Sustained Elevation Of Blood Pressure Research Articles

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

Self-administered and yoked nicotine produce robust increases in blood pressure and changes in heart rate with modest effects of behavioral contingency in rats

Experimenter-administered nicotine produces reliable increases in blood pressure and changes in heart rate. However, an extensive literature demonstrates that the effects of psychoactive drugs are dependent on whether administration is contingent on behavior. The present study assessed the cardiovascular effects of nicotine and whether those effects vary as a function of whether nicotine was self-administered or response-independent. Rats were divided into three groups according to a yoked design. The pattern of infusions for each triad was determined by the animal self-administering nicotine; the other two animals received either yoked nicotine or saline. Heart rate and blood pressure were measured during eighteen daily, 1h drug sessions by radiotelemetry. Each session was preceded and followed by a 20minute period during which cardiovascular function was monitored in the operant chambers, but drug was not available. Acute exposure to yoked nicotine produced a rapid rise in blood pressure that was larger than the increase observed with self-administered nicotine. Additional infusions during the first session resulted in a similar sustained elevation in blood pressure in the nicotine groups. Over subsequent sessions, self-administered nicotine produced a larger effect on systolic blood pressure particularly early in each session, although for both self-administered and yoked nicotine the hypertensive effects waned partially with repeated test sessions. This decrease was fully accounted for by a pre-session decrease in pressure; relative to pre-session levels the strong hypertensive effects of nicotine persisted. Initial exposure to nicotine produced a short-lived bradycardia that in subsequent sessions was replaced with a longer-lasting nicotine-induced tachycardia; neither effect was related to the behavioral contingency of nicotine delivery. Together, these data provide a rich picture of the cardiovascular effects of nicotine. Effects of behavioral contingency were observed, but differences were limited. Other non-pharmacological factors such as baseline shifts potentially related to nicotine-associated cues deserve further attention.

Critical Role of Neuropeptides B/W Receptor 1 Signaling in Social Behavior and Fear Memory

Neuropeptide B/W receptor 1 (NPBWR1) is a G-protein coupled receptor, which was initially reported as an orphan receptor, and whose ligands were identified by this and other groups in 2002 and 2003. To examine the physiological roles of NPBWR1, we examined phenotype of Npbwr1 −/− mice. When presented with an intruder mouse, Npbwr1 −/− mice showed impulsive contact with the strange mice, produced more intense approaches toward them, and had longer contact and chasing time along with greater and sustained elevation of heart rate and blood pressure compared to wild type mice. Npbwr1 −/− mice also showed increased autonomic and neuroendocrine responses to physical stress, suggesting that impairment of NPBWR1 leads to stress vulnerability. We also observed that these mice show abnormality in the contextual fear conditioning test. These data suggest that NPBWR1 plays a critical role in limbic system function and stress responses. Histological and electrophysiological studies showed that NPBWR1 acts as an inhibitory regulator on a subpopulation of GABAergic neurons in the lateral division of the CeA and terminates stress responses. These findings suggest important roles of NPBWR1 in regulating amygdala function during physical and social stress.

Management of Hypertension among Patients with Coronary Heart Disease

Evidence suggests that coronary heart disease (CHD) is the most common outcome of hypertension. Hypertension accelerates the development of atherosclerosis, and sustained elevation of blood pressure (BP) can destabilize vascular lesions and precipitate acute coronary events. Hypertension can cause myocardial ischemia in the absence of CHD. These cardiovascular risks attributed to hypertension can be reduced by optimal BP control. Although several antihypertensive agents exist, the choice of agent and the appropriate target BP for patients with CHD remain controversial. In this succinct paper, we examine the evidence and the mechanisms for the linkage between hypertension and CHD and we discuss the treatment options and the goals of therapy that are consistent with the report of the seventh Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and American Heart Association scientific statement. We anticipate changes in the recommendations of the forthcoming JNC 8.

