Stages Of Hypertension Development Research Articles

Age-Dependent Changes in the Relationships between Traits Associated with the Pathogenesis of Stress-Sensitive Hypertension in ISIAH Rats

Hypertension is one of the most significant risk factors for many cardiovascular diseases. At different stages of hypertension development, various pathophysiological processes can play a key role in the manifestation of the hypertensive phenotype and of comorbid conditions. Accordingly, it is thought that when diagnosing and choosing a strategy for treating hypertension, it is necessary to take into account age, the stage of disorder development, comorbidities, and effects of emotional–psychosocial factors. Nonetheless, such an approach to choosing a treatment strategy is hampered by incomplete knowledge about details of age-related associations between the numerous features that may contribute to the manifestation of the hypertensive phenotype. Here, we used two groups of male F2(ISIAHxWAG) hybrids of different ages, obtained by crossing hypertensive ISIAH rats (simulating stress-sensitive arterial hypertension) and normotensive WAG rats. By principal component analysis, the relationships among 21 morphological, physiological, and behavioral traits were examined. It was shown that the development of stress-sensitive hypertension in ISIAH rats is accompanied not only by an age-dependent (FDR < 5%) persistent increase in basal blood pressure but also by a decrease in the response to stress and by an increase in anxiety. The plasma corticosterone concentration at rest and its increase during short-term restraint stress in a group of young rats did not have a straightforward relationship with the other analyzed traits. Nonetheless, in older animals, such associations were found. Thus, the study revealed age-dependent relationships between the key features that determine hypertension manifestation in ISIAH rats. Our results may be useful for designing therapeutic strategies against stress-sensitive hypertension, taking into account the patients’ age.

Dynamic Regulation of microRNA Networks in the Brainstem Characterize Hypertension Development

This study aims to elucidate the mechanisms by which microRNAs (miRNA) regulate autonomic control networks driving hypertension development. Using a high‐throughput assay for 419 miRNAs in the Spontaneously Hypertensive Rat (SHR) and Wistar‐Kyoto (WKY) control at three stages of hypertension development, significant differences in expression occurred in 9 miRNAs of the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM). Alterations were stage‐ and region‐dependent, differing at hypertension onset in NTS vs prehypertension stage in RVLM. 144 gene targets corresponding to catecholaminergic processes and neuromodulation were predicted using miRWALK and RNA22 databases and tested with high‐throughput qPCR. Using correlational relationships between miRNAs and mRNAs, we observed a double‐negative regulatory motif consisting of a miRNA down‐regulating a negative regulator of a pro‐hypertensive signaling pathway like Angiotensin II signaling or leukotriene‐based inflammation. We observe during the development of hypertension cells in NTS and RVLM alter their patterns of miRNA and gene expression related to neural function. These include many genes related to Ang II and inflammatory processes affecting autonomic balance leading to an increase in blood pressure set point. We confirmed expression of key miRNAs in the brainstem using fluorescent in situ hybridization, and we examined the cell‐type specificity of each miRNA using 10 cell pools of neurons and astrocytes taken from the NTS and RVLM using laser capture microdissection. We demonstrated for the first time that the broad concordance of miRNA dynamics and target gene expression compose a regulatory network in the brainstem underlying hypertension.

Cardiovascular alterations at different stages of hypertension development during ethanol consumption: Time-course of vascular and autonomic changes

The aim of the present work was to establish a time-course correlation between vascular and autonomic changes that contribute to the development of hypertension during ethanol ingestion in rats. For this, male Wistar rats were subjected to the intake of increasing ethanol concentrations in their drinking water during four weeks. Ethanol effects were investigated at the end of each week. Mild hypertension was already observed at the first week of treatment, and a progressive blood pressure increase was observed along the evaluation period. Increased pressor response to phenylephrine was observed from first to fourth week. α1-adrenoceptor protein in the mesenteric bed was enhanced at the first week, whereas β2-adrenoceptor protein in the aorta was reduced after the second week. In the third week, ethanol intake facilitated the depressor response to sodium nitroprusside, whereas in the fourth week it reduced nitrate content in aorta and increased it plasma. The bradycardic component of the baroreflex was impaired, whereas baroreflex tachycardia was enhanced at the third and fourth weeks. AT1A receptor and C-type natriuretic peptide (CNP) mRNAs in the nucleus tractus solitarius were increased at the fourth week. These findings suggest that increased vascular responsiveness to vasoconstrictor agents is possibly a link factor in the development and maintenance of the progressive hypertension induced by ethanol consumption. Additionally, baroreflex changes are possibly mediated by alterations in angiotensinergic mechanisms and CNP content within the brainstem, which contribute to maintaining the hypertensive state in later phases of ethanol ingestion. Facilitated vascular responsiveness to nitric oxide seems to counteract ethanol-induced hypertension.

