Established Hypertension Research Articles

Effects of EXRD 4605, a soluble epoxide hydrolase inhibitor, on angiotensin II dependent hypertension in rodents

EETs are vasoactive AA metabolites generated by the CYP450 enzymatic pathway. EETs exhibit vasodilation in vitro and can be further metabolized to their less active diols, DHET by soluble epoxide hydrolase, sEH. Angiotensin II induces sEH expression in rodents. We examined the effects of EXRD4605 (EX), a sEH inhibitor, on angiotensin II‐induced vascular and blood pressure (BP) responses in rodents. EX is a potent inhibitor of human (Kd=2 nM) and mouse (0.4 nM) sEH and exhibits a cellular ED50 of 2.4 nM. EX induces dose‐responsive (25%–175%) increases in gracilis muscle arteriolar diameters that is blocked in the presence of the CYP inhibitor miconazole. Administration of ang II (100–1000 ng/kg, IV) in anesthetized mice induces acute BP increases (25%–53%) that are blunted (29%*–32%*p<0.05) by pre‐treatment with EX (30 mg/kg). We hypothesized the attenuation of the BP increase is the result of increased EET by EX pretreatment. EX had no effect in sEH gene deleted mice suggesting the role of sEH in this response. In mice with established hypertension (angII 1 mg/kg/d), EX (10 mg/kg) reduced BP from 136 to 117* mmHg compared to 139 mmHg to 142 mmHg in vehicle control. We conclude that pharmacological inhibition of sEH with EX induces vasodilation in resistance vessels ex vivo and attenuates ang II‐dependent hypertension in vivo. These data support sEH as an intriguing target for blood pressure regulation and hypertension.

Ixolaris, a tissue factor inhibitor, reduces vascular pruning and delays death in rats with established pulmonary arterial hypertension

We have observed increased tissue factor (TF) expression in pulmonary arterial hypertension (PAH) patients and in a rat model of severe PAH. We hypothesized that TF, the glycoprotein that initiates coagulation and facilitates angiogenesis, contributes to PAH pathogenesis and that blocking TF activity with the tick peptide Ixolaris (IXO) would delay disease progression.Methods/Results: 34 rats underwent left pneumonectomy followed 7 days later by SQ injection of 50 mg/kg monocrotaline (MCT). On day 11 after MCT (d11, RV pressures generally 60 mmHg), we randomized rats to receive SQ injection of IXO (20 mcg/kg daily) or normal saline (NS) until death. The NS group had 50% mortality by d28; IXO treated animals died an average of 10 days later (p<0.03). In a similar experiment, treatment began at d11 and continued 10 days before rats were acutely vasodilated with sodium nitroprusside and sacrificed for heart weights to measure RV hypertrophy and CT scans to visualize vascular pruning. IXO animals had less RV hypertrophy (p<0.01). IXO prevented macrovascular pruning visualized by CT (Figure, represents 3 pairs of rats). Histology showed reduced neointimal formation in pre‐capillary arterioles.

MECHANICAL AND CIRCULATING BIOMARKERS IN ISOLATED CLINIC HYPERTENSION

1. This review examines the current evidence for altered mechanical and circulating biomarkers in isolated clinic hypertension and their potential significance. 2. Arterial stiffness, as assessed by central pulse wave velocity, is influenced by multiple cardiovascular risk factors; however, an independent association with isolated clinic hypertension (ICHT) has not been convincingly shown in four small studies. 3. Endothelial dysfunction, as assessed by brachial artery flow-mediated vasodilation, circulating levels of endothelial markers (e.g. nitrite/nitrate, von Willebrand factor, endothelin-1) and/or circulating levels of inhibitors of vascular nitric oxide (plasma asymmetric dimethylarginine, homocysteine), has been shown to be present in established hypertension and to a variable and inconsistent extent in subjects with ICHT. 4. Evidence of increased oxidative stress in ICHT versus normotensive subjects was found in two of three studies. 5. Circulating inflammatory markers C-reactive protein and plasminogen activator inhibitor-1 were significantly increased in two of three and two of two studies, respectively, in ICHT compared with normotensive subjects. 6. Urinary albumin excretion is a marker of both arterial and renal disease. The consensus from seven studies in patients with ICHT is that albuminuria is not an independent marker for ICHT. 7. Studies to date assessing biomarkers in ICHT have been small and cross-sectional. Larger, long-term longitudinal studies of arterial functional and circulating biomarkers are required to assess the potential vascular impact of ICHT.

