Sustained Elevation Of Blood Pressure Research Articles

Interlobular Arteries From 2-Kidney, 1-Clip Goldblatt Hypertensive Rats’ Exhibit-Impaired Vasodilator Response to Epoxyeicosatrienoic Acids

BackgroundSmall renal arteries have a significant role in the regulation of renal hemodynamics and blood pressure (BP). To study potential changes in the regulation of vascular function in hypertension, we examined renal vasodilatory responses of small arteries from nonclipped kidneys of the 2-kidney, 1-clip Goldblatt hypertensive rats to native epoxyeicosatrienoic acids (EETs) that are believed to be involved in the regulation of renal vascular function and BP. A total of 2 newly synthesized EET analogues were also examined. Materials and MethodsRenal interlobular arteries isolated from the nonclipped kidneys on day 28 after clipping were preconstricted with phenylephrine, pressurized and the effects of a 14,15-EET analogue, native 14,15‐EET and 11,12‐ether-EET‐8ZE, an analogue of 11,12-EET, on the vascular diameter were determined and compared to the responses of arteries from the kidneys of sham-operated rats. ResultsIn the arteries from nonclipped kidneys isolated in the maintenance phase of Goldblatt hypertension, the maximal vasodilatory response to 14,15-EET analogue was 30.1 ± 2.8% versus 49.8 ± 7.2% in sham-operated rats; the respective values for 11,12-ther-EET-8ZE were 31.4 ± 6.4% versus 80.4 ± 6%, and for native EETs they were 41.7 ± 6.6% versus 62.8 ± 4.4% (P ≤ 0.05 for each difference). ConclusionsWe propose that reduced vasodilatory action and decreased intrarenal bioavailability of EETs combined with intrarenal angiotensin II levels that are inappropriately high for hypertensive rats underlie functional derangements of the nonclipped kidneys of 2-kidney, 1-clip Goldblatt hypertensive rats. These derangements could play an important role in pathophysiology of sustained BP elevation observed in this animal model of human renovascular hypertension.

Abstract 035: Differential Sodium-evoked Activation of Pvn Magnocellular vs. Parvocellular Neurons in Rats Lacking Central GαI<SUB.2 Proteins Contributes to Sustained Elevations in Blood Pressure

Aim: To determine the role of brain Gαi 2 proteins in mediating sodium-evoked PVN neuronal activation and blood pressure regulation in conscious rats. Methods: 24-h intracerebroventricular scrambled (SCR) or Gαi 2 oligodeoxynucleotide (ODN; 25μg/5μl)-pretreated conscious Sprague-Dawley rats were monitored for changes in MAP in response to HS (IV 3M NaCl; 0.14 ml/100g). Rats were sacrificed at control (C), 10, 40, or 100-min post-HS for PVN cFos IHC and analysis of plasma AVP and NE. Separate groups received a V 1a receptor antagonist (IV; 10 μg/ml/kg) 5-min prior to HS. Results: No difference was observed in sodium-evoked peak change in MAP and MAP remained elevated at 100-min in Gαi 2 but not SCR ODN rats (MAP 100-min post-HS [mmHg] SCR 134±2 vs Gαi 2 146±3, P<0.05). Significant increases in the number of Fos + PVN magnocellular neurons were observed post-HS in SCR and Gαi 2 ODN groups ([Fos + cells] SCR C 3±1 vs 100-min 31±5; Gαi 2 C 2±0 vs 100-min 26±4, P <0.05). A rapid increase in circulating AVP was observed at 10-min in both SCR (plasma AVP [pg/mL] C 12.2±1.6 vs 10-min 62.8±6.9, P <0.05) and Gαi 2 ODN (plasma AVP [pg/mL] C 12.1±1.5 vs 10-min 67.7±7.7 P <0.05) groups and returned to control levels at 40- and 100-min. SCR ODN rats exhibited significant increases in the number of Fos + PVN parvocellular neurons ([Fos+ cells] C 15±1 vs 100-min 67±4, P <0.05) and a significant suppression in circulating NE post-HS (plasma NE [nmol/L] C 44.1±4.9 vs 10-min 17.4±3.9, P <0.05). Gαi 2 ODN rats exhibited significantly less Fos + parvocellular neurons compared to SCR ODN rats (100-min [Fos+ cells] SCR 67±4 vs Gαi 2 30±2, P <0.05) and failed to suppress circulating NE ( P >0.05). V 1a receptor blockade prevented a HS-evoked increase in MAP in SCR ODN rats while Gαi 2 ODN rats exhibited elevated MAP (MAP 100-min [mmHg] SCR 125±2 vs Gαi 2 135±0, P <0.05). Conclusion: Brain Gαi 2 proteins are required to mediate sodium-evoked parvocellular sympathetic, but not magnocellular vasopressinergic, responses to maintain physiological blood pressure regulation. A significant component of blood pressure control in this setting is regulated by the sympathetic nervous system, as supported by the attenuated activation of PVN parvocellular neurons and a failure to suppress circulating levels of NE in Gαi 2 ODN rats.

