulation of these two genes likely play a major role in renal LEC function during hypertension.

Plasmatic Concentrations of ADMA and Homocystein in Llama (Lama glama) and Regulation of Arginase Type II: An Animal Resistent to the Development of Pulmonary Hypertension Induced by Hypoxia.

There are animal species that have adapted to life at high altitude and hypobaric hypoxia conditions in the Andean highlands. One such species is the llama (Lama glama), which seem to have developed efficient protective mechanisms to avoid maladaptation resulting from chronic hypoxia, such as a resistance to the development of hypoxia -induced pulmonary hypertension. On the other hand, it is widely known that different models of hypertension can arise as a result of changes in endothelial function. The respect, one of the common causes of deregulation in endothelial vasodilator function have been associated with down-regulation of the NO synthesis and an increase in plasma levels of asymmetric dimethylarginine (ADMA) and homocysteine. Additionally, it is also known that NO production can be regulated by plasma levels of L-arginine as a result of the competition between nitric oxide synthase (NOS) and arginase. The objective of this study, was to determine the baseline concentrations of ADMA and homocysteine in llama, and to evaluate their effect on the arginase pathway and their involvement in the resistance to the development of altitude-induced pulmonary hypertension. METHOD: Lowland and highland newborn sheep and llama were investigated near sea level and at high altitude. Blood determinations of arterial blood gases, ADMA and homocysteíne are made and the effect of these on the arginase activity was evaluated. RESULTS: The basal concentrations of ADMA and homocysteine were determined in llama, and they were found to be significantly lower than those found in other species and in addition, the exposure to hypoxia is unable to increase its concentration. On the other hand, it was observed that the llama exhibited 10 times less arginase II activity as compared to sheep, and the expression was not induced by hypoxia. Finally, ADMA y Hcy, has no effect on the type II arginase pathway. CONCLUSION: Based on our results, we propose that low concentrations of ADMA and homocysteine found in llamas, the low expression of arginase type II, DDAH-2 and CBS, as well as its insensitivity to activation by homocysteine could constitute an adaptation mechanism of these animals to the hypoxia.

Angiotensin II Promotes KV7.4 Channels Degradation Through Reduced Interaction With HSP90 (Heat Shock Protein 90).

Voltage-gated Kv7.4 channels have been implicated in vascular smooth muscle cells' activity because they modulate basal arterial contractility, mediate responses to endogenous vasorelaxants, and are downregulated in several arterial beds in different models of hypertension. Angiotensin II (Ang II) is a key player in hypertension that affects the expression of several classes of ion channels. In this study, we evaluated the effects of Ang II on the expression and function of vascular Kv7.4. Western blot and quantitative polymerase chain reaction revealed that in whole rat mesenteric artery, Ang II incubation for 1 to 7 hours decreased Kv7.4 protein expression without reducing transcript levels. Moreover, Ang II decreased XE991 (Kv7)-sensitive currents and attenuated membrane potential hyperpolarization and relaxation induced by the Kv7 activator ML213. Ang II also reduced Kv7.4 staining at the plasma membrane of vascular smooth muscle cells. Proteasome inhibition with MG132 prevented Ang II-induced decrease of Kv7.4 levels and counteracted the functional impairment of ML213-induced relaxation in myography experiments. Proximity ligation assays showed that Ang II impaired the interaction of Kv7.4 with the molecular chaperone HSP90 (heat shock protein 90), enhanced the interaction of Kv7.4 with the E3 ubiquitin ligase CHIP (C terminus of Hsp70-interacting protein), and increased Kv7.4 ubiquitination. Similar alterations were found in mesenteric vascular smooth muscle cells isolated from Ang II-infused mice. The effect of Ang II was emulated by 17-AAG (17-demethoxy-17-(2-propenylamino) geldanamycin) that inhibits HSP90 interactions with client proteins. These results show that Ang II downregulates Kv7.4 by altering protein stability through a decrease of its interaction with HSP90. This leads to the recruitment of CHIP and Kv7.4 ubiquitination and degradation via the proteasome.