Ambulatory blood pressure and cardiac abnormalities

It is well-known that children with established hypertension are at increased risk to develop left ventricular hypertrophy. It is less clear whether children who are at risk of developing hypertension, or who have pre-hypertension, are also at risk of cardiac abnormalities. In this issue of The Journal, Richey et al evaluated young patients with blood pressure greater than the 90th percentile, or with a first degree relative with hypertension. They used 24-Hour Ambulatory Blood Pressure Monitoring (ABPM) to better characterize the level of blood pressure. They found a positive correlation between left ventricular mass index and ABPM measures. These results suggest that ABPM may be a useful method to evaluate blood pressure in young patients who have hypertension or are at risk of hypertension.

Late-onset endothelin receptor blockade in hypertensive heterozygous REN-2 transgenic rats

Our previous studies in heterozygous Ren-2 transgenic rats (TGR) have shown that early treatment with selective endothelin (ET) A receptor blockade is superior to nonselective ET A/B receptor blockade. The aim of this study was to evaluate the role of the ET system in male heterozygous TGR with established hypertension (late-onset treatment). TGR and control Hannover Sprague–Dawley (HanSD) rats were fed a high-salt diet and were treated concomitantly with the nonselective ET A/B receptor blocker bosentan or the selective ET A receptor blocker atrasentan from day 52 of age on. Survival rate was partly increased by bosentan and fully normalized with atrasentan. Bosentan transiently decreased blood pressure (BP), whereas atrasentan significantly reduced BP as early as one week after the start of the treatment. This effect persisted for the whole experimental period. Atrasentan also substantially reduced cardiac hypertrophy, proteinuria, glomerulosclerosis and left ventricle ET-1 content. Bosentan improved and atrasentan almost restored podocyte architecture and reversed changes in podocyte phenotype represented by the expression of CD 10, desmin and vimentin. Our results demonstrate that selective ET A receptor blockade has more favorable effects than nonselective ET A/B receptor blockade and, unlike observed in homozygous TGR, ET A receptor blockade has similar effects in heterozygous rats with established hypertension as in young animals with developing hypertension.

Hypothetical mechanism of sodium pump regulation by estradiol under primary hypertension

Causal relationship between sodium and hypertension has been proposed and various changes in Na +,K +-ATPase (sodium pump) activity have been described in established primary hypertension. A number of direct vascular effects of estradiol have been reported, including its impact on the regulation of sodium pump activity and vasomotor tone. The effects of estradiol involve the activation of multiple signaling cascades, including phosphatydil inositol-3 kinase (PI3K) and p42/44 mitogen-activated protein kinase (p42/44 MAPK). In addition, some of the effects of estradiol have been linked to activity of cytosolic phospholipase A 2 (cPLA 2). One possible cardioprotective mechanism of estradiol involves of the interaction between estradiol and the rennin–angiotensin system (RAS). Elevated circulating and tissue levels of angiotensin II (Ang II) have been implicated in the development of hypertension and heart failure. The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump, in vascular smooth muscle cells (VSMC). The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump activity/expression in VSMC, with particular emphasis on PI3K/cPLA 2/p42/44 MAPK signaling pathways. Our primary hypothesis is that estradiol stimulates sodium pump activity/expression in VSMC via PI3K/cPLA 2/p42/44 MAPK dependent mechanism and, that impaired estradiol-stimulated sodium pump activity/expression in hypertensive rodent models (i.e. SHR), Ang II-mediated vascular impairment of estradiol is related to a decrease ability of estradiol to stimulate the PI3K/cPLA 2/p42/44 MAPK signaling pathways. An important corollary to this hypothesis is that in hypertensive state (i.e. SHR rats) the decreasing in ACE enzyme activity and/or AT1 receptor expression caused by administration of estradiol is accompanying with abrogated ability of Ang II to decrease IRS-1/PI3K association, and consequent PI3K/cPLA 2/p42/44 MAPK activity and associated sodium pump activity/expression. A clear characterization of how Ang II attenuates estradiol signaling may lead to a better understanding of the molecular mechanism(s) underlying pathophysiological conditions such as hypertension and to understanding how certain pathophysiological situations affect sodium pump activity/expression in VSMC.