Central pulse pressure is a determinant of heart and brain remodeling in the elderly: a quantitative MRI and PET pilot study.

The sustained elevation of blood pressure (BP) and especially of central pulse pressure (cPP) leads to heart and brain damage. This pilot study was aimed to precise the relationships between peripheral and central BP levels, and the remodeling of heart and brain as objectively quantified by cardiac MRI and brain F-fluorodeoxyglucose (FDG)-PET imaging in the elderly. Twenty-eight apparently healthy elderly individuals (66-85 years old, 14 women) were prospectively recruited and allocated into two half groups, one with and one without hypertension, and all were referred for the quantitative determinations of peripheral and central BP using applanation tonometry, indexed left ventricular mass (per m of body surface area) using cardiac MRI, and brain metabolism with a voxel-based analysis of FDG-PET images adjusted for age and sex. Indexed left ventricular mass, reflecting cardiac remodeling, was correlated with the overall pressure variables involving both peripheral and central levels of systolic and pulse pressure (all P ≤ 0.001). By contrast, brain metabolism was significantly correlated with only cPP (P < 0.02). A cPP of at least 50 mmHg was associated with both a lower metabolism in frontal areas (P = 0.005) and a higher indexed left ventricular mass (P = 0.03). This pilot study suggests that, when quantified by MRI and PET imaging, left ventricular mass and brain metabolism of elderly individuals are related to the cPP and to the 50 mmHg threshold, corresponding to what has previously been documented for the risk of cardiovascular event.

Performance of parental history for the targeted screening of hypertension in children

Several guidelines recommend universal screening for hypertension in childhood and adolescence. Targeted screening to children with parental history of hypertension could be a more efficient strategy than universal screening. Therefore, we assessed the association between parental history of hypertension and hypertension in children, and estimated the sensitivity, specificity, negative, and positive predictive values of parental history of hypertension for hypertension in children. The present study was a school-based cross-sectional study including 5207 children aged 10-14 years from all public 6th grade classes in the Canton of Vaud, Switzerland. Children had hypertension if they had sustained elevated blood pressure over three separate visits. In children, the prevalence of hypertension was 2.2%. Some 8.5% of mothers and 12.9% of fathers reported to be hypertensive. Maternal history of hypertension (odds ratio 2.0, 95% confidence interval 1.2-3.3) and paternal history of hypertension (odds ratio 2.2, 95% confidence interval 1.4-3.6) were independent risk factors for hypertension in children. Nevertheless, the sensitivity of parental history of hypertension for the identification of hypertension in children was low (from 4% for both parents' positive history up to 41% for at least one parent's positive history). Positive predictive values were also low (between 4 and 5%). Children with hypertensive parents were at higher risk of hypertension. Nevertheless, parental history of hypertension helped only marginally to identify hypertension in offspring. Targeting screening only toward children with a parental history of hypertension may not be a substantially better strategy to identify hypertension in children compared with universal screening.

