Animal Models Of Hypertension Research Articles

Analysis of animal models of hypertension based on characteristics of clinical symptoms of Chinese and western medicine

Hypertension, a cardiovascular disease with main clinical manifestations of dizziness and elevated blood pressure, especially elevated arterial pressure, features high prevalence rate and low control rate, which affects patients' quality of life. Therefore, establishing a good animal model of hypertension is of great significance for its diagnosis and clinical prevention and treatment. Based on the clinical characteristics of hypertension in traditional Chinese and western medicine, this study summarized the advantages and disadvantages of current hypertension animal models: gene-related model, surgery-caused model, drug-induced model, and environment-induced model, and investigated the similarity to the clinical symptoms in traditional Chinese medicine and Western medicine. Among them, spontaneously hypertensive rats, models established with the surgical two-kidney one-clip, one-kidney one-clip, two-kidney two-clip, and abdominal aorta constriction methods, models induced with the drug deoxycorticosterone acetate, and models induced with the high-fat high-purine diet showed symptoms highly similar to the clinical manifestations. Then, the corresponding evaluation and improvement methods of hypertension animal models were proposed. This study provides suggestions for the establishment of hypertension animal model so that the symptoms are more similar to the clinical characteristics of hypertension in traditional Chinese and Western medicine, which is important for the clinical diagnosis and treatment of hypertension.

Hypotensive Effects of the Triterpene Oleanolic Acid for Cardiovascular Prevention.

Hypertension is a highly prevalent chronic disease worldwide and a major cardiovascular risk factor. Oleanolic acid (3β-hydroxy-olea-12-en-28-oic acid) is a widely distributed bioactive pentacyclic triterpenoid with diverse biological activities such as anti-inflammatory, hepaprotective, anti-diabetic or anti-hypertensive. The aim of this study was to review and highlight the available data regarding the antihypertensive activity of oleanolic acid and the described mechanisms of action. Extensive searches were made in the available literature on oleanolic acid and the data investigating its antihypertensive effects were analysed. Most of the research has been performed on animal models of hypertension, ex vivo studies with aortic ring and some in vitro tests with cell cultures, whereas clinical trials are still lacking. Treatment of hypertensive animals with oleanolic acid significantly ameliorated the rise in the systolic blood pressure. In addition, the hypotensive effects of oleanolic acid are also related to a potent diuretic-natriuretic activity and nephroprotection. In vitro studies have characterized the participation of various signalling pathways that modulate the release of vasodilation mediators. In vitro and in vivo studies suggest that oleanolic acid effectively reduces blood pressure and could be an interesting co-adjuvant to conventional treatment of hypertension.

Detection of extracellular superoxide in isolated human immune cells and in an animal model of arterial hypertension using hydropropidine probe and HPLC analysis

Detection of extracellular superoxide in isolated human immune cells and in an animal model of arterial hypertension using hydropropidine probe and HPLC analysis

Integrating network pharmacological and experimental models to investigate the therapeutic effects of baicalein in glaucoma

BackgroundTraditional Chinese medicine (TCM) has a long history of treating glaucoma with remarkable effects, but there is no clear conclusion on its mechanism.MethodsNetwork pharmacology and molecular docking were used to analyze the mechanism and targets of TCM in the treatment of glaucoma, and baicalein was used to treat chronic ocular hypertension animal models rats for observation.ResultsThe results of animal experiments showed that baicalein could significantly reduce intraocular pressure (IOP) in a rat model of chronic ocular hypertension and protect the structure of the retina and optic nerve, as shown by hematoxylin–eosin (H&E) staining and transmission electron microscopy (TEM). Reducing the apoptosis of retinal ganglion cells (RGCs) by upregulating the expression of the antiapoptotic protein BCL-2 is basically consistent with the results of molecular docking. In the network pharmacology analysis, many key proteins of biological pathways involved in the herbal therapeutic processes in glaucoma, such as threonine kinase 1 (AKT1, core protein of PI3K/AKT signaling), tumor protein p53 (TP53, a tumor suppressor gene coding tumor protein P53), signal transducer and activator of transcription 3 (STAT3, core protein of JAK/STAT signaling), interleukin 6 (IL-6) and interleukin 17 (IL-17, proinflammatory factors), were identified. Their interactions built complicated chain reactions in the process of glaucoma.ConclusionBy combining the analysis of network pharmacology and animal experimental results, baicalein could effectively improve the symptoms of glaucoma and reduce RGC apoptosis, suggesting that the potential mechanism of TCM in treating glaucoma is related to regulating inflammation and cellular immunity and reducing apoptosis.