Ischemic colitis secondary to inferior mesenteric arteriovenous fistula and portal vein stenosis in a liver transplant recipient

Arteriovenous fistula (AVF) involving the inferior mesenteric vessels is rare, and the affected patients usually present with abdominal pain, mass, or features of established portal hypertension. Colonic ischemia is a less common and more serious manifestation of AVF. We report a case of ischemic colitis secondary to inferior mesenteric AVF in a patient who underwent a previous liver transplantation, subsequently developed portal vein stenosis, and then presented with acute lower gastrointestinal bleeding. He underwent percutaneous transhepatic placement of a portal vein stent and left colectomy.

Role of pre-eclamptic toxaemia or eclampsia in hypertensive women attending cardiac clinic of Ahmadu Bello University teaching hospital Zaria, Nigeria

Patients with pre-eclampsia and eclampsia constitute a special high risk group for future hypertension. They require a long term follow up to be able to detect and treat emerging hypertension early enough to prevent complications. Unfortunately, this is not so. This study was undertaken to find out the incidence of history of pre-eclamptic toxaemia (PET) in our female hypertensive patients attending cardiac clinic and to also determine the incidence of complications of hypertension in those with previous history of PET. Fifty consecutive female hypertensive patients seen in cardiac clinic were recruited. Detailed history including full obstetric and family history was taken. A full clinical examination was done including blood pressure and a search for complications of hypertension. Findings were then analyzed and various frequencies determined. Forty-nine patients were studied. The mean age was 47.29 +/- 11.46 years. The mean SBP, DBP and MAP were 143.18 +/- 25.05, 90.49 +/- 14.19 and 108.12 +/- 16.71 mmHg respectively. Between the last child birth and the time of established hypertension in those who had PET ranged from 3-25 years. Sixteen, (32.7%) of the 49 patients had history of PET and 7(43.75%) of these 16 patients had complications of hypertension. The incidence of history of PET in our female hypertensive patients attending cardiac clinic is significant (32.7%). Also the 43.8% incidence of complications of hypertension seen in those patients with history of PET in this study is high. PET patients, therefore, constitute a special risk group for future hypertension. Therefore collaboration between the Obstetricians and the Cardiologists is important for patients with PET and eclampsia.

Clinical significance of the metabolic syndrome in the absence of established hypertension and diabetes: A community-based study

Aims/hypothesis Our aim was to determine the predictive values on the all-cause and cardiovascular mortality and the future risks of hypertension and diabetes of the metabolic syndrome defined by the third report of the National Cholesterol Education Program's Adult Treatment Panel in the absence of established hypertension and diabetes (who may still have elevated blood pressure within 130–139/85–89 mmHg and/or elevated fasting blood glucose within 5.5–6.9 mmol/L (100–125 mg/dL)). Methods A community-based population of 11,058 Chinese aged 30 years and above in Kinmen island was followed up for 10.6 years. All-cause and cardiovascular mortality and incidence of hypertension and diabetes mellitus were determined. Results The hazard ratios and 95% confidence intervals for all-cause and cardiovascular mortality in subjects with metabolic syndrome but without hypertension and diabetes versus subjects without metabolic syndrome, hypertension, and diabetes, were 0.81 (0.51–1.30) and 0.89 (0.57–1.37) in men, and 1.14 (0.45–2.92) and 0.73 (0.27–2.68) in women, respectively. In the non-diabetic non-hypertensives at baseline, the odds ratios and 95% confidence intervals for predicting hypertension and diabetes for subjects with versus without the metabolic syndrome were 2.25 (1.80–2.82) and 3.12 (2.30–4.24), respectively. Conclusions/interpretation In this Chinese population, metabolic syndrome in the absence of hypertension and diabetes was not associated with increased risk of all-cause or cardiovascular mortality. In contrast, the presence of metabolic syndrome predicted future risk of hypertension and diabetes. Therefore, the intervention strategies for subjects with metabolic syndrome may be focused on the prevention of hypertension and diabetes.