AT1a Receptor Upregulation in the MnPO Following CIH Leads to Sustained Hypertension

Angiotensin type 1 (AT1) receptors play a central role in many forms of neurogenic hypertension. Two distinct subtypes, At1a and AT1b, exist for AT1 receptors. Activation of the AT1a subtype is characterized by increased sympathetic nerve activity and hypertension. The Median Preoptic Nucleus (MnPO) expresses both subtypes of the angiotensin receptor and our lab has previously demonstrated that AT1a message is increased in MnPO brain punches following CIH. This study sought to determine if changes in expression of the angiotensin receptor subtypes play a role in the sustained hypertension that develops from chronic intermittent hypoxia (CIH). We hypothesized that AT1a receptor expression increased and AT1b receptor expression remained unchanged resulting in the sustained elevation in blood pressure from CIH. Rats were microinjected in MnPO with an adeno‐associated virus loaded with a shRNA construct to prevent AT1a expression (shAT1a) or a scramble construct (shSCR). After recovery, rats were exposed to a 7 day CIH or normoxic protocol. Laser Capture Microdissection and qRTPCR was performed to determine the receptor subtype expression in MnPO with ribosomal subunit S18 as the control. shSCR rats exposed to CIH had significantly more AT1a RNA than their normoxic counterparts (P&lt;.05), but their expression of AT1b remained constant. shAT1a CIH rats did not exhibit the sustained component of hypertension found in shSCR CIH animals and their MnPO AT1a message was reduced compared to control. Overall this indicates that the pathophysiological blood pressure increase during CIH is in part mediated by increases in AT1a receptor subtype expression in the MnPO.

Caveolin-1 prevents sustained angiotensin II-induced resistance artery constriction and obesity-induced high blood pressure.

The type 1 angiotensin II (ANG II) receptor (AT1R) undergoes internalization following stimulation by ANG II. Internalization reduces cell surface AT1Rs, and it is required for AT1R resensitization. In this process AT1R may interact with caveolin-1 (Cav1), the main scaffolding protein of caveolae. We hypothesized that the interaction between Cav1 and AT1R delays AT1R resensitization and thereby prevents sustained ANG II-induced resistance artery (RA) constriction under normal conditions and in experimental obesity. In rat and mouse skeletal muscle RA (diameter: ∼90-120 μm) ANG II-induced constrictions were reduced upon repeated (30-min apart) administrations. Upon disruption of caveolae with methyl-β-cyclodextrin or in RA of Cav1 knockout mice, repeated ANG II applications resulted in essentially maintained constrictions. In vascular smooth muscle cells, AT1R interacted with Cav1, and the degree of cell surface interactions was reduced by long-term (15-min), but not short-term (2-min), exposure to ANG II. When Cav1 was silenced, the amount of membrane-associated AT1R was significantly reduced by a short-term ANG II exposure. Moreover, Cav1 knockout mice fed a high-fat diet exhibited augmented and sustained RA constriction to ANG II and had elevated systemic blood pressure, when compared with normal or high-fat fed wild-type mice. Thus, Cav1, through a direct interaction, delays internalization and subsequent resensitization of AT1R. We suggest that this mechanism prevents sustained ANG II-induced RA constriction and elevated systemic blood pressure in diet-induced obesity.

Adiposity indicators and blood pressure in children: nothing beyond body mass index?