Renal sympathetic denervation can significantly reduce blood pressure and improve arterial stiffness in hypertensive beagles

To investigate the effect of renal sympathetic denervation (RDN) on blood pressure and arterial stiffness in hypertensive beagles and explore the underlying mechanism. Sixteen beagles were randomly divided into RDN group (n=8, fed with a high-salt high-fat diet to establish models of hypertension and treated with RDN), sham-operated group (n=4, fed with a high-salt high-fat diet to induce hypertension but only examined with renal arteriography) and control group (n=4, fed with formula dog food). The changes in blood pressure, arterial stiffness, endothelial function, and sympathetic activity were compared among the 3 groups and correlation analysis was performed. All the animal models of hypertension were established successfully in the beagles. At 3 months after the RDN, the changes in systolic blood pressure (SBP) differed significantly among the 3 groups (P=0.006), and the reduction in SBP was significantly greater in RDN group than in the other two groups (P < 0.05). The variations of diastolic blood pressure (DBP) also differed significantly among the 3 groups (P=0.016), and DBP reduction was more obvious in RDN group than in the control group (P=0.007), but similar to that in the sham-operated group (P=0.052). The changes of resistance index (RI) after the procedure were significantly different among the 3 groups (P=0.043), and the RDN group showed a greater reduction of RI than the control group (P=0.032) and sham group (P=0.043). Serum levels of eNOS, NO and Ang Ⅱ did not differ significantly among the groups either before or after RDN (P>0.05), but serum NE level was significantly higher in RDN group than in the control groupafter successful modeling (P=0.014), but similar to that in the sham group (P=0.560). Compared with the sham operation, RDN in the hypertensive beagles resulted in a significantly greater decrease of serum NE level (P=0.032) to almost the control level (P= 0.080). The changes of RI following RDN were significantly correlated with the changes of SBP, DBP and serum levels of NO and NE (P < 0.05). RDN can significantly reduce blood pressure and improve arterial stiffness in hypertensive beagles possibly by reducing sympathetic activity and blood pressure and promoting NO synthesis.

Abstract 11502: Elevations in Proinflammatory Cytokines Il-1β and Il-12 in the Transgenic (mren2)27 Rat: A Clinically-Relevant Animal Model of Metabolic Syndrome

Introduction: Spontaneous intracerebral hemorrhage (ICH) accounts for 10-15% of strokes and carries a 40% mortality rate within one month. Neuroinflammation plays a key role in secondary brain injury after ICH and inflammatory pathways may represent important therapeutic targets. A major obstacle in developing novel therapeutics is the lack of a translatable animal model that recapitulates the comorbidities of patient’s that suffer from ICH. Hypertension, diabetes, and obesity are components of the metabolic syndrome often seen in ICH patients, and may modulate the neuroinflammatory response to ICH. Thus, we aimed to characterize peripheral markers of systemic inflammation in a transgenic hypertensive (mRen2)27 rat model of metabolic syndrome. Methods: Serum proinflammatory cytokines IL-1β and IL-12 were measured using ELISA in naïve male and female (mRen2)27 (n=15) and healthy SD rats at 32 weeks of age (n=14). Systolic blood pressure (SBP) was measured by tail-cuff plethysmography. Statistical analyses of group differences were conducted using two-sample t-tests. Results: SBP (mm Hg) was significantly higher in the (mRen2)27 transgenic rats compared to SD rats, in both males (195 ± 4, n=8 vs. 125 ± 4, n=6, p&lt; 0.05) and females (183±7, n=7 vs. 114±10, n=8, p&lt; 0.05). Female (mRen2)27 rats had significantly higher serum concentrations (pg/mL) of IL-12 (1073±47, n=7 vs. 438±101, n=8, p&lt; 0.05) and IL-1β (pg/mL) (11±3, n=7;. 4±1 , n=8, p&lt; 0.05). Similarly, male (mRen2)27 rats had significantly higher levels of IL-12 compared to SD rats (825±58 , n=8 v. 582±90 , n=6, p&lt; 0.05). IL-12 levels were higher in mRen female rats compared with males (1073±47, n=7 v. 825±58 , n=8, p&lt; 0.05). Serum levels of IL-1β was not significantly different between male SD and (mRen2)27 rats. Conclusion: Compared to healthy SD rats, the pro-inflammatory cytokines IL-1β and IL-12 are elevated in a clinically-relevant animal model of spontaneous hypertension. These findings simulate human studies that have linked cardiometabolic disease with elevated levels of pro-inflammatory cytokines. Future studies using this animal model will seek to further characterize changes in perihematomal and peripheral levels of proinflammatory and inflammation-resolving cytokines following ICH.

