Significant Elevation Of Blood Pressure Research Articles

Greater cardiovascular reactivity to a cold stimulus is due to higher cold pain perception in black Africans

To evaluate the role of pain perception and pain stimulus components for blood pressure responses to stress in the black and the white African population with hypertension. Cardiovascular regulation in response to a cold pressor stimulus was studied in hypertensive black (n = 110) and white (n = 95) Africans. Perception of stressfulness of the task was assessed on a seven-point Likert scale. Chronic stress levels were evaluated by the General Health Questionnaire and the Coping Strategy Indicator was used to assess individual coping behavior. Autonomic and baroreflex function was evaluated by spectral analysis. The cold pressor test elicited significant blood pressure elevations with higher relative increases in the black Africans. The higher blood pressure reactivity in black Africans was accompanied by a substantially greater cardiac response and lower parasympathetic outflow as compared with white Africans. Black Africans also reported higher chronic stress levels and rated the stimulus as more painful than their white counterparts. A significant interaction was observed for cardiovascular responses with pain perception but not with chronic stress. Individuals with high pain perception exhibited less dampening of autonomic cardiac exertion than those with low or moderate pain perception. Black Africans display a more pronounced cold pressor test-induced rise in heart rate and blood pressure, which may be explained by greater pain-related increments in blood pressure. A higher cognitive appraisal of pain and a blunted baroreflex-mediated dampening of autonomic structures may contribute to the exaggerated blood pressure reactivity in black Africans.

Cyclosporine-Romiplostim-IVIG Combination Therapy in Refractory ITP

AbstractAbstract 1095 Introduction:Refractory ITP can be very difficult to treat and may not respond to a single agent. Even the thrombopoeitic agents (TPO-A) and IVIG, which have response rates of 60–90%, are at the lower end of this range in the worst cases. Therefore combination therapy may be required. Previous studies using small numbers of patients have suggested CHOP (Figueroa,NEJM,1993); danazol and azathioprine[aza](Boruchov, Blood, 2007);3 low dose immunosuppressives (cyclosporine[CSA]-mycophenalate[MMF]-aza)(Arnold, Blood, 2010); and alemtuzumab-rituximab (Gómez-Almaguer, Blood, 2010). The latter 2 combinations tend to have overlapping mechanisms of effect; none of the 4 have been widely validated. Methods:Patients with very difficult ITP were selected for combination treatment utilizing 3 different mechanisms: CSA, a T cell modulating agent; weekly injections of romiplostim [Nplate], a TPO-A; and as-needed IVIG. CSA was administered at sub-transplant doses aiming for 100–200 ng/ml to minimize toxicity. This retrospective study sought to analyze the treatment effect of the addition of CSA to IVIG and TPO-A in patients unresponsive to the latter agents. Patients were responders if they had higher platelet counts, required less frequent IVIG infusions, and/or used a lower dose or frequency of romiplostim while taking CSA. Results:Nine patients with chronic ITP were treated with this CSA, romiplostim, and IVIG combination including 6 females and 7 patients who had undergone splenectomy. The average patient age was 41 yrs. Patients had received an average of 7.667 prior treatments for ITP and 8/9 patients were non-responders to TPO-A. Seven of 9 patients (4 females, 3 males) were responders. Two responding patients tapered to lower romiplostim doses, and 1 more completely discontinued romiplostim. Four required no IVIG after starting CSA and 1 patient required a single IVIG treatment 3 weeks into CSA treatment; the other 2 responding patients reduced their frequency and/or dose of IVIG therapy. All 7 responders achieved a platelet count ≥ 50 x103/uL and 6/7 ≥ 100 x103/uL. These 6 had > 50% of platelet counts ≥ 50 x103/uL. Four of 7 had > 50% of their counts ≥ 100 x103/uL. The 2 non-responders were both female and splenectomized. They continued to need rescue IVIG at similar intervals to those before CSA treatment; CSA was discontinued after 3–4 months.Of the 9 patients on the study, 6 experienced headaches (4 responders) and 4 patients experienced abdominal discomfort. One responder discontinued CSA therapy after 12 weeks due to toxicity, which included headaches, increased irritability and worsening of preexisting molluscum contagiosum. There was not a clinically significant elevation of blood pressure in any responder; however, 1 non-responder with pre- existing treated hypertension had a clinically significant increase in blood pressure, which resolved upon discontinuation of the medication. None of the patients developed renal dysfunction or de novo infection while on combination therapy. Conclusions:These results suggest that cyclosporine can be used as part of an effective combination with romiplostim and IVIG to manage patients with difficult ITP. The 3 agents were chosen to target different mechanisms of disease pathobiology: FcR “blockade” (IVIG), stimulation of platelet production (TPO-A) and inhibition of T cell activation (CSA). The efficacy of added CSA suggests that activated T cells contribute to refractoriness in difficult ITP. Future research would aim to identify patients in whom activated T cells play an important role and which T-cell agent, eg CSA, MMF or sirolimus, might be indicated in which patients.Table 1Responder DataSexAge (yrs)Number of Prior ITP TreatmentsSplenectomy (yes/no)Headache (yes/no)Abdominal Issues: Pain, Discomfort, Diarrhea (yes/no)Peripheral Neuropathy (yes/no)Significant Change In Blood Pressure (yes/no)IVIG while on CSA:1=none needed, 2=required 1 dose, 3= decreased frequencyDecrease in romiplostim dose on CSABaseline Plt Count (×103/uL)Peak Plt Count on CSA (×103/uL)Patient 1F317YNYNx1No20107Patient 2M36NNNNN1Yes14373Patient 3M348YYNYN2Yes5730Patient 4 (discontinued CSA due to toxicity)M67NYYYN1No1671Patient 5F777YNNNx3No34113Patient 6F667YYYNN3No16714Patient 7F248YYYNN1Able to stop911.5 million”x” = insufficient data available. [Display omitted] Disclosures:Bussel:Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.