Obesity is a major risk factor for elevated blood pressure in children.1, 2, 3, 4 For instance, in a school-based study of 5207 children aged 10–12 years, the prevalence of hypertension, which is sustained elevated blood pressure over several visits, was 1.5%, 3.9% and 17.5% in normal weight, overweight and obese children, respectively.4 High body mass index (BMI) is commonly used to define overweight and obesity. However, because BMI is merely a proxy for adiposity, there is a longstanding debate about its performance to predict elevated blood pressure (or any other health conditions associated with adiposity) and whether other adiposity indicators, such as waist circumference, waist-to-hip ratio or hip circumference, should not be preferred.5,6

Elevated arterial blood pressure and body mass index among Nigerian preschool children population

BackgroundArterial blood pressure tends to rise with growth and development. Elevated blood pressure (EBP) in children usually occurs during the first two decades of life, and the children with hypertension tend to grow into adulthood with the high level of blood pressure. The prevalence of hypertension in children is increasing, the causes likely to be of different combination of factors. In this study we ascertained the prevalence of EBP in pre-school children in Enugu metropolis, South-East Nigeria and also determined its association with some factors like the Body Mass Index (BMI), urinalysis finding, family history, gender, age and socioeconomic class.MethodA Stratified method of sampling was used to select subjects from registered nursery schools (Pre- elementary school) within Enugu metropolis. Physical examination of the recruited pupils was done with emphasis on arterial blood pressure, anthropometric measurements and urinalysis.ResultSix hundred and thirty children (630) were studied out of which 345 (54.8%) were males and 285 (45.2%) were females. Sustained EBP (mainly systolic) were recorded in 12 pupils (1.9%) giving a prevalence of 1.9% of the pre-school population. The twelve (1.9%) pupils were all 5 years of age (p value = 0.001) and 11 (1.72%) of them were of under-weight BMI. The prevalence of obesity is 0.5% and that of under-weight is 92% of the studied population. There is no association between EBP and obesity (p value = 0.679). All the pupils with EBP had protein-free urine and no hematuria.ConclusionsEBP and under-weight malnutrition is common in children in 5 years age group. EBP in preschool children is not influenced by their body mass index, urinalysis finding, gender, family history of hypertension or socioeconomic class.

Paraganglioma Presenting With Marked Proteinuria

Paragangliomas are rare neuroendocrine tumors that arise from sympathetic and parasympathetic paraganglia. In children, most of them are functional tumors. Presenting symptoms such as sustained or paroxysmal elevations in blood pressure, headache, sweating, and palpitations are related to catecholamine hypersecretion. A previously healthy 8-year-old boy presented with marked proteinuria, hypertension, and heart murmur. Imaging revealed an 81×43×45 mm sized solid mass extending from right retroaortic area to left suprarenal region. Measurements of catecholamines suggested the diagnosis of paraganglioma. Pathologic examination confirmed the diagnosis. Complete tumor resection was performed. Proteinuria, hypertension, and cardiac signs resolved after surgery. Proteinuria has been described as a rare manifestation of paragangliomas in adult patients. This is the first case of a paraganglioma presenting with massive proteinuria in a child.

Diferencias y similitudes entre inhibidores de la enzima de conversión de la angiotensina y antagonistas de los receptores de la angiotensina II

Renin-angiotensin-aldosterone system blockade is one of the key therapeutic targets in the hypertensive patient because its overactivation is directly associated with a sustained elevation in systemic blood pressure and deterioration of the vascular system. The two main pharmacological groups, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, inhibit different levels of the system and share a large number of similarities and some differences in their clinical efficacy. Both groups share a substantial number of indications among hypertensive patients. However, some evidence hasangiohighlighted an individual effect of certain molecules, which should be considered to optimize antihypertensive therapy according to the latest guidelines. Recent evidence on antihypertensive treatment in diabetic patients with dual renin-angiotensin-aldosterone system blockade (KDIGO guidelines) does not support its generalized use due to the increased risk of cardiovascular events.

Irreversible Renal Damage after Transient Renin-Angiotensin System Stimulation: Involvement of an AT1-Receptor Mediated Immune Response

Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-Ren2 transgenic rats. In our current study we hypothesized that activation of the AT1-receptor (AT1R) leads to a T-cell response causing irreversible impairment of renal function and hypertension. Cyp1a1-Ren2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C). Rats were fed a I3C diet between 4–8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4–8 weeks. Rats were placed for 24h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. The development of sustained hypertension was completely prevented by losartan, whereas hydralazine only caused a partial decrease in BP. Markers of renal damage: KIM-1 and osteopontin were highly expressed in urine and kidney samples of I3C-treated rats, even until 20 weeks of age. Additionally, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas the expression of T-helper 1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes. In young Cyp1a1-Ren2 rats AT1R activation leads to induction of an immune response, causing a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension.