Emerging Insights Into Chronic Renal Disease Pathogenesis in Hypertension From Human and Animal Genomic Studies.

The pathogenic links between elevated blood pressure and chronic kidney disease remain obscure. This article examines progress in population genetics and in animal models of hypertension and chronic kidney disease. It also provides a critique of the application of genome-wide association studies to understanding the heritability of renal function. Emerging themes identified indicate that heritable risk of chronic kidney disease in hypertension can arise from genetic variation in (1) glomerular and tubular protein handling mechanisms; (2) autoregulatory capacity of the renal vasculature; and (3) innate and adaptive immune mechanisms. Increased prevalence of hypertension-associated chronic kidney disease that occurs with aging may reflect amplification of heritable risks by normal aging processes affecting immunity and autoregulation.

The Intraocular Pressure Lowering Effect of a Dual Kinase Inhibitor (ITRI-E-(S)4046) in Ocular Hypertensive Animal Models.

PurposeThe purpose of this study was to develop a preclinical compound, ITRI-E-(S)4046, a dual synergistic inhibitor of myosin light chain kinase 4 (MYLK4) and Rho-related protein kinase (ROCK), for reducing intraocular pressure (IOP).MethodsITRI-E-(S)4046 is an amino-pyrazole derivative with physical and chemical properties suitable for ophthalmic formulation. In vitro kinase inhibition was evaluated using the Kinase-Glo Luminescent Kinase Assays. A comprehensive kinase selectivity analysis of ITRI-E-(S)4046 was performed using the KINOMEscan assay from DiscoverRx. The IOP reduction and tolerability of ITRI-E-(S)4046 were assessed in ocular normotensive rabbits, ocular normotensive non-human primates, and ocular hypertensive rabbits. In vivo studies were conducted to assess drug concentrations in ocular tissue. The adverse ocular effects of rabbit eyes were evaluated following the OECD405 guidelines.ResultsITRI-E-(S)4046 showed highly selective kinase inhibitory activity against ROCK1/2, MYLK4, and mitogen-activated protein kinase kinase kinase 19 (MAP3K19), with high specificity against protein kinase A, G, and C families. In ocular normotensive rabbits and non-human primates, the mean IOP reductions of 0.1% ITRI-E-(S)4046 eye drops were 29.8% and 28.5%, respectively. In hypertonic saline-induced and magnetic beads-induced ocular hypertensive rabbits, the mean IOP reductions of ITRI-E-(S)4046 0.1% eye drops were 46.9% and 22.0%, respectively. ITRI-E-(S)4046 was well tolerated with only temporary and minor signs of hyperemia.ConclusionsITRI-E-(S)4046 is a novel type of highly specific ROCK1/2 and MYLK4 inhibitor that can reduce IOP in normotensive and hypertensive animal models. It has the potential to become an effective and well-tolerated treatment for glaucoma.

Acid-sensing ion channel 1 contributes to pulmonary arterial smooth muscle cell depolarization following hypoxic pulmonary hypertension.