Quercetin decreases the activity of matrix metalloproteinase-2 and ameliorates vascular remodeling in renovascular hypertension

Background and aimsIncreased activity of matrix metalloproteinase (MMP)-2 is observed in aortas of different models of hypertension, and its activation is directly mediated by oxidative stress. As quercetin is an important flavonoid with significant antioxidant effects, the hypothesis here is that quercetin will reduce increased MMP-2 activity by decreasing oxidative stress in aortas of hypertensive rats and then ameliorate hypertension-induced vascular remodeling. MethodsMale two-kidney one-clip (2K1C) hypertensive Wistar rats and controls were treated with quercetin (10 mg/kg/day) or its vehicle for three weeks by gavage. Rats were then analyzed at five weeks of hypertension. Systolic blood pressure (SBP) was determined by tail-cuff plethysmography. Aortas were used to determine MMP activity by in situ zymography and reactive oxygen species (ROS) levels by dihydroethidium. Western blot was performed to detect focal adhesion kinase (FAK) and phosphorylated-FAK levels. ResultsSBP was increased in 2K1C rats and only a borderline reduction in SBP was observed after treating 2K1C rats with quercetin. Cross-sectional area and the number of vascular smooth muscle cells were significantly increased in aortas of hypertensive rats, and quercetin reduced them. Quercetin reduced ROS levels in aortas of 2K1C rats and the increased activity of gelatinases in situ. However, quercetin did not affect the levels of tissue inhibitor of MMP (TIMP)-2 and did not interfere with FAK and p-FAK levels in aortas of hypertensive rats. Furthermore, different concentrations of quercetin did not directly reduce the activity of human recombinant MMP-2 in vitro. ConclusionsQuercetin reduces hypertension-induced vascular remodeling, oxidative stress and MMP-2 activity in aortas.

The gene-expression profile of renal medulla in ISIAH rats with inherited stress-induced arterial hypertension.

BackgroundThe changes in the renal function leading to a reduction of medullary blood flow can have a great impact on sodium and water homeostasis and on the long-term control of arterial blood pressure. The RNA-Seq approach was used for transcriptome profiling of the renal medulla from hypertensive ISIAH and normotensive WAG rats to uncover the genetic basis of the changes underlying the renal medulla function in the ISIAH rats being a model of the stress-sensitive arterial hypertension and to reveal the genes which possibly may contribute to the alterations in medullary blood flow.ResultsMultiple DEGs specifying the function of renal medulla in ISIAH rats were revealed. The group of DEGs described by Gene Ontology term ‘oxidation reduction’ was the most significantly enriched one. The other groups of DEGs related to response to external stimulus, response to hormone (endogenous) stimulus, response to stress, and homeostatic process provide the molecular basis for integrated responses to homeostasis disturbances in the renal medulla of the ISIAH rats. Several DEGs, which may modulate the renal medulla blood flow, were detected. The reduced transcription of Nos3 pointed to the possible reduction of the blood flow in the renal medulla of ISIAH rats.ConclusionsThe generated data may be useful for comparison with those from different models of hypertension and for identifying the common molecular determinants contributing to disease manifestation, which may be potentially used as new pharmacological targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0462-6) contains supplementary material, which is available to authorized users.

Features of the inducible nitric oxide synthase expression in paraventricular and supraoptic nuclei of hypothalamus in different models of arterial hypertension