Desvenlafaxine-Induced Worsening of Hypertension

Desvenlafaxine-Induced Worsening of Hypertension

Impact of long-term measures of glucose and blood pressure on the retinal microvasculature

ObjectiveRetinopathy and retinal microvascular abnormalities are common in adult populations, yet few long-term predictors have been identified. We therefore examined the association between systolic blood pressure (SBP) and fasting plasma glucose, assessed over 18 years, with retinopathy and retinal vascular caliber in 2066 Carotid MRI participants, an Atherosclerosis Risk in Communities ancillary study. MethodsRetinopathy and retinal vascular caliber were assessed by retinal photography. Confounder-adjusted weighted regression models were used to examine exposures defined as cumulative, long-term prospective, concurrent, and 18-year change. ResultsLong-term prospective (prevalence odds ratio (POR) per 10 mm Hg: 1.14 (95% CI: 1.01, 1.30)) and cumulative (POR per 10 mm Hg: 1.30 (95% CI: 1.09, 1.56) effects spanning approximately 18 years were found for SBP and retinopathy. The strongest long-term prospective association for plasma glucose and retinopathy was identified at the baseline visit (POR per 10 mg/dl: 1.26 (95% CI: 1.16, 1.38)); sustained glucose elevations over 18 years were also associated with prevalent retinopathy (POR per 10 mg/dl: 1.33 (95% CI: 1.24, 1.43)). Results were robust to the exclusion of participants with diabetes. ConclusionsModest and sustained long-term elevations in glucose and blood pressure are associated with retinopathy and retinal vascular caliber.

Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets?

Hypertension, the condition characterized by sustained elevated blood pressure, affects over 25% of adults in developed countries and is accompanied by pathological cardiac remodeling (i.e., hypertrophy and fibrosis), thus being a major risk factor for cardiac failure. Life style, the environment, genetic factors, diabetes or obesity can all promote development and progression of hypertension associated cardiovascular disease in part because these conditions induce an excess production of pro-hypertensive, pro-hypertrophic and pro-fibrotic agonists. Here we review signaling pathways shared by major agonists including angiotensin II, catecholamines and endothelins. At the cellular level, these agonists initiate disease signaling by activating cognate G protein-coupled receptors (GPCRs). Early events in agonist-signaling include Ca2+ release from intracellular stores, Ca2+ uptake from extracellular millieu into cells and reactive oxygen species (ROS) generation by NADPH oxidase. ROS production in turn contributes to activation of matrix metalloproteinases (MMPs) and 'a disintegrin and metalloproteinases' (ADAMs). Activated MMPs and ADAMs cleave growth factors, cytokines as well as cell surface receptors, including GPCRs. Excessive activation of MMPs and ADAMs links agonist receptors with transcription and translation of disease-associated genes, including those of MMPs and ADAMs. Recent research indicates a complex and dynamic regulation of MMPs and ADAMs activity and expression by agonists, which poses a significant challenge to strategies aiming at targeting specific MMPs or ADAMs in cardiovascular disease.

704 IS THERE AN ESSENTIAL ROLE FOR ADAPTIVE IMMUNITY UNDERLYING RENIN-ANGIOTENSIN-INDUCED RENAL DAMAGE?

Objective: Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-mRen2 transgenic rats. We hypothesize that activation of the AT1-receptor induces an adaptive immune response underlying this irreversible impairment of renal function and pathology. Methods: Cyp1a1-mRen2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C). Rats were fed a I3C diet between 4-8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan or hydralazine treatment between 4-8 weeks. Rats were placed for 24 h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. Results: Losartan prevented the development of sustained hypertension, whereas hydralazine only caused a partial decrease in BP. KIM-1 and osteopontin, markers of renal damage linked to inflammation, were highly expressed in urine and kidney samples of I3C-treated rats, even till 20 weeks. Furthermore, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas expression of T-helper1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was ineffective. Conclusion: In young Cyp1a1-mRen2 rats AT1-receptor activation leads to induction of an adaptive immune response, a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension. This study was performed within the framework of TI-Pharma projectT2-301.