Pulmonary hypertension is characterized by sustained vasoconstriction and remodelling of the small pulmonary arteries, which is associated with persistent depolarization of the resting membrane potential (Em ) of pulmonary arterial smooth muscle cells (PASMCs). It is well-known that the underlying mechanism of this depolarization includes inhibition of K+ channels; however, whether other ion channels contribute to this depolarization is unknown. We previously reported that acid-sensing ion channel 1 (ASIC1), a non-selective cation channel (NSCC) that conducts both Na+ and Ca2+ , is present in PASMCs and contributes to the development of chronic hypoxia (CH)-induced pulmonary hypertension. Therefore, we tested the hypothesis that ASIC1-mediated Na+ influx contributes to PASMC Em regulation following CH-induced pulmonary hypertension. Using sharp electrode intracellular recordings in isolated, pressurized small pulmonary arteries from rats and mice, we show that exposure to CH leads to PASMC membrane depolarization compared with control animals, and this is independent of intraluminal pressure-induced depolarization. In addition to a decrease in PASMC whole-cell K+ currents following CH, we demonstrate that whole-cell NSCC currents are increased and essential to the persistent CH-induced Em depolarization in PASMCs. Both the specific inhibitor of ASIC1, psalmotoxin 1, and global knockout of ASIC1 (Asic1-/- ) prevents CH-induced Em depolarization and largely inhibits whole-cell NSCC currents, without affecting whole-cell K+ currents. Our results show a combination of factors, including inhibition of K+ efflux and augmented Na+ influx, mediate CH-induced PASMC depolarization. Furthermore, this study demonstrates a novel role for ASIC1 in the regulation of Em in PASMCs during CH-induced pulmonary hypertension. KEY POINTS: In pulmonary hypertensive patients and animal models of pulmonary hypertension, the resting membrane potential (Em ) of pulmonary arterial smooth muscle cells (PASMCs) is persistently depolarized. In addition to the well-established reduction of K+ conductance, we show that non-selective cation channel currents are increased and essential to the persistent Em depolarization in PASMCs following chronic hypoxia (CH)-induced pulmonary hypertension. The current study provides novel evidence that acid-sensing ion channel 1 (ASIC1)-mediated Na+ influx induces membrane depolarization and regulates Em in PASMCs following CH exposure. Although fairly quiescent under control conditions, our findings demonstrate a pathological function of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension.

Treprostinil palmitil inhibits the hemodynamic and histopathological changes in the pulmonary vasculature and heart in an animal model of pulmonary arterial hypertension

Treprostinil palmitil (TP) is a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE). In this study, TP was delivered by inhalation (treprostinil palmitil inhalation suspension, TPIS) in a rat Sugen 5416 (Su)/hypoxia (Hx) model of pulmonary arterial hypertension (PAH) to evaluate its effects on hemodynamics, pulmonary vascular remodeling, and cardiac performance and histopathology. Male Sprague-Dawley rats received Su (20 mg/kg, s.c), three weeks of Hx (10% O2) and 5 or 10 weeks of normoxia (Nx). TPIS was given during the 5–10 week Nx period after the Su/Hx challenge. Su/Hx increased the mean pulmonary arterial blood pressure (mPAP) and right heart size (Fulton index), reduced cardiac output (CO), stroke volume (SV) and heart rate (HR), and increased the thickness and muscularization of the pulmonary arteries along with obliteration of small pulmonary vessels. In both the 8- and 13-week experiments, TPIS at inhaled doses ranging from 39.6 to 134.1 μg/kg, QD, dose-dependently improved pulmonary vascular hemodynamics, reduced the increase in right heart size, enhanced cardiac performance, and attenuated most of the histological changes induced by the Su/Hx challenge. The PDE5 inhibitor sildenafil, administered at an oral dose of 50 mg/kg, BID for 10 weeks, was not as effective as TPIS. These results in Su/Hx challenged rats demonstrate that inhaled TPIS may have superior effects to oral sildenafil. We speculate that the improvement of the pathobiology in this PAH model induced by TPIS involves effects on pulmonary vascular remodeling due to the local effects of TRE in the lungs.