The influence of sodium- and calcium-regulatory hormone interventions on adipocytokines in obesity and diabetes

ObjectiveThe renin–angiotensin–aldosterone system (RAAS), vitamin D, and parathyroid hormone have all been implicated as regulators of adipocytokines and inflammation. We evaluated human interventional study protocols to investigate whether controlled modulations of these calcium- and sodium-regulatory hormones could influence adipocytokines and inflammation in obesity and diabetes. MethodsPost-hoc analyses of two separate human protocols (Protocol 1, n=14; Protocol 2, n=24) conducted in a clinical research setting after rigorous control of diet, posture, medications, and diurnal rhythm, were performed. Protocol 1 evaluated obese hypertensives with vitamin D deficiency who received an infusion of angiotensin II (AngII) before and after 1month of vitamin D3 therapy. Protocol 2 evaluated obese subjects with type 2 diabetes who also received AngII. Adipocytokines and inflammatory markers were measured before and after vitamin D3 therapy, and also before and after infusions of AngII. ResultsVitamin D3 therapy significantly raised 25(OH)D and 1,25(OH)2D concentrations, and lowered parathyroid hormone, but had no effect on concentrations of adiponectin, resistin, leptin, IL-6, PAI-1, urinary TGFβ1, or HOMA-IR. AngII infusions, despite significant elevations in blood pressure and serum aldosterone, did not influence adipocytokine concentrations in either protocol. ConclusionIn contrast to prior studies conducted in healthy populations, or those that could not control major regulators of the RAAS or adipocytokines, we observed that robust modulations in calcium- and sodium-regulatory hormones did not influence adipocytokines or inflammation in obesity or diabetes. Adipose-tissue physiology in these conditions may alter the hormonal regulation of inflammatory parameters.