Abstract 163: Prorenin-induced Pro-inflammatory Effect In Hypothalamic Astrocytes From Spontaneously Hypertensive Rats

Over-activation of the renin-angiotensin system (RAS) at the paraventricular nucleus of the hypothalamus (PVN) enhances the central immune response contributing to the development and maintenance of neurogenic hypertension. Astrocytes contribute to the production and secretion of pro-inflammatory cytokines (PICs) and are a vital component of the innate immune response in the brain. The contribution of astrocyte activation during hypertension has not been investigated and the actions of prorenin (PRO) on this cell type are undefined. Astrocytes cultured from the hypothalamus of normotensive rats (Sprague Dawley; SD) or spontaneously hypertensive rats (SHR; a model of neurogenic hypertension), contain (pro)renin receptor mRNA. When compared with non-treated cells (SD: 1.0 ± 0.04; SHR: 1.0 ± 0.05), treatment of SD cultures with PRO (60 nM; 3 h) increased the mRNA levels (normalized to GAPDH) of the PICs interleukin-6 (IL-6; 2.5 ± 0.3), interleukin-1β (IL-1β; 46.7 ± 12.1) and tumor necrosis factor-α (TNF-α; 13.8 ± 2.9) (n=6; p<0.05). In SHR cells, the PIC levels after PRO treatment were 5.0 ± 0.9 (IL-6), 133.6 ± 34.9 (IL-1β) and 59.9 ± 30.8 (TNF-α) (n=5). PIC production by PRO was significantly (p < 0.05) enhanced in SHR cultures. Treatment of astrocytes with angiotensin II (Ang II; 100 nM) or angiotensin III (Ang III; 100 nM & 1 μM) failed to increase PIC mRNA levels. PRO treatment also increased the levels of lipocalin-2 (LCN-2; p < 0.05), an early marker of astrogliosis, in astrocytes from both strains and this effect was enhanced in SHR cells (3.1 ± 0.6 vs. 6.7 ± 2.4). Evidence of astrogliosis (p < 0.05) was apparent in the PVN of adult SHR brain at different stages of hypertension development (9, 12 and 16 weeks of age; 10.6 ± 0.5, 9.9 ± 0.7 and 8.9 ± 0.7 [astroglial fractional area in PVN; AfaPVN], n=4 per age group), based on glial fibrillary acidic protein (GFAP) immunostaining and quantification using Image J. Age-matched SD or Wistar Kyoto rats exhibited lower GFAP-positive staining in the PVN (6.2 ± 0.6; 4.7 ± 1.3; 5.2 ± 1.2, AfaPVN, n=4 per age group). Our findings indicate that PRO, not Ang II or III, activates hypothalamic astrocytes inducing a pro-inflammatory response, possibly contributing to the astrogliosis observed in the PVN of adult SHR.

Abstract 119: Central Phospholipase A2, Cyclooxygenase-1, Prostaglandin D Synthase and DP1 Receptor Expression During the Development of Angiotensin II-salt Hypertension