The regulation of the paraventricular (PVN) and supraoptic (SON) nuclei’s activity is carried out with a great amount of different neurotransmitters, in particular, with nitric oxide. In order to get clear understanding of the local NO effects in hypothalamus in normal condition and different models of hypertension it is necessary to study all isoforms of NOS in PVN and SON. Our purpose was to find out the features of the inducible nitric oxide synthase (iNOS) expression in magnocellular SON and PVN in SHR and endocrine-saline model of hypertension in rats. Materials and methods. For all rats the mean blood pressure (mBP) was measured. In Wistar rats mBP was stable during the experiment. In SHR mBP was higher than normal. In animals of the 3 rd group with ESM the first measurement (before the modelling) demonstrated normal rates of mBP. Since the 7 th day of modelling mBP started increase and became steadily increased from the 21 st day. We obtained the frontal slices of hypothalamus and performed the assessment of iNOS expression using immunofluorescence assay. The results showed the presence of the constitutive expression of iNOS in the magnocellular neurons of hypothalamus in Wistar rats as well as in both groups of experimental hypertension. The level of iNOS expression in magnocellular nuclei was dependent both on type of hypertension and topography of magnocellular neurons in hypothalamus. In SHR there was high expression of iNOS in PVN and low one in SON, whereas in endocrine-saline model there was high expression in SON and there were no substantial changes of the iNOS expression in PVN. Conclusions. We believe the alteration of iNOS expression in magnocellular nuclei of hypothalamus could participate in development and/or adaptation to hypertension.

Hippocampal neurogenesis response: What can we expect from two different models of hypertension?

Hypertension is associated with cerebrovascular disease, white matter lesion and cognitive deficit, both in experimental models and clinical observations. Furthermore, in non-clinical models it is shown that hippocampus is affected by hypertension and hypoxia. Herein, two distinct hypertension models were used to study neurogenic response in hippocampus. Dahl salt sensitive (DSS) rat model is a genetic based idiopathic model, while chronic intermittent hypoxia (CIH) mimics the hypertension observed in patients with obstructive sleep apnea (OSA). Both models are chronic and trigger hypertension. No macroscopic alterations based on histological analysis were found in hippocampus derived from DSS and CIH exposure rats. Nevertheless, in hippocampus derived from CIH-induced hypertensive rats, there was a decrease on neuronal population (MAP2 and NeuN positive cells) and an increase on astrocytic marker GFAP. Accordingly, a higher increase on Ki67 expressing cells was found in dentate gyrus (DG) region, suggesting an enhancement of cell proliferation, concomitantly with an increase of Nestin staining, which indicates the presence of immature neurons under differentiation. While, in hippocampus of DSS rats with or without high salt diet, there was no remarkable difference indicating potential neuronal loss, astrocytic activation or neurogenesis. Furthermore, in both models hypertension did not alter the levels of expression of the stress response enzyme heme oxygenase-1 in DG. These data indicate that intermittent hypoxia might be the key factor involved in neurogenesis modulation in hippocampus. Furthermore, two hypotheses can be explored: (i) activation of neurogenesis is a response against neuronal loss induced by hypertension and/or hypoxia or (ii) neurogenesis can be directly stimulated by hypoxia as a neuroprotective mechanism.

The features of expression of constitutive isoforms of the nitric oxide synthase in paraventricular and supraoptic nuclei of the hypothalamus in hypertension of different origins

Aim. The purpose was to evaluate the features of the neuronal and endothelial nitric oxide synthase expression pattern in supraoptic and magnocellular part of paraventricular nuclei of the hypothalamus in different models of hypertension. Materials and methods. The study was carried out on 20 Wistar male rats and 10 SHR male rats. There were two experimental models of hypertension used: the genetically predisposed to age-related hypertension SHR and rats with endocrine-saline model of hypertension (ESM). The object was the hypothalamus of rats. The immunohystochemical assay was used to determine the expression of NOS isoforms.Results showed the imbalance of constitutive NOS isoforms in SON and PVN of hypothalamus in both of SHR and ESM. The eNOS and nNOS expression pattern is dependent on etiological factor, topographical peculiarities of the nuclei and their functions.Conclusions. We believe the imbalance of constitutive NOS isoforms take part in the hypertension development, its progression and the formation of complications.

A clinician's perspective of the role of renal sympathetic nerves in hypertension.

The renal sympathetic nerves have significant contribution to the control of different aspects of kidney function. Early animal studies of renal denervation in a large number of different models of hypertension showed that that RDN improved BP control. Recently, data from prospective cohorts and randomized studies showed that renal denervation therapy (RDN) is a safe procedure but is associated with only modest reduction of ambulatory blood pressure (BP) in patients on intensive medical therapy. The main goal of this article is to review the results of preclinical and clinical studies on the contribution of the renal sympathetic nervous system to hypertension and the therapeutic applications of catheter-based renal denervation.