Proteolytic Cleavage of Human Chromogranin A Containing Naturally Occurring Catestatin Variants: Differential Processing at Catestatin Region by Plasmin

The plasma level of chromogranin A (CgA) is elevated in genetic hypertension. Conversely, the plasma level of the CgA peptide catestatin is diminished in individuals with established hypertension and those with a genetic risk of this disease. Resequencing of the human CHGA gene identified three naturally occurring variants of catestatin (Gly364Ser, Pro370Leu, and Arg374Gln) that exhibit different potencies in inhibiting catecholamine secretion. Here, we have examined whether there is any differential processing of the three CHGA variants to catestatin by the endoproteolytic enzyme plasmin. Plasmin digestion of the purified CgA proteins generated a stable biologically active 14-amino acid peptide (human CgA(360-373)) from the wild-type, Gly364Ser, and Arg374Gln proteins despite the disruption of the dibasic site (Arg(373)Arg(374)) in the Arg374Gln variant. Unexpectedly, the action of plasmin in generating the catestatin peptide from the Pro370Leu protein was less efficient. The efficiency of cleavage at the dibasic Arg(373) downward arrowArg(374) site in synthetic human CgA(360-380) was 3- to 4-fold less in Pro370Leu CgA, compared with the wild type. Circular dichroism of the synthetic CgA(352-372) suggested a difference in the amount of alpha-helix and beta-sheet between the wild-type and Pro370Leu CgA peptides. Because the Pro(370) residue is in the P4 position, the local secondary structure in the vicinity of the cleavage site may enforce the specificity or accessibility to plasmin. The less efficient proteolytic processing of the Pro370Leu protein by plasmin, coupled with the strong association of this variant with ethnicity, suggests that the Pro370Leu CHGA gene variant may contribute to the differential prevalence of cardiovascular disease across ethnic groups.

Recombinant adeno-associated virus-mediated delivery of antisense angiotensin II receptor 1 gene attenuates hypertension development

The renin-angiotensin system plays a crucial role in the development and establishment of hypertension, and the pharmacological blockade of the system results in a reduction in blood pressure. In the present study, we investigated whether the effects of a novel, double-stranded, recombinant adeno-associated virus vector (rAAV)-mediated antisense angiotensin II receptor 1 (AT1R) gene efficiently prevents the development of hypertension induced by a high-salt diet in adult, male Sprague-Dawley (SD) rats. A rAAV was prepared with a cassette containing a cytomegalovirus promoter and partial cDNA (660 base pairs) for the AT1R inserted in the antisense direction (rAAV-AT1-AS). A single tail vein injection of the rAAV-AT1-AS or rAAV-GFP (green fluorescent protein, a reporter gene) was performed in adult, male SD rats. Two weeks after injection, the animals were fed a diet containing 8% NaCl, and the systolic blood pressure was measured weekly using the tail-cuff method for 12 weeks. The high-salt diet induced a significant rise in systolic blood pressure in the rAAV-GFP-treated animals; however, the rAAV-AT1-AS treatment attenuated the rise in blood pressure (142.7+/-4.5 mmHg vs 117+/-3.8 mmHg, P<0.01), and the hypotensive effect was maintained until the experiments ended at 12 weeks. In the rAAV-GFP-treated animals AT1 was overexpressed in various tissues, especially in the aorta and kidney at mRNA levels; in contrast, rAAV-AT1-AS treatment markedly attenuated AT1 expression. Furthermore, rAAV-AT1-AS treatment prevented target organ damages from hypertension, including cardiac dysfunction and renal injury compared to the rAAV-GFP group. These results suggest that rAAVmediated anti-AT1 delivery attenuates the development of hypertension and protects against renal injury and cardiac remodeling.

Functional characterization and sex differences in small mesenteric arteries of the estrogen receptor-β knockout mouse

The role of the estrogen receptor (ER) subtypes in the modulation of vascular function is poorly understood. The aim of this study was to characterize ex vivo the functional properties of small arteries and their response to estrogens in the mesenteric circulation of female and male ER-beta knockout mice (beta-ERKO) and their wild-type (WT) littermates. Responses to changes in intraluminal flow and pressure were obtained before and after incubation with 17beta-estradiol or ER-alpha agonist propyl-pyrazole-triol (3 h; 10 nM). Cumulative concentration-response curves to acetylcholine, norepinephrine, and passive distensibility were compared with respect to sex and genotype. The collagen and elastin content within the vascular wall and ER expression were also determined. Endothelial morphology was visualized by scanning electron microscopy. 17beta-Estradiol and propyl-pyrazole-triol-treated arteries from female beta-ERKO and WT mice showed enhanced flow-mediated dilation, but this was not evident in males. Distensibility was decreased in arteries from beta-ERKO females. Sex differences in myogenic tone were observed in 17beta-estradiol-treated arteries, but were similar between beta-ERKO and WT mice. Acetylcholine- and norepinephrine-induced responses were similar between groups and sexes. ER-alpha was similarly expressed in the endothelium and media of arteries from all groups studied, as well as ER-beta in WT animals. Endothelial morphology was similar in arteries from animals of both sexes and genotype; however, arterial elastin content was decreased, and collagen content was increased in beta-ERKO male compared with WT male and with beta-ERKO female. We suggest that ERs play a sex-specific role in estrogen-mediated flow responses and distensibility, and that deletion of ER-beta affects artery structure but only in male animals. Further studies in beta-ERKO mice with established hypertension and in alpha-ERKO mice are warranted.