Atorvastatin prevents dehydromonocrotaline-induced pulmonary hypertension in beagles

ABSTRACTBackground: Pulmonary arterial hypertension is a life-threatening disease characterized by marked and sustained elevation of blood pressure in the lungs. Statins, 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, have been shown to attenuate the effects of pulmonary hypertension resulting from hypoxia, Monocrotaline exposure, or Monocrotaline exposure in the setting of pneumonectomy. In particular, the effects of Simvastatin have been well studied. Whether other statins, such as Atorvastatin, are capable of preventing dehydromonocrotaline-induced pulmonary hypertension in beagles has not been explored. Methods: We used eighteen 3-month-old beagles of both genders, weighing 10.3 ± 3.2 kg. The experimental animals were randomized into one of 3 groups: the control group (n = 6), the dehydromonocrotaline (DHMC) + vehicle group (n = 5), and the DHMC + Atorvastatin group (n = 7). The beagles were injected with DHMC (n = 12) on day 1, and from day 5 to day 65 they received Atorvastatin (2 mg/kg, daily by gavage) or vehicle (0.9% saline, daily by gavage) treatment. We used the thermodilution method of hemodynamic measurements at baseline and at day 65 of treatment. At day 65, pulmonary tissue was sampled for morphometry and real-time quantitative PCR. Results: After 65 days, DHMC increased mean pulmonary arterial pressure (mPAP), and this increase was prevented with Atorvastatin treatment (32 ± 11 mmHg vs. 15 ± 3 mmHg, P < .05). Hematoxylin and eosin staining demonstrated less pulmonary endothelium destruction and smooth muscle cell proliferation in the Atorvastatin-treated beagles, compared with the DHMC group. The eNOS mRNA expression was increased in the DHMC group, and this increase was prevented in the Atorvastatin-treated group. In addition, IL-1β, prepro-ET-1, TNF-α, and VEGF (vascular endothelial growth factor) mRNA expression levels were increased in the lungs of the DHMC group, and these increases were reduced toward normal levels in the Atorvastatin-treated group. Conclusion: Atorvastatin prevents the effects of monocrotaline-induced pulmonary hypertension in beagles.

Capillary Remodeling in Infants Born to Hypertensive Pregnancy: Pilot Study

Capillary rarefaction is pathognomonic of essential hypertension. We have previously shown significant capillary rarefaction in normotensive adult offspring of hypertensive parents, suggesting a familial predisposition in which capillary rarefaction represents a primary vascular abnormality that antedates the onset of sustained elevation of blood pressure (BP). We have recently reported that low-birth weight (LBW) infants, born at term or preterm, to normotensive mothers do not have capillary rarefaction at birth. We hypothesized that infants born to mothers with hypertensive disorders of pregnancy (HDP) would have significant capillary rarefaction at birth when compared to infants of normotensive mothers. We studied 22 infants born to hypertensive mothers and compared them to 40 normal birth weight infants born at term to normotensive mothers. We used orthogonal polarized spectroscopy to measure basal (i.e., functional) and maximal (i.e., structural) skin capillary densities according to a well-validated protocol. We found that term infants born to hypertensive mothers had significantly lower maximal capillary density (MCD) (mean difference of -5.0 capillaries/mm(2); P < 0.05). However, preterm infants with LBW born to hypertensive mothers tended to have higher basal and maximal skin capillary densities compared with term infants. While the results in term infants are consistent with our belief that capillary rarefaction in essential hypertension is likely to be a primary vascular abnormality, the results in preterm infants may suggest that the intrauterine environment may exert some influences on the remodeling of the microcirculation which may delay the onset of capillary rarefaction in these infants.