Sodium nitrite therapy rescues ischemia-induced neovascularization and blood flow recovery in hypertension

Arterial hypertension is a major risk factor that can lead to complication of peripheral vascular disease due, in part, to endothelial dysfunction. Because sodium nitrite (SN) can be converted to nitric oxide (NO), which counteracts endothelial dysfunction, we explored the effect of nitrite on neovascularization following hind limb ischemia in different models of hypertension (HT). Chronic delivery of angiotensin II (Ang II, 400ng/kg/min) or N(omega)-nitro-L-arginine-methyl-ester (L-NAME, 0.1g/L) was used for a 2-week period to induce hypertension. Mice were subjected to femoral artery ligation-induced ischemia in the hind limb followed by treatment with SN (50mg/L) for 2weeks. SN significantly reduced systolic arterial blood pressure in mice receiving Ang II and L-NAME but had no effect in sham animals. After 2weeks, blood flow and microangiography showed 60% ± 1.0 recovery in sham compared with 40% ± 1.3 in HT mice. Importantly, sham and HT mice treated with SN showed a 100% blood flow recovery associated with normalization in capillary density. The inhibition of xanthine-oxido-reductase (allopurinol) or VEGFR (SU-5416) prevented the neovascularization in HT mice treated with SN. Cyclic GMP (cGMP) content in the hind limb was significantly increased in mice treated with SN compared with non-treated mice. Nitrite/nitrate content was only increased in the sham group treated with SN. Immunoprecipitation and Western blot analysis revealed an increase in eNOS/Akt/VEGFR phosphorylation in skeletal muscle from mice treated with SN compared with non-treated mice. Our findings indicate that SN therapy rescues the neovascularization and blood flow recovery in the ischemic hind limb of sham and HT mice likely through the Akt/NO/cGMP and VEGFR pathways.

Abstract 523: Sodium Nitrite Therapy Augments Ischemia-Induced Neovascularization and Blood Flow Recovery in Different Models of Hypertension

Background: Arterial hypertension is a major risk factor that can lead to exacerbation of peripheral vascular disease due, in part, to endothelial dysfunction. Because sodium nitrite (SN) can be converted to nitric oxide (NO), which counteracts endothelial dysfunction, we explored the effect of nitrite on neovascularization following hind-limb ischemia in different models of hypertension (HT). METHODS: Chronic infusion of angiotensin-II (Ang-II, 400ng/Kg/min) or N(omega)-nitro-L-arginine-methyl-ester (L-NAME, 0.1g/L) were used for a two week period to induce hypertension. Mice were subjected to femoral artery ligation induced-ischemia in the hind-limb followed by treatment with SN (50mg/L) for 2-weeks. Results: SN significantly reduced systolic arterial blood pressure in mice receiving Ang-II and L-NAME, but had no effect in sham animals. After 2 weeks, blood flow and microangiography showed 60% recovery in sham compared to 40% in HT mice. Importantly, sham and HT mice treated with SN had a 100% blood flow recovery associated with normalization in capillary density. The inhibition of xanthine-oxido-reductase (allopurinol) or VEGFR (SU-5416) prevented the neovascularization in HT mice treated with SN. Cyclic GMP (cGMP) content in the hind-limb was significantly increased in mice treated with SN compared to non-treated mice. Nitrite/nitrate content was only increased in the sham group treated with SN. Immunoprecipitation and Western blot analysis revealed an increase in eNOS/Akt/VEGFR phosphorylation in skeletal muscle from mice treated with SN compared to non-treated mice. Conclusion: Our findings determine that SN therapy rescues the neovascularization and blood flow recovery in ischemic hind-limb of sham and HT mice likely through the Akt/NO/cGMP and VEGFR pathways.