Abstract MP01: Deacetylation Of Mitochondrial Cyclophilin D K166 Inhibits Cytokine-induced Oxidative Stress And Attenuates Hypertension

We have previously reported that depletion Cyclophilin D (CypD), a regulatory subunit of mitochondrial permeability transition pore, improves vascular function and attenuates hypertension, however, specific regulation of CypD in hypertension is not clear. Analysis of human arterioles from hypertensive patients did not reveal alterations in CypD levels but showed 3-fold increase in CypD acetylation. We hypothesized that CypD-K166 acetylation promotes vascular oxidative stress and hypertension, and measures to reduce CypD acetylation can improve vascular function and reduce hypertension. Essential hypertension and animal models of hypertension are linked to inactivation of mitochondrial deacetylase Sirt3 by highly reactive lipid oxidation products, isolevuglandins (isoLGs), and supplementation of mice with mitochondria targeted scavenger of isoLGs, mito2HOBA, improves CypD deacetylation. To test the specific role of CypD-K166 acetylation, we developed CypD-K166R deacetylation mimic mutant mice. Mitochondrial respiration, vascular function and systolic blood pressure in CypD-K166R mice was similar to wild-type C57Bl/6J mice. Meanwhile, angiotensin II-induced hypertension was substantially attenuated in CypD-K166R mice (144 mmHg) compared with wild-type mice (161 mmHg). Angiotensin II infusion in wild-type mice significantly increased mitochondrial superoxide, impaired endothelial dependent relaxation, and reduced the level of endothelial nitric oxide which was prevented in angiotensin II-infused CypD-K166R mice. Hypertension is linked to increased levels of inflammatory cytokines TNFα and IL-17A promoting vascular oxidative stress and end-organ damage. We have tested if CypD-K166R mice are protected from cytokine-induced oxidative stress. Indeed, ex vivo incubation of aorta with the mixture of angiotensin II, TNFα and IL-17A (24 hours) increased mitochondrial superoxide by 2-fold in wild-type aortas which was abrogated in CypD-K166R mice. These data support the pathophysiological role of CypD acetylation in inflammation, oxidative stress and hypertensive end-organ damage. We propose that targeting CypD acetylation may have therapeutic potential in treatment of vascular dysfunction and hypertension.

Curcumin ameliorates hypertension via gut-brain communication in spontaneously hypertensive rat

Gut dysbiosis and dysregulation of gut–brain communication have been identified in hypertensive patients and animal models. Previous studies have shown that probiotic or prebiotic treatments exert positive effects on the pathophysiology of hypertension. This study aimed to examine the hypothesis that the microbiota-gut-brain axis is involved in the antihypertensive effects of curcumin, a potential prebiotic obtained from Curcuma longa. Male 8- to 10-week-old spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats were divided into four groups: WKY rats and SHRs treated with vehicle and SHRs treated with curcumin in dosage of 100 or 300 mg/kg/day for 12 weeks. Our results show that the elevated blood pressure of SHRs was markedly decreased in both curcumin-treated groups. Curcumin treatment also altered the gut microbial composition and improved intestinal pathology and integrity. These factors were associated with reduced neuroinflammation and oxidative stress in the hypothalamus paraventricular nucleus (PVN). Moreover, curcumin treatment increased butyrate levels in the plasma, which may be the result of increased butyrate-producing gut microorganisms. In addition, curcumin treatment also activated G protein-coupled receptor 43 (GPR 43) in the PVN. These results indicate that curcumin reshapes the composition of the gut microbiota and ameliorates the dysregulation of the gut-brain communication to induce antihypertensive effects.

Inflammatory markers assessment in an animal model of intracranial hypertension: a randomized trial