Chronic angiotensin II (Ang II) infusion combined with high salt in the diet has been used to study the development of Hypertension (HT). We have found that cyclooxygenase (COX) inhibition during the early stages of Ang II infusion prevented the development of HT and sympathetic hyper-activity in AngII-salt model. It is likely that these changes are mediated through alterations in the levels of COX and related enzymes. Therefore, we hypothesized that enzymes such as phospholipase A2 (PLA2), prostaglandin D synthase (PGDS) and COX-1 may be altered in specific brain regions to promote AngII-salt HT. To test this, adult male Sprague Dawley rats were implanted with radio-telemeters and placed on a 2% NaCl diet. They were infused with Ang II (150 ng/kg/min, sc) or the vehicle after obtaining 3 days of basal recording. Mean arterial pressure was significantly elevated in AngII-treated animals compared to controls. Animals were sacrificed 4 days after Ang-II infusion. The brains were removed, frozen and sectioned. Middle cerebral artery (MCA), paraventricular nucleus (PVN), organum vasculosum lamina terminalis (OVLT), subfornical organ (SFO), rostral ventrolateral medulla (RVLM) and choroid plexus (CP) were dissected and processed for western blotting. Western blot analysis showed a significant up-regulation of PLA2 in the MCA, PGDS in the choroid plexus. However, there was no change in the protein levels of COX in AngII treated rats. Next, we measured the levels of PGDS receptor, DP1 and found up-regulation of the receptor in the PVN. The results indicated that there is alteration in the protein levels of PLA2, PGDS and DP1 during the early stages of HT development in this model. This altered protein expression could be critical in driving the development of AngII-salt HT.

The Renin-Angiotensin System in Different Stages of Spontaneous Hypertension in the Rat (S H R)

The present study analyzed the concentration of renin-like activity and angiotensinogen concentration (AoC) in different brain areas related to cardiovascular control in SHR and Wistar Kyoto (WKY) animals. Male rats of both strains were studied at 8, 16 and 30 weeks of age. The following brain areas were isolated: anterior, medial and posterior hypothalamus, septal area, periaqueductal gray (PG) and the remaining brain stem; nucleus tractus solitarius (NTS) and the remaining medulla oblongata. Plasma renin activity (PRA) and plasma and cerebrospinal fluid (CSF) AoC were determined. Renin-like concentration was higher in SHR than in WKY in the anterior hypothalamus, PG and NTS at different stages of hypertension development. AoC was also higher in some areas of the SHR brain during different periods. PRA, plasma and CSF angiotensinogen concentration showed significant differences between both strain of rats during the development of high blood pressure. Present data support the possibility that the central and peripheral renin-angiotensin system may participate in the maintenance of high blood pressure in the SHR animals.

Possible Mechanisms of Abnormal Norepinephrine Sensitivity and Reactivity of Resistance Vessels and the Development of Hypertension in Spontaneously Hypertensive Rats: A Hypothesis

This study examined structural and functional changes of mesenteric resistance vessels in early, developing, and established stages of hypertension development in spontaneously hypertensive rats in an attempt to identify possible mechanisms of the development and maintenance of hypertension. Our results suggest that the development of hypertension in spontaneously hypertensive rats may be caused by genetic structural and functional abnormalities of resistance vessels. Both abnormalities may be caused by hyperreactivity to norepinephrine through an altered signal transduction process, including the regulation of protein kinase C in smooth muscle cells of resistance vessels in spontaneously hypertensive rats.

Altered hemodynamic responses to acute hypoxemia in spontaneously hypertensive rats.

Conscious spontaneously hypertensive rats (SHR), 5--7 wk old, were studied hemodynamically by the direct Fick procedure to determine whether high total peripheral resistance (TPR) coexisted with increased oxygen consumption (QO2) at an early stage of hypertension development. Since under resting conditions cardiac output in SHR was not significantly different from normotensive controls, the elevated arterial pressure and QO2 were associated with increased TPR. Arterial hypoxemia was induced to reduce oxygen availability and to assess whether increased TPR in SHR could be reversed by this procedure. During hypoxemia, normotensive controls (WKY) responded with increased cardiac output and decreased arterial pressure and TPR. In contrast, arterial pressure and cardiac output fell in SHR; and the increased TPR persisted. QO2 fell in hypoxemic SHR demonstrating that the relationship between total body oxygen consumption and cardiac output was abnormal in young SHR, and that increased TPR in SHR was not dependent on resting levels of QO2 or oxygen availability. Although QO2 was elevated in SHR compared to age-matched WKY, this condition was not essential for maintained elevated vascular resistance.