Interventional Approaches to Reduce Sympathetic Activity in Resistant Hypertension

See related article, pp 331–338 In this issue of Hypertension , Lohmeier et al compare, in a dog model of obesity-hypertension, 2 interventional techniques currently being tested in clinical trials for the treatment of resistant hypertension.1 Sympathetic inhibition is the mechanism by which these interventions are proposed to control hypertension. That sympathetic activity plays a role in hypertension is not a new concept. From the mid 1930s until late 1950s, surgical sympathectomy was practically the only effective treatment for malignant hypertension, and, although plagued by significant side effects, it improved survival of an otherwise fatal disease. Ganglionic blockers and reserpine were the earliest antihypertensives developed, and central sympatholytics followed shortly thereafter. Drugs targeting the sympathetic nervous system, however, are no longer considered as first-line antihypertensives. Central sympatholytics are limited by their side effects, and outcome trials have shown that α- and β-blockers are inferior in lowering the incidence of heart failure and strokes, respectively, compared with other drugs. There is, therefore, a mismatch between the need to target sympathetic activation in hypertension and the limitations of available medical therapies. Novel interventional approaches are trying to fill this void. One of these approaches relates to the work by Lohmeier et al, who showed that chronic carotid sinus stimulation produced a sustained decrease in blood pressure in a dog model of obesity-induced hypertension.2 This work provided further evidence that sympathetic activation plays a role in obesity hypertension and demonstrated that the autonomic nervous system not only plays a role in transient blood pressure regulation but can also contribute to sustained elevations of blood pressure. Treatment of human hypertension with carotid sinus stimulation was attempted for a short period in the 1960s, but only recently have technological advances …

Transient renin–angiotensin system stimulation in an early stage of life causes sustained hypertension in rats

Transient administration of inhibitors of the renin-angiotensin system (RAS) during the prehypertensive period in rats and humans leads to a long-lasting lowering of blood pressure (BP). Our aim was to unravel the critical period in which activation of the RAS induces chronic effects on BP and to determine the role of renal function and structure in this process. Studies were performed in Cyp1a1-Ren2 rats, which harbor a construct for the production of mouse renin. This construct becomes activated when indole-3-carbinol (I3C) is added to the diet. Young (4 weeks old) and adult (30 weeks old) Cyp1a1-Ren2 rats were randomly assigned to either the I3C treatment group or the control group. Renin production was stimulated from week 4 to 8 in young and week 30 to 34 in adult rats. BP follow-up was performed via photoelectric/oscillometric tail cuff method and intra-arterial BP was determined at 4, 8, 12 and 20 weeks of age or 34 and 38 weeks of age. Additionally, renal vascular resistance, albuminuria, renal inflammation and renal pathology were determined. Up to 20 weeks of age, that is, 12 weeks after I3C withdrawal, mean arterial pressure (MAP) was significantly elevated in young I3C-treated rats (141 ± 7 mmHg) compared with controls (125 ± 6 mmHg). In adult rats, renin stimulation caused only a transient elevation in MAP, which returned to control values after I3C withdrawal. In young rats, the sustained pressor response was associated with increased indices of renal vascular resistance, glomerulosclerosis and tubulointerstitial damage as well as with a moderate inflammatory response. In adult rats, renal pathology and inflammation was significantly less than in young rats and was reversible. Transient RAS stimulation causes sustained elevation in BP in young, but not in adult Cyp1a1-Ren2 transgenic rats and is associated with irreversible changes in renal structure and function and a moderate renal inflammatory response.

Background and rationale for mechanism of action, efficacy, and safety of fingolimod (Gilenya), the first oral therapy for remitting-relapsing multiple sclerosis

Background and rationale for mechanism of action, efficacy, and safety of fingolimod (Gilenya), the first oral therapy for remitting-relapsing multiple sclerosis