High-normal blood pressure and future risks a new concern for clinicians?

The fact that hypertension (>140/ > 90 mmHg) is a well established cardiovascular risk factor in numerous studies has led epidemiologists to expand their interest also to the risks associated with high-normal blood pressure (130–139/85–89 mmHg). As blood pressure is documented to show properties of tracking over time,1 it is no wonder that people in the high-normal range tend to develop established hypertension after a follow-up period more frequently than subjects with a normal (120–129/80–84 mmHg) or even optimal (<120/ < 80 mmHg) blood pressure. Furthermore, as blood pressure is most often a part of a cardiovascular risk factor syndrome, whether called metabolic syndrome or even cardiometabolic syndrome,2 it is reasonable to believe that the tracking phenomenon could also influence other long-term risks, e.g. for type 2 diabetes and cardiovascular disease. In two recent publications from the Women's Health Study of 38 172 health professionals followed for 10.2 years,3,4 it has now been shown that subjects in the high-normal blood pressure range run an increased risk of type 2 diabetes3 as well as established hypertension and cardiovascular disease,4 when compared with other women in the normal or optimal blood pressure range at baseline. The risk is, however, less pronounced than in established hypertension. This indicates that the screening of subjects for a high-normal blood pressure could result in the … *Corresponding author. Tel: +46 40 33 24 15; fax: +46 40 92 32 72. E-mail address: Peter.Nilsson{at}med.lu.se

Ambulatory blood pressure monitoring and target organ damage in pediatrics

The prevalence of hypertension in children and adolescents is rising in association with the increasing rate of childhood obesity, and it is associated with early target organ damage. Published guidelines on high blood pressure in children and adolescents, focused on the early and accurate diagnosis of hypertension, resulted in improved ability to identify children with hypertension. Although auscultation using a mercury sphygmomanometer remains the method of choice for evaluation of hypertension in children, accumulating evidence suggests that ambulatory blood pressure monitoring is a more accurate method for diagnosis, and it is more closely associated with target organ damage. In addition, ambulatory blood pressure monitoring is a valuable tool in the assessment of white-coat hypertension, and masked hypertension in children and adolescents. Masked hypertension in children and adolescents is associated with a similar risk of target organ damage as in established hypertension.

Counterpoint: Chronic Hypoxia-induced Pulmonary Hypertension does not Lead to Loss of Pulmonary Vasculature

Exposure of native sea level dwellers to chronic hypoxia due to migration to high altitude leads to the development of increased pulmonary vascular resistance causing pulmonary hypertension. In some susceptible individuals this progressively worsens causing right ventricular failure and ultimately

EARLY RENAL DENERVATION PREVENTS DEVELOPMENT OF HYPERTENSION IN GROWTH‐RESTRICTED OFFSPRING

1. Low birth weight is associated with an increased risk for the development of hypertension. Our laboratory uses a model of reduced uterine perfusion in the pregnant rat that results in intrauterine growth-restricted (IUGR) offspring that develop hypertension at a prepubertal age. Although hypertension develops in both prepubertal male and female IUGR offspring, only male IUGR offspring remain hypertensive after puberty. We reported previously that bilateral renal denervation abolishes hypertension in adult male IUGR offspring, indicating an important role for the renal nerves in the maintenance of established IUGR-induced hypertension. We also reported that angiotensin-converting enzyme inhibition abolishes hypertension in adult male IUGR offspring. However, activation of the renin-angiotensin system does not occur in male IUGR offspring until after puberty, or after the development of established IUGR-induced hypertension. Therefore, the mechanisms involved in the development of IUGR-induced hypertension may differ from those involved in the maintenance of established IUGR-induced hypertension. Thus, the purpose of the present study was to determine whether the renal nerves play a causative role in the early development of IUGR-induced hypertension in prepubertal IUGR offspring. 2. Intrauterine growth-restricted and control offspring were subjected to either bilateral renal denervation or sham denervation, respectively, at 4 weeks of age. Mean arterial pressure (MAP) was determined at 6 weeks of age in conscious, chronically instrumented animals. Adequacy of renal denervation was verified by renal noradrenaline content. 3. Whereas renal denervation had no effect on MAP in control offspring (103 +/- 2 vs 102 +/- 3 mmHg for sham vs denervated, respectively), it reduced blood pressure in growth-restricted offspring (114 +/- 3 vs 104 +/- 1 mmHg for sham vs denervated, respectively; P < 0.01). Renal noradrenaline content was significantly reduced in denervated animals relative to sham operated rats. 4. Thus, the data indicate a role for the renal nerves in the aetiology of IUGR-induced hypertension and suggest that the renal nerves may participate in the early development of hypertension in IUGR offspring in addition to established hypertension observed in adult male IUGR offspring.