Beneficial effect of genistein on lowering blood pressure and kidney toxicity in fructose-fed hypertensive rats

The study evaluates the effects of genistein on blood pressure (BP) and ultrastructural changes in kidney of fructose-fed hypertensive rats. Male Wistar rats were fed a diet containing 60 % starch or 60 % fructose as the source of carbohydrate. After 15 d, rats in each dietary group were divided into two groups and were treated with either genistein (1 mg/kg per d) in dimethylsulfoxide (DMSO) or 30 % DMSO alone. BP, pressor mechanisms, protein kinase C-βII (PKC-βII) expression, endothelial NO synthase (eNOS) expression and renal ultrastructural changes were evaluated after 60 d. Fructose-fed rats displayed significant elevation in BP and heart rate. Significant increase in plasma angiotensin-converting enzyme (ACE) activity, alterations in renal lipid profile, nitrite and kallikrein activity, enhanced expression of membrane-associated PKC-βII and decreased expression of eNOS were observed in them. Histology and electron microscopic studies showed structural changes in the kidney. Genistein administration lowered BP, restored ACE, PKC-βII and eNOS expression and preserved renal ultrastructural integrity. These findings demonstrate that genistein has effects on eNOS activity in renal cells, leading to eNOS activation and NO synthesis. These effects could have been mediated by activation of PKC-βII. The observed benefits of genistein make it a promising candidate for therapy of diabetic kidney disease.

Contribution of Social Isolation, Restraint, and Hindlimb Unloading to Changes in Hemodynamic Parameters and Motion Activity in Rats

The most accepted animal model for simulation of the physiological and morphological consequences of microgravity on the cardiovascular system is one of head-down hindlimb unloading. Experimental conditions surrounding this model include not only head-down tilting of rats, but also social and restraint stresses that have their own influences on cardiovascular system function. Here, we studied levels of spontaneous locomotor activity, blood pressure, and heart rate during 14 days under the following experimental conditions: cage control, social isolation in standard rat housing, social isolation in special cages for hindlimb unloading, horizontal attachment (restraint), and head-down hindlimb unloading. General activity and hemodynamic parameters were continuously monitored in conscious rats by telemetry. Heart rate and blood pressure were both evaluated during treadmill running to reveal cardiovascular deconditioning development as a result of unloading. The main findings of our work are that: social isolation and restraint induced persistent physical inactivity, while unloading in rats resulted in initial inactivity followed by normalization and increased locomotion after one week. Moreover, 14 days of hindlimb unloading showed significant elevation of blood pressure and slight elevation of heart rate. Hemodynamic changes in isolated and restrained rats largely reproduced the trends observed during unloading. Finally, we detected no augmentation of tachycardia during moderate exercise in rats after 14 days of unloading. Thus, we concluded that both social isolation and restraint, as an integral part of the model conditions, contribute essentially to cardiovascular reactions during head-down hindlimb unloading, compared to the little changes in the hydrostatic gradient.

OS061. Placental growth factor reduces blood pressure and proteinuria in experimental preeclampsia

Preeclampsia is a disorder related to an imbalance in the angiogenesis axis manifesting as endothelial dysfunction. Animal and human studies have shown that sFLT-1 (soluble fms like tyrosine kinase 1) is increased and PlGF (placental growth factor) reduced during the disease state. There are a paucity of studies investigating the clinical significance of normalising angiogenic axis. To use a non-human primate uteroplacental ischemic (UPI) model of preeclampsia to assess if reversing the angiogenic imbalance, by increasing circulating PlGF, is able to ameliorate the hypertension and proteinuria. Hypertensive proteinuria was induced in a non-human primate (Papio hamadryas) by ligation of a unilateral uterine artery at 130days of an 182day pregnancy. After two weeks of UPI, PlGF was administered by subcutaneous injection (100mg/kg/day) for 5 days (n=3) or normal saline in an equivalent volume (n=3). Blood pressure was monitored via intra-arterial radiotelemetry, sFLT-1 measured via ELISA and spot urinary protein:creatinine ratios were measured to monitor proteinuria. Data was analysed using SPSS by t-tests and analysis of repeated measures. Significance was set at p<0.05 and data expressed as the mean ±SEM. After two weeks of UPI both groups demonstrated a significant elevation in blood pressure, proteinuria (p<0.05) and sFLT-1 (p<0.001). The systolic BP increased by 12.4±2.3mmHg and 11.7±2.9mmHg in the PlGF and control groups respectively compared to baseline (p<0.005). After PlGF administration, there was a significant reduction in blood pressure in the treated group (-5.2s±0.8mmHg) compared to the increase in BP in the control group (+6.5±3mmHg). Proteinuria also reduced in the treated group from 112±51mg/mmol to 38±12mg/mmol whilst proteinuria in the control group was unchanged. The total circulating sFLT-1 was not significantly affected by the administration of PlGF after 5days. Although this study was not designed to assess fetal safety or outcomes, there was no adverse fetal outcome attributable to the administration of the PlGF. Administration of PlGF resulted in a reduction in BP and proteinuria without significantly affecting total sFLT-1 levels. Correcting the angiogenic axis imbalance may improve the clinical parameters in a non-human primate animal model of preeclampsia.