BackgroundIntracranial hypertension (ICH) is a common final pathway of most neurosurgical pathologies and leads to poor prognosis if not detected and treated properly. Inflammatory markers have been assessed in clinical scenarios of neurological injuries, in which systemic and brain tissue aggressions may introduce bias. There is a lack of studies under controlled settings to isolate the ICH effect on inflammation. This study aims to evaluate the effects of ICH on the serum concentration of cytokines as biomarkers of neuroinflammation in an experimental model which isolates ICH from potential confounding variables.MethodsAn established model of ICH using an intracerebral pediatric bladder catheter and a multisensor intraparenchymal catheter was used in adult pigs (Sus domesticus). The animals were randomly allocated to 2 groups based on the catheter balloon volume used to simulate the ICP increase (4 ml or 7 ml). Cytokines were measured in 4 timepoints during the experiment: (1) 15 min before balloon insufflation; (2) 5 min after insufflation; (3) 125 min after insufflation; (4) 60 min after deflation. The following cytokines were measured IL-1α; IL-1β; IL–1ra; IL-2; IL-4; IL-6; IL-8; IL-10; IL-12; IL-18; TNFα. Generalized estimating equations were modeled to compare the ICP and cytokines values between the groups along the experiment. The study sample size was powered to detect interactions between the groups and the study moments with an effect size (f) of at least 0.3. The ARRIVE checklist was followed.ResultsA total of 20 animals were studied (10 in each group, 4 ml or 7 ml balloon volume insufflation). The animal model was successful in increasing the ICP along the moments of the experiment (p < 0,001) and in creating an ICP gradient between the groups (p = 0,004). The interaction term (moment × group) was also significant (p < 0,001). There was a significant association between ICP elevation and most cytokines variation. The cytokines IL-1α, IL-1β, IL1-ra, IL-6, IL-12, and IL-18 increased, whereas IL-2, IL-4, and TNF-α decreased. IL-10 did not vary significantly in response to the ICP elevation.ConclusionThe serum concentration of cytokines varied in response to intracranial hypertension. The study demonstrated the specific changes in each cytokine after intracranial hypertension and provides key information to guide neuroinflammation clinical research. The proposed experiment was successful as an animal model to the study of neuroinflammation biomarkers

Washed Microbiota Transplantation Lowers Blood Pressure in Patients With Hypertension.

BackgroundAlthough transplantation of the fecal microbiota from normotensive donors has been shown to have an antihypertensive effect in hypertensive animal models, its effect on blood pressure in patients with hypertension is unclear. This study aimed to assess the effect of washed microbiota transplantation (WMT) from normotensive donors on blood pressure regulation in hypertensive patients.MethodsThe clinical data of consecutive patients treated with washed microbiota transplantation (WMT) were collected retrospectively. The blood pressures of hypertensive patients before and after WMT were compared. The factors influencing the antihypertensive effect of WMT in hypertensive patients and fecal microbial composition of donors and hypertensive patients were also analyzed.ResultsWMT exhibited an antihypertensive effect on blood pressure: the blood pressure at hospital discharge was significantly lower than that at hospital admission (change in systolic blood pressure: −5.09 ± 15.51, P = 0.009; change in diastolic blood pressure: −7.74 ± 10.42, P < 0.001). Hypertensive patients who underwent WMT via the lower gastrointestinal tract (β = −8.308, standard error = 3.856, P = 0.036) and those not taking antihypertensive drugs (β = −8.969, standard error = 4.256, P = 0.040) had a greater decrease in systolic blood pressure, and hypertensive patients not taking antihypertensive drugs also had a greater decrease in diastolic blood pressure (β = −8.637, standard error = 2.861, P = 0.004). After WMT, the Shannon Diversity Index was higher in six of eight hypertensive patients and the microbial composition of post-WMT samples tended to be closer to that of donor samples.ConclusionWMT had a blood pressure-lowering effect in hypertensive patients, especially in those who underwent WMT via the lower gastrointestinal tract and in those not taking antihypertensive drugs. Therefore, modulation of the gut microbiota by WMT may offer a novel approach for hypertension treatment.

Effect of Curcuma longa L. extract on noninvasive cardiovascular biomarkers in hypertension animal models

Effect of Curcuma longa L. extract on noninvasive cardiovascular biomarkers in hypertension animal models

Sympathetic modulation by antihypertensive drugs.

Sympathetic modulation by antihypertensive drugs.

A Large Animal Model for Pulmonary Hypertension and Right Ventricular Failure: Left Pulmonary Artery Ligation and Progressive Main Pulmonary Artery Banding in Sheep

A Large Animal Model for Pulmonary Hypertension and Right Ventricular Failure: Left Pulmonary Artery Ligation and Progressive Main Pulmonary Artery Banding in Sheep

A Large Animal Model for Pulmonary Hypertension and Right Ventricular Failure: Left Pulmonary Artery Ligation and Progressive Main Pulmonary Artery Banding in Sheep