CELLULAR DISTRIBUTION OF THE RENAL BUMETANIDE‐SENSITIVE Na–K–2Cl COTRANSPORTER BSC‐1 IN THE INNER STRIPE OF THE OUTER MEDULLA DURING THE DEVELOPMENT OF HYPERTENSION IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. The renal bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1) is expressed only in the thick ascending limb and selectively traffics from intracellular vesicles (IVs) to apical plasma membranes (PMs), where BSC-1 regulates sodium reabsorption. We showed previously that in kidneys from adult spontaneously hypertensive rats (SHR; model of essential hypertension) total protein expression of BSC-1 was higher compared with kidneys from normotensive Wistar-Kyoto (WKY) rats. However, whether this change is associated with an increased trafficking of BSC-1 from IVs to PMs is unknown. The goal of the present study was to test the hypothesis that the increase in total renal BSC-1 protein expression in SHR is accompanied by an augmented distribution of BSC-1 from IVs to PMs. 2. To test the hypothesis, we obtained renal tissue from the inner stripe of the outer medulla (ISOM; enriched in thick ascending limbs) and isolated IVs and PMs from this tissue by differential centrifugation. Total BSC-1 protein expression in ISOM and BSC-1 protein expression in ISOM IVs and PMs were measured by semiquantitative western blotting in SHR and aged-matched WKY rats at different ages and stages of hypertension. 3. At 5 weeks of age, SHR were prehypertensive (mean arterial blood pressure (MABP) 97 mmHg). At this age, both the total abundance and cellular distribution of BSC-1 were similar in ISOM from SHR and WKY rats. 4. As SHR aged, their hypertension progressed (MABP 137 and 195 mmHg at 8 and 14 weeks of age, respectively). Associated with the increase in MABP was an increase in both steady state protein levels of ISOM BSC-1 and the distribution of ISOM BSC-1 to PMs (four- and sixfold increases at 8 and 14 weeks of age, respectively, compared with age-matched WKY rats; P < 0.001). 5. Using semiquantitative reverse transcription-polymerase chain reaction, BSC-1 mRNA was measured and was found not to differ between SHR and WKY rat ISOM at any age or level of MABP. 6. We conclude that as SHR transition from prehypertensive to established hypertension, there is a marked increase in the total expression of BSC-1 in ISOM that is not related to increases in steady state levels of BSC-1 mRNA and therefore unlikely to be due to changes in either the rate of BSC-1 gene transcription or the stability of BSC-1 mRNA. This suggests changes in either translational efficiency or BSC-1 protein stability in SHR. 7. We also conclude that the age/hypertension-related increase in BSC-1 protein levels in ISOM is accompanied by an equally marked increased trafficking of BSC-1 to PMs in SHR ISOM.

Aging impairs the protective effect of magnesium supplementation on hypertension in spontaneously hypertensive rats.

Preeclampsia is a hypertensive disorder that is unique to pregnancy. Magnesium (Mg2+) supplementation is a potential new therapy to ameliorate development of hypertension. The aim of this work was to compare the effects of Mg2+ supplementation on systolic blood pressure (SBP) in young and aged rats. Spontaneously hypertensive rats (SHR) were divided into young (6-week-old male, n = 10) and old (16-week-old male, n = 10) groups. Each group of rats comprised two subgroups made of a control subgroup fed with normal rat chow (0.2% Mg2+, n = 5) and a high Mg2+ subgroup nourished with a Mg2+ rich diet (0.8% Mg2+, n = 5). Age-matched Wistar-Kyoto rats (WKY) were also allocated into two groups. SBP was assessed weekly for 12 weeks indirectly by the tail-cuff method. SBP increased progressively in SHR-young rats after 7 weeks. This increase was greater in the control subgroup compared to high Mg2+ subgroup at 7 weeks (p < 0.05). No difference in the SBP was registered between old SHR subgroups. Mg2+ supplementation does not exert antihypertensive effects in the WKY rats. In conclusion, Mg2+ supplementation may provide beneficial effect in the developmental phase of hypertension but not in established hypertension.