Editorial [Hot topic: Crucial Role of Redox Signaling in the Regulation of Heart Health (Guest Editor: Dipak K. Das)

Editorial [Hot topic: Crucial Role of Redox Signaling in the Regulation of Heart Health (Guest Editor: Dipak K. Das)

Modulation of Gi Proteins in Hypertension: Role of Angiotensin II and Oxidative Stress.

Guanine nucleotide regulatory proteins (G-proteins) play a key role in the regulation of various signal transduction systems including adenylyl cyclase/cAMP and phospholipase C (PLC)/phosphatidyl inositol turnover (PI). These are implicated in the modulation of a variety of physiological functions such as platelet functions, cardiovascular functions, including arterial tone and reactivity. Several abnormalities in adenylyl cyclase activity, cAMP levels and G proteins have shown to be responsible for the altered cardiac performance and vascular functions observed in cardiovascular disease states. The enhanced or unaltered levels of inhibitory G-proteins (Giα-2 and Giα-3) and mRNA have been reported in different models of hypertension, whereas Gsα levels were shown to be unaltered. These changes in G-protein expression were associated with Gi functions. The enhanced levels of Giα proteins precede the development of blood pressure and suggest that overexpression of Gi proteins may be one of the contributing factors for the pathogenesis of hypertension. The augmented levels of vasoactive peptides, including angiotensin II (AngII), were shown to contribute to enhanced expression of Giα proteins and associated adenylyl cyclase signaling and thereby increased blood pressure. In addition, enhanced oxidative stress in hypertension due to Ang II may also be responsible for the enhanced expression of Giα proteins observed in hypertension. The mechanism by which oxidative stress enhances the expression of Gi proteins appears to be through the activation of mitogen activated protein (MAP) kinase activity.

Does Chronic Pain Alter the Normal Interaction Between Cardiovascular and Pain Regulatory Systems? Pain Modulation in the Hypertensive-Monoarthritic Rat

Hypertension-associated hypoalgesia is widely recognized in acute pain conditions. In chronic pain states, however, the relationship between blood pressure and pain sensitivity is still ill-defined, with different authors reporting negative, positive, or even no relationship at all. This work addresses this issue, using complete Freund's adjuvant (CFA)-induced monoarthritis in different models of hypertension: Spontaneous (spontaneously hypertensive rats, SHR), induced by infusion of angiotensin II (ANG) or 1,3-dipropyl-8-sulfophenylxanthine (DPSPX, an adenosine receptors' antagonist), and renal artery ligation (RAL). Nociceptive responses associated with monoarthritis were evaluated by different behavioral tests (von Frey, ankle-bend and CatWalk) and by quantification of Fos expression at the dorsal horn upon noxious stimulation. In all hypertension models, higher von Frey thresholds and lower Fos expression were detected in hypertensive rats with chronic inflammatory pain, as compared to normotensive monoarthritic rats. In SHR and DPSPX, but not ANG or RAL models, hypertensive animals displayed lower inflammation than normotensives. Ankle-bend and CatWalk results indicated lower pain sensitivity in hypertensive rats only in SHR and DPSPX models. The present study shows the importance of using multiple models of hypertension, and evaluating pain responses by various methods, to better understand the complexity of the interactions between pain and cardiovascular regulatory systems. This study used different models of hypertension to investigate whether chronic pain alters the normal integration of cardiovascular and pain regulatory systems. A complete understanding of the mechanisms underlying the complex interactions between these systems may disclose future therapeutic approaches to treat hypertension/chronic pain comorbidity states.