Decompensated right ventricular failure (RVF) in pulmonary hypertension (PH) is fatal, with limited medical treatment options. Developing and testing novel therapeutics for PH requires a clinically relevant large animal model of increased pulmonary vascular resistance and RVF. This manuscript discusses the latest development of the previously published ovine PH-RVF model that utilizes left pulmonary artery (PA) ligation and main PA occlusion. This model of PH-RVF is a versatile platform to control not only the disease severity but also the RV's phenotypic response. Adult sheep (60-80 kg) underwent left PA (LPA) ligation, placement of main PA cuff, and insertion of RV pressure monitor. PA cuff and RV pressure monitor were connected to subcutaneous ports. Subjects underwent progressive PA banding twice per week for 9 weeks with sequential measures of RV pressure, PA cuff pressures, and mixed venous blood gas (SvO2). At the initiation and endpoint of this model, ventricular function and dimensions were assessed using echocardiography. In a representative group of 12 animal subjects, RV mean and systolic pressure increased from 28 ± 5 and 57 ± 7 mmHg at week 1, respectively, to 44 ± 7 and 93 ± 18 mmHg (mean ± standard deviation) by week 9. Echocardiography demonstrated characteristic findings of PH-RVF, notably RV dilation, increased wall thickness, and septal bowing. The longitudinal trend of SvO2 and PA cuff pressure demonstrates that the rate of PA banding can be titrated to elicit varying RV phenotypes. A faster PA banding strategy led to a precipitous decline in SvO2 < 65%, indicating RV decompensation, whereas a slower, more paced strategy led to the maintenance of physiologic SvO2 at 70%-80%. One animal that experienced the accelerated strategy developed several liters of pleural effusion and ascites by week 9. This chronic PH-RVF model provides a valuable tool for studying molecular mechanisms, developing diagnostic biomarkers, and enabling therapeutic innovation to manage RV adaptation and maladaptation from PH.

Reader Response: White Matter Hyperintensities Mediate the Association of Nocturnal Blood Pressure With Cognition.

Chesebro et al.1 bring us full circle on the consensus that hypertension is a multisystem illness with small vessel cerebral disease with related parenchymal changes as part of its spectrum. As for animal models of hypertension—and, certainly, now in human chronic hypertension—the position of hypertensive cerebrovascular disease is variable along the dynamic interactions and outcomes that arise once these processes begin. Such realizations are consistent with the recent review that illustrates how peripheral and cerebral autoregulation and reactivity are invariably intertwined in hypertension.2 In reviewing the Classification of Cerebrovascular Diseases published in 1958, Raymond Adams posited, “It must be remembered that in the final analysis the distinguishing attributes of all these diseases are the vascular changes themselves and not merely the parenchymal lesion which they induce.”3 From a clinical and pathology viewpoint, a more complete perspective of hypertension becomes apparent and fundamentally corroborates the 1978 WHO classification of cerebrovascular disease.4 As reiterated by Harsha5 recently, there is danger in assigning imprecise eponyms for cerebrovascular diseases. Rather than being exclusory, it becomes both scientific and practical that hypertension and cerebrovascular disease are spoken of in the same breath.

The abnormalities of adrenomedullary hormonal system in genetic hypertension: Their contribution to altered regulation of blood pressure.

It is widely accepted that sympathetic nervous system plays a crucial role in the development of hypertension. On the other hand, the role of adrenal medulla (the adrenomedullary component of the sympathoadrenal system) in the development and maintenance of high blood pressure in man as well as in experimental models of hypertension is still controversial. Spontaneously hypertensive rats (SHR) are the most widely used animal model of human essential hypertension characterized by sympathetic hyperactivity. However, the persistence of moderately elevated blood pressure in SHR subjected to sympathectomy neonatally as well as the resistance of adult SHR to the treatment by sympatholytic drugs suggests that other factors (including enhanced activity of the adrenomedullary hormonal system) are involved in the pathogenesis of hypertension of SHR. This review describes abnormalities in adrenomedullary hormonal system of SHR rats starting with the hyperactivity of brain centers regulating sympathetic outflow, through the exaggerated activation of sympathoadrenal preganglionic neurons, to the local changes in chromaffin cells of adrenal medulla. All the above alterations might contribute to the enhanced release of epinephrine and/or norepinephrine from adrenal medulla. Special attention is paid to the alterations in the expression of genes involved in catecholamine biosynthesis, storage, release, reuptake, degradation and adrenergic receptors in chromaffin cells of SHR. The contribution of the adrenomedullary hormonal system to the development and maintenance of hypertension as well as its importance during stressful conditions is also discussed.