Abstract P332: Effects of Intravenous Infusion of Polyunsaturated Fatty Acids and Dextrose on Blood Pressure and Endothelial Function in Obese Subjects

Hyperglycemia and elevated free fatty acids (FFAs) are implicated in the development of hypertension and endothelial dysfunction. We recently reported that 8-hour infusion of soy-bean oil containing polyunsaturated fatty acids (Intralipid) results in the elevation of blood pressure (BP) and endothelial dysfunction in obese healthy subjects. However, the effects of dextrose infusion or combination of dextrose and Intralipid on BP, endothelial function and insulin action are not known. Accordingly, we compared the effects of 8-hour infusion of normal saline at 40 ml/hr, Intralipid 20% at 40 mL/hr, dextrose 10% at 40 ml/hr and combination of Intralipid and dextrose on BP, endothelial function in 12 obese healthy subjects [ages:41±7 yrs, BMI:32±2 kg/m 2 , BP:113/65 mmHg, HOMA-IR: 2.0±1.0]. Blood pressure, brachial artery flow-mediated dilatation (FMD), and levels of FFAs, glucose, and insulin were measured at 0, 4 and 8 h of infusion. Intralipid infusion significantly increased BP, decreased FMD, and increased plasma FFAs (Table). Unlike Intralipid alone, the combination of Intralipid and dextrose did not increase BP but resulted in FMD changes similar to Intralipid alone. Levels of plasma glucose and insulin increased over time after dextrose infusion alone or in combination with Intralipid but not with lipid infusion alone. Compared with Intralipid, the addition of dextrose to Intralipid led to restoration of FFAs to normal level. In summary, Intralipid but not dextrose infusion alone or in combination with Intralipid results in significant elevation in blood pressure in obese healthy subjects. In contrast, dextrose administration had no effect on Intralipid-induced endothelial dysfunction. The mechanisms underlying differences in vascular response after addition of dextrose to Intralipid are not known, but these results indicate that dextrose-induced mild hyperinsulinemia may regulate adverse hemodynamic effects of fat administration in obese subjects.

Sex differences in social stress-induced pressor and behavioral responses in normotensive and hypertensive rats

This study investigated sex differences in chronic social stress-induced pressor and behavioral responses in normotensive and prehypertensive rats. Adult Wistar and borderline hypertensive (BH) rats (offspring of Wistar dams and spontaneously hypertensive sires) of both sexes were exposed to crowding stress (200 cm²/rat, 5 rats/cage) for 6 weeks. Controls were kept 4 rats/cage (480 cm²/rat). Blood pressure (BP) and open field activity were determined before experiment and after 1, 3 and 6 weeks of stress. Basal BP of BH rats was higher than in Wistar (p < 0.001) in both males and females. Horizontal and vertical activity of BH males and females was elevated vs. Wistar (p < 0.01) and females in both phenotypes were more active than the respective males (p < 0.01). Crowding resulted in delayed between-session habituation and significant elevation of BP only in BH males (143 ± 2 vs. 134 ± 3 mmHg in controls after 6-week crowding). No changes of BP were observed in crowded females of both phenotypes regardless of their delayed between-session habituation. Thus chronic social stress produced by crowding seems to represent a significant risk factor for development of stress-related hypertension only in males with genetic predisposition to high blood pressure while females of both phenotypes responded to stress by impaired between-session habituation.