Effect of Prepro-Calcitonin Gene-Related Peptide–Expressing Endothelial Progenitor Cells on Pulmonary Hypertension

Calcitonin gene-related peptide (CGRP) is a potent smooth muscle cell proliferation inhibitor and vasodilator. It is now believed that CGRP plays an important role in maintaining a low pulmonary vascular resistance. We evaluated the therapeutic effect of intravenously administered CGRP-expressing endothelial progenitor cells (EPCs) on left-to-right shunt-induced pulmonary hypertension in rats. Endothelial progenitor cells were obtained from cultured human peripheral blood mononuclear cells. The genetic sequence for CGRP was subcloned into cultured EPCs by human expression plasmid. Pulmonary hypertension was established in immunodeficient rats with an abdominal aorta to inferior vena cava shunt operation. The transfected EPCs were injected through the left jugular vein at 10 weeks after the shunt operation. Mean pulmonary artery pressure and total pulmonary vascular resistance were detected with right cardiac catheterization at 4 weeks. The distribution of EPCs in the lung tissue was examined with immunofluorescence technique. Histopathologic changes in the structure of the pulmonary arteries was observed with electron microscopy and subjected to computerized image analysis. The lungs of rats transplanted with CGRP-expressing EPCs demonstrated a decrease in both mean pulmonary artery pressure (17.64 +/- 0.79 versus 22.08 +/- 0.95 mm Hg; p = 0.018) and total pulmonary vascular resistance (1.26 +/- 0.07 versus 2.45 +/- 0.18 mm Hg x min/mL; p = 0.037) at 4 weeks. Immunofluorescence revealed that intravenously administered cells were incorporated into the pulmonary vasculature. Pulmonary vascular remodeling was remarkably attenuated with the administration of CGRP-expressing EPCs. The transplantation of CGRP-expressing EPCs may effectively attenuate established pulmonary hypertension and exert reversal effects on pulmonary vascular remodeling. Our findings suggest that the therapy based on the combination of both CGRP transfection and EPCs may be a potentially useful strategy for the treatment of pulmonary hypertensive disorders.

Exercise as a Physiologic Intervention to Counteract Hypertension

Various treatment strategies have been developed to treat hypertension and affect its clinical outcome. These include early lifestyle modifications such as weight loss, nutritional changes, and exercise as well as pharmacological interventions that are based on diuresis, inhibition of the renin-angiotensin system, calcium channel blockade, central and peripheral sympatolysis, as well as α- and β-receptor blockade.1 In individuals with prehypertension and patients with established hypertension, initial treatment, before the administration of pharmacological therapies, focuses on lifestyle changes targeting nutrition and exercise.1 In particular exercise is an intervention that is widely prescribed and recommended. Multiple clinical trials have shown effects of exercise on blood pressure with an average reduction of −10 mm Hg systolic and −8 mm Hg diastolic.2 Unfortunately, exercise is notoriously difficult to observe, evaluate, and dose in an outpatient population with hypertension.2,3 Exercise is a physiological intervention with a broad variety of positive cardiovascular effects that include changes in lipid metabolism, insulin resistance, weight, arterial hypertension, inflammation, endogenous anabolism, and mood.2 It seems, in fact, reasonable to hypothesize that metabolic abnormalities associated with the primarily sedentary lifestyle in modern Western civilizations are not only counteracted but normalized by physical activity. Therefore, regular exercise would be a physiological correction rather than a medical treatment intervention. Exercise programs distinguish between primarily aerobic dynamic (eg, running and cycling) and resistance (eg, strength training) exercises. Dynamic exercise with alternating muscle contraction and relaxation results in a steady rise of systolic blood pressure when intensity increases, whereas the diastolic pressure varies minimally. In contrast, resistance exercise is characterized by prolonged isometric muscle contraction before relaxation with high interstitial pressure that causes collapse of arterioles and capillaries. Blood pressure increases in relation to intensity and duration of the contraction. Effects of exercise on the myocardium have been well established. …