Participation of nitric oxide in different models of experimental hypertension

This review concerns the role of nitric oxide (NO) in the pathogenesis of different models of experimental hypertension (NO-deficient, genetic, salt-dependent), which are characterized by a wide range of etiology. Although the contribution of NO may vary between different models of hypertension, a unifying characteristic of these models is the presence of oxidative stress that participates in the maintenance of elevated arterial pressure and seems to be a common denominator underlying endothelial dysfunction in various forms of experimental hypertension. Besides the imbalance between the endothelial production of vasorelaxing and vasoconstricting compounds as well as the relative insufficiency of vasodilator systems to compensate augmented vasoconstrictor systems, there were found numerous structural and functional abnormalities in blood vessels and heart of hypertensive animals. The administration of antihypertensive drugs, antioxidants and NO donors is capable to attenuate blood pressure elevation and to improve morphological and functional changes of cardiovascular system in some but not all hypertensive models. The failure to correct spontaneous hypertension by NO donor administration reflects the fact that sympathetic overactivity plays a key role in this form of hypertension, while NO production in spontaneously hypertensive rats might be enhanced to compensate increased blood pressure. A special attention should be paid to the modulation of sympathetic nervous activity in central and peripheral nervous system. These results extend our knowledge on the control of the balance between NO and reactive oxygen species production and are likely to be a basis for the development of new approaches to the therapy of diseases associated with NO deficiency.

Vascular microarray profiling in two models of hypertension identifies caveolin-1, Rgs2 and Rgs5 as antihypertensive targets

BackgroundHypertension is a complex disease with many contributory genetic and environmental factors. We aimed to identify common targets for therapy by gene expression profiling of a resistance artery taken from animals representing two different models of hypertension. We studied gene expression and morphology of a saphenous artery branch in normotensive WKY rats, spontaneously hypertensive rats (SHR) and adrenocorticotropic hormone (ACTH)-induced hypertensive rats.ResultsDifferential remodeling of arteries occurred in SHR and ACTH-treated rats, involving changes in both smooth muscle and endothelium. Increased expression of smooth muscle cell growth promoters and decreased expression of growth suppressors confirmed smooth muscle cell proliferation in SHR but not in ACTH. Differential gene expression between arteries from the two hypertensive models extended to the renin-angiotensin system, MAP kinase pathways, mitochondrial activity, lipid metabolism, extracellular matrix and calcium handling. In contrast, arteries from both hypertensive models exhibited significant increases in caveolin-1 expression and decreases in the regulators of G-protein signalling, Rgs2 and Rgs5. Increased protein expression of caveolin-1 and increased incidence of caveolae was found in both smooth muscle and endothelial cells of arteries from both hypertensive models.ConclusionWe conclude that the majority of differences in gene expression found in the saphenous artery taken from rats with two different forms of hypertension reflect distinctive morphological and physiological alterations. However, changes in common to caveolin-1 expression and G protein signalling, through attenuation of Rgs2 and Rgs5, may contribute to hypertension through augmentation of vasoconstrictor pathways and provide potential targets for common drug development.

T-cells in angiotensin-II-induced vascular damage

In this study, Guzik et al. proved that mice lacking T- and B-cells do not develop hypertension and associated vascular dysfunction in two different models of hypertension, either with high angiotensin II (angiotensin II infusion) or with low angiotensin II (DOCA salt). Transfusion of T, but not B, cells restored these abnormalities, leading to the conclusion that T-cells play an important role in the genesis of hypertension. To gain an insight into how T-cells may be involved in the mechanisms that finally cause hypertension, they examined the effects of angiotensin II on vascular infiltration of these cells. Angiotensin II markedly increased the number of T-cells in aortic periadventitial fat and stimulated vascular expression of the chemokine receptor 5 ligand RANTES. The infiltrated T-cells showed high levels of CCR5 and were negative for CD4 and CD8. Angiotensin II infusion increased T-cell expression of three specific NADPH oxidase subunits, raising the ability of T-cells to produce O2 − and inducing the production of TNFα and IFNγ. Adoptive transfer of T-cells lacking the angiotensin type 1receptor or afunctional NADPH oxidase resulted in blunted angiotensin-II-dependent hypertension. Treatment with the soluble TNFα receptor etanercept prevented hypertension and reduced the increase in vascular O2 − by angiotensin II, whereas the anti-IFNγ antibody had no effect. What do cells of the immune system have to do with blood pressure? In several studies, it was shown that end organ damage of hypertension, especially in the kidney, is associated with activation of the renin–angiotensin system and infiltration of T-cells in the renal cortical interstitium. Treatment with either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker significantly reduces the number of infiltrating T-cells [1]. In the twokidney, one-clip renovascular hypertensive rat, intercellular