Comparison of angiotensin II type 1-receptor blockers to regress pressure overload-induced cardiac hypertrophy in mice

Angiotensin II (AngII) type 1-receptor blockers (ARBs) have been effectively used not only in the treatment of hypertension but also in cardiac protection. However, whether and why there are differences in these effects still remain unclear. Here we compared the effects of five commonly used ARBs (Candesartan, Olmesartan, Losartan, Telmisartan and Valsartan) on pressure overload-induced cardiac hypertrophy in mice model. Pressure overload was produced by constriction of the transverse aorta (TAC) for 2 weeks, which induced a significant elevation of blood pressure; ARBs or saline was administered through a stomach tube; Cardiac hypertrophy was evaluated by transthoracic echocardiography, cardiac histology and specific gene expression analyses. Although all the five ARBs, which did not repress the elevation of left ventricular pressure after TAC, attenuated the development of cardiac hypertrophy in the wild-type mice, the degrees of regression by Candesartan, Olmesartan and Losartan tended to be larger than those by Telmisartan and Valsartan. Furthermore, in angiotensinogen-knockout mice lacking endogenous AngII, TAC-induced cardiac hypertrophy was regressed by Candesartan, Olmesartan and Losartan but not by Telmisartan and Valsartan administration. Our data suggest that Candesartan, Olmesartan and Losartan can effectively inhibit pressure overload-induced cardiac hypertrophy even in the absence of AngII, whereas Telmisartan and Valsartan could exert the inhibitory effects only in the presence of AngII.

Hypertension as a biological marker of systemic atherosclerotic disease

There is a close link between hypertension and atherosderosis. Hypertension causes atherosclerotic damage of several organs, called target organs and the risk factors for hypertension and atherosderosis are very similar. The risk of mortality associated to hypertension increases with blood pressure values below the cutoff point of normality (140/90 mm Hg), even below 130/85 mm Hg, and includes a stage called pre hypertension. Moreover, the initial damage of the arterial walls and target organs are present before there is a significant elevation of blood pressure. Therefore, hypertension could become a biological marker of the evolution of an underlying atherosclerotic process. A new pathophysiological paradigm has been proposed in which the severity of hypertension is not classified according to blood pressure values, but rather on the initiation and progression of vascular damage among target organs. These alterations determine the prognosis and management of systemic vascular damage that can be called "hypertensive atherosclerotic disease" or simply systemic atherosclerotic disease.

Vasomotor hot flushes and 24-hour ambulatory blood pressure in recently post-menopausal women

Background. Menopausal hot flushes may be a marker for a difference in vascular function. We studied the associations between hot flushes of varying severity and ambulatory blood pressure (BP) and heart rate (HR).Methods. A total of 147 women with onset of menopause within the preceding 6–36 months reported no hot flushes (n = 23) or mild (n = 33), moderate (n = 30), or severe (n = 61). Ambulatory BP and HR were registered for 24 hours. The variables, analyzed separately for day-time and night-time, were compared among the four study groups.Results. Hot flushes failed to show any relationship to mean day- or night-time BP, nocturnal dipping of BP, or HR. However, severe night-time hot flushes were accompanied by elevations in systolic BP (4.1 ± 10.5 mmHg, P = 0.061), diastolic BP (3.1 ± 6.8 mmHg, P = 0.032), and heart rate (3.0 ± 7.2 beats/minute, P = 0.043).Conclusion. Hot flushes are not associated with ambulatory BP or heart rate in normotensive, recently post-menopausal women, although severe night-time hot flush episodes are followed by significant elevations in BP and heart rate. The latter may be of clinical significance.

Angiotensin II enhances GABAB receptor-mediated responses and expression in nucleus tractus solitarii of rats

Angiotensin II (ANG II) increases GABA(B) receptor expression in neuronal cultures from the nucleus tractus solitarii (NTS). In the present study, the chronic effects of ANG II on GABA(B) receptor expression and activity were examined in the NTS of Sprague-Dawley rats. Intracerebroventricular infusion of ANG II caused a significant elevation in blood pressure (BP) and an increase in GABA(B) receptor expression in the NTS. Conversely, chronic N(G)-nitro-l-arginine methyl ester (l-NAME) treatment also increased BP, but had no effect on GABA(B) receptor expression in the NTS. Next, we examined the BP response to the GABA(B) receptor agonist baclofen microinjected into the NTS of ANG II- or artificial cerebrospinal fluid (aCSF)-infused rats. NTS microinjection of baclofen increased BP in both groups of rats. However, the pressor response to baclofen was enhanced in ANG II-infused rats compared with aCSF-infused rats. In addition, bilateral microinjection of the GABA(B) receptor antagonist CGP-35348 into the NTS evoked a decrease in BP in both group of rats, and the depressor responses to CGP-35348 were enhanced in the ANG II-infused rats. In contrast, the pressor responses to the GABA(A) receptor agonist muscimol and the depressor responses to the GABA(A) receptor antagonist bicuculline were comparable between aCSF- and ANG II-infused rats. These results indicate that chronic ANG II infusion stimulates GABA(B) receptor expression and augments GABA(B) receptor-mediated responses in the NTS. This effect could contribute to the central nervous system actions of ANG II that result in dampening of baroreflexes and elevation in arterial BP.

Desvenlafaxine in major depressive disorder: an evidence-based review of its place in therapy.

Desvenlafaxine, the active metabolite of venlafaxine, is a serotonin norepinephrine reuptake inhibitor (SNRI) recently approved for the treatment of major depressive disorder. It is one of only three medications in this class available in the United States. The objective of this article is to review the published evidence for the safety and efficacy of desvenlafaxine, and to compare it to other antidepressants to delineate its role in the treatment of depression. At the recommended dose of 50 mg per day the rate of response and remission was similar to other SNRIs, as was the adverse effect profile. The rate of discontinuation was no greater than placebo, and a discontinuation syndrome was not observed at this dose. Higher doses were not associated with greater efficacy, but they did lead to more side effects, and the use of a taper prior to discontinuation. The most common side effects reported were insomnia, somnolence, dizziness, and nausea. Some subjects experienced clinically significant blood pressure elevation. Like duloxetine, desvenlafaxine inhibits the reuptake of both norepinephrine and serotonin at the starting dose. Dual reuptake inhibitors have been shown to have small but statistically significantly greater rates of response and remission compared to selective serotonin reuptake inhibitors, and they have also shown early promise in the treatment of neuropathic pain. Desvenlafaxine may prove to be a valuable treatment option by expanding the limited number of available dual reuptake inhibitors.

Predictors of Progression From Prehypertension to Hypertension in Japanese Men

This 3-year prospective study in middle-aged Japanese men with prehypertension examined the usefulness of the plasma levels of C-reactive protein (CRP) and the brachial-ankle pulse wave velocity (baPWV) as predictors of the development to hypertension as compared with other previously proposed markers, such as the age, initial blood pressure, heart rate, obesity, smoking, and alcohol intake. Among 777 men with prehypertension (42 +/- 8 years old), hypertension developed in 58 men during the observation period. Significant elevation of blood pressure during this 3-year follow-up was not observed in some, but not all, subjects. Univariate linear regression analysis demonstrated that baPWV, body mass index (BMI), age, and alcohol intake, but not plasma levels of CRP, heart rate, and smoking, on the first examination were significant variables related to the changes in systolic blood pressure from the first examination to the second examination. Multivariate linear regression analysis confirmed that baPWV and BMI were weak but significant independent variables related to the changes in systolic blood pressure (R(2) = 0.03). The logistic regression analysis demonstrated that baPWV >13.5 m/s (adjusted odds ratio = 3.32 (1.79-6.15)) and BMI >25.0 (adjusted odds ratio = 2.27 (1.25 - 4.13)) were significant predictors of future hypertension independent of blood pressure on the first examination. This 3-year prospective study suggested that the baPWV and BMI, but not plasma CRP levels, are not powerful but significant independent markers to identify middle-aged Japanese men with prehypertension at high risk for hypertension.

Oral contraceptive administration aggravates nitric oxide synthesis inhibition-induced high blood pressure in female rats

The use of estrogen–progestogen oral contraceptive (OC) is associated with high blood pressure, although mechanisms responsible are still unclear. This study sought to investigate the effects of administration of OC on high blood pressure resulting from nitric oxide (NO) synthesis inhibition in female Sprague– Dawley rats. Rats were given ethinyl estradiol in combination with norgestrel and were treated with NO synthase inhibitor, N G-nitro- l-arginine methyl ester ( l-NAME) in the drinking water or drinking water alone for 6 weeks. OC treatment alone led to a significant increase in blood pressure and positive water balance. Treatment with l-NAME alone resulted in a significant elevation of blood pressure without significant positive water balance. Concomitant treatment with OC and l-NAME produced significant increases in blood pressure and water balance. These magnitudes of increases were significantly greater than those observed in rats treated with OC or l-NAME alone. Treatment with OC did not affect NO biosynthesis with or without concurrent l-NAME treatment. Treatment with OC and/or l-NAME did not significantly affect body weight, food intake, heart rate, cardiac weight/body weight ratio, plasma sodium, glomerular filtration rate and urinary sodium output. Conclusion: These data demonstrate that OC administration resulted in a modest increased blood pressure via enhanced water retention that was not associated with impaired NO synthesis. On the other hand, these results showed that increased blood pressure induced by inhibition of NO synthesis was not associated with water retention. The study also indicated that OC administration aggravated increase in blood pressure during NO synthesis inhibition, via enhanced water retention.

Metabolic Syndrome: Comparison of the Two Commonly Used Animal Models

The etiology of the metabolic syndrome (MS) includes both genetic and environmental factors. The two most commonly studied animal models of the MS are the high-sucrose diet given to spontaneously hypertensive rats (SHRs) and high-fructose diet given to Sprague Dawley rats (SDRs). This study compares between these two models. The two rat strains were examined; within each group, the rats were assigned to either the high-sugar diet (SDRs with fructose-enriched diet and SHRs with sucrose-enriched diet) or standard rat chow (control group). The rats were followed for 7 weeks. The main MS components (obesity, hypertension, impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia) were measured. At baseline systolic blood pressure (SBP), fasting blood levels of triglycerides and insulin, as well as glucose intolerance, were significantly higher among the SHRs compared to SDRs. Following fructose enrichment, SDRs became hyperinsulinemic, hypertriglyceridemic, hypercholesterolemic, hypertensive, and insulin resistant, whereas SHRs responded to sucrose supplementation by a significant elevation in blood pressure and mild worsening of insulin resistance. Endpoint results revealed superiority of sucrose--SHR model in terms of hypertension and superiority of fructose--SDR model in terms of hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia. Both models showed similar postintervention degree of glucose tolerance. The fructose-fed SDR model represents a predominantly environmentally acquired MS, whereas the SHR model is less affected by dietary intervention and better displays the predominantly genetic spontaneous appearance of the syndrome. This fundamental difference should be taken into consideration when choosing an animal model to study the MS.

Vascular inflammation in absence of blood pressure elevation in transgenic murine model overexpressing endothelin-1 in endothelial cells

We previously showed that in transgenic mice with endothelium-targeted overexpression of human preproendothelin-1, mesenteric resistance arteries exhibited vascular remodeling, endothelial dysfunction and increased oxidative stress early in life in the absence of significant elevation of blood pressure. To further characterize this model, the role of vascular inflammation was investigated in young male transgenic and wild-type littermate mice. Systemic and local inflammatory markers in mesenteric arteries were assessed by Luminex-based enzyme-linked immunosorbent assay technique, confocal microscopy, electrophoretic mobility shift assay and western blotting in 10-week old male transgenic and wild-type mice. Although no differences were found for systemic inflammatory markers, vascular staining for monocyte chemoattractant protein-1 and macrophage infiltration were significantly increased (P < 0.05) in transgenic mice compared with wild-type littermates. Transgenic mice exhibited significant increase (P < 0.01) in the activation of transcription factors activator protein-1 and nuclear factor kappa B compared with wild-type littermates. Western blotting analysis showed significantly increased (P < 0.05) blood vessel wall expression of vascular cell adhesion molecule-1 in transgenic mice. These findings suggest that in this murine model of endothelial cell-restricted preproendothelin-1 overexpression, endothelin-1 induces vascular inflammation by multiple pathways in young animals in the absence of blood pressure elevation or systemic inflammation.

Proteomic Analysis Permits the Identification of New Biomarkers of Arterial Wall Remodeling in Hypertension

Hypertension represents one of the main risk factors for vascular diseases. Genetic susceptibility may influence the rate of its development and the associated vascular remodeling. To explore markers of hypertension-related morbidity, we have used surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry to study changes in proteins released by the aorta of two rat strains with different susceptibilities to hypertension. Fischer and Brown Norway (BN) rats were divided into a control group and a group receiving low-dose N(Omega)-nitro-L-arginine methyl ester (L-NAME), a hypertensive drug, interfering with endothelial function. In spite of a significant elevation of blood pressure in both strains in response to L-NAME, BN rats exhibited a lower vascular remodeling in response to hypertension. Proteomic analysis of secreted aortic proteins by SELDI-TOF MS allowed detection of four mass-to-charge ratio (m/z) peaks whose corresponding proteins were identified as ubiquitin, smooth muscle (SM) 22alpha, thymosin beta4, and C-terminal fragment of filamin A, differentially secreted in Fischer rats in response to L-NAME. We have confirmed a strain-dependent difference in susceptibility to L-NAME-induced hypertension between BN and Fischer rats. The greater susceptibility of Fischer rats is associated with aortic wall hypertrophic remodeling, reflected by increased aortic secretion of four identified biomarkers. Similar variations in one of them, SM22alpha, also were observed in plasma, suggesting that this marker could be used to assess vascular damage induced by hypertension.

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) is a neurological disorder characterized by signs of posterior cerebral edema upon radiographic examination. RPLS has been strongly associated with abrupt and significant elevations in blood pressure or the administration of immunosuppressive drugs. Here, we report a case of RPLS occurring in a 30-year-old-mother with a presumed amniotic fluid embolism subsequent to delivery by cesarean section. On the fifth day after the initial successful resuscitation from the cardiorespiratory collapse, she manifested generalized seizure activity and abnormal radiological findings, which were found to be consistent with RPLS. Through our experience, we have suggested that RPLS might occur more easily at lower blood pressures than has been previously recognized. It is important to consider the lower limit at which blood pressure is controlled, especially if accompanied with fever.

Blood pressure reactions to insulin treatment in patients with type 2 diabetes.

The initiation of insulin therapy may be easy and uncomplicated in some patients with type 2 diabetes, but in others, mainly in obese patients, problems often arise (ie, poor compliance, worsening B-cell function and/or insulin resistance). As a substudy of a broader investigation concerning hemorheological effects of insulin treatment in insufficiently controlled type 2 diabetes, blood pressure was recorded in 12 patients at baseline, after two months and after four months on insulin. After two months on insulin, analyses of triglycerides, high-density lipoprotein cholesterol and total cholesterol indicated metabolic improvement (P<0.05 to 0.001) and a surprisingly uniform increase of blood pressure values (P<0.05 to 0.01) was found. At the same time, the serum sodium concentration increased (P<0.01) and was positively correlated to both systolic and diastolic blood pressure (P<0.01). After four months on insulin, blood pressure returned to pretreatment values or lower (P<0.05 to 0.01). Serum sodium also decreased to pretreatment values. No significant changes of the flow behaviour of blood were seen after the initiation of insulin. The number of patients was small and the study was not primarily designed to examine blood pressure. The preliminary conclusion from the present study, however, is that the initiation of insulin treatment in poorly controlled type 2 diabetes causes a temporary and possibly clinically significant elevation of blood pressure. A change in renal treatment of sodium caused by insulin may be one of several possible explanations of the results, but further studies are warranted to confirm the findings.