NADPH Oxidase 2 Mediates Intermittent Hypoxia-Induced Mitochondrial Complex I Inhibition: Relevance to Blood Pressure Changes in Rats

Previous studies identified NADPH oxidases (Nox) and mitochondrial electron transport chain at complex I as major cellular sources of reactive oxygen species (ROS) mediating systemic and cellular responses to intermittent hypoxia (IH). In the present study, we investigated potential interactions between Nox and the mitochondrial complex I and assessed the contribution of mitochondrial ROS in IH-evoked elevation in blood pressure. IH treatment led to stimulus-dependent activation of Nox and inhibition of complex I activity in rat pheochromocytoma (PC)12 cells. After re-oxygenation, Nox activity returned to baseline values within 3 h, whereas the complex I activity remained downregulated even after 24 h. IH-induced complex I inhibition was prevented by Nox inhibitors, Nox2 but not Nox 4 siRNA, in cell cultures and was absent in gp91(phox-/Y) (Nox2 knock-out; KO) mice. Using pharmacological inhibitors, we show that ROS generated by Nox activation mobilizes Ca(2+) flux from the cytosol to mitochondria, leading to S-glutathionylation of 75- and 50-kDa proteins of the complex I and inhibition of complex I activity, which results in elevated mitochondrial ROS. Systemic administration of mito-tempol prevented the sustained but not the acute elevations of blood pressure in IH-treated rats, suggesting that mitochondrial-derived ROS contribute to sustained elevation of blood pressure.

Pulmonary hypertension with left-sided heart disease

Pulmonary hypertension (PH) with left-sided heart disease is defined, according to the latest Venice classification, as a Group 2 PH, which includes left-sided ventricular or atrial disease, and left-sided valvular diseases. These conditions are all associated with increased left ventricular filling pressure. Although PH with left-sided heart disease is a common entity, and long-term follow-up trials have provided firm recognition that development of left-sided PH carries a poor outcome, available data on incidence, pathophysiology, and therapy are sparse. Mitral stenosis was reported as the most frequent cause of PH several decades ago, but PH with left-sided heart disease is now usually caused by systemic hypertension and ischemic heart disease. In patients with these conditions, PH develops as a consequence of impaired left ventricular relaxation and distensibility. Chronic sustained elevation of cardiogenic blood pressure in pulmonary capillaries leads to a cascade of untoward retrograde anatomical and functional effects that represent specific targets for therapeutic intervention. The pathophysiological and clinical importance of the hemodynamic consequences of left-sided heart disease, starting with lung capillary injury and leading to right ventricular overload and failure, are discussed in this Review, focusing on PH as an evolving contributor to heart failure that may be amenable to novel interventions.

L-NAME-treatment alters ectonucleotidase activities in kidney membranes of rats

Aims To investigate the effect of Nω-Nitro- l-arginine methyl ester ( l-NAME) treatment, known to induce a sustained elevation of blood pressure, on ectonucleotidase activities in kidney membranes of rats. Main methods l-NAME (30 mg/kg/day) was administered to Wistar rats for 14 days in the drinking water. Enzyme activities were determined colorimetrically and their gene expression patterns were analyzed by semi-quantitative RT-PCR. The metabolism of ATP and the accumulation of adenosine were evaluated by HPLC in kidney membranes from control and hypertensive rats. PKC phosphorylation state was investigated by Western blot. Key findings We observed an increase in systolic blood pressure from 115 ± 12 mmHg (control group) to 152 ± 18 mmHg ( l-NAME-treated group). Furthermore, the hydrolysis of ATP, ADP, AMP, and p-Nph-5′TMP was also increased (17%, 35%, 27%, 20%, respectively) as was the gene expression of NTPDase2, NTPDase3 and NPP3 in kidneys of hypertensive animals. Phospho-PKC was increased in hypertensive rats. Significance The general increase in ATP hydrolysis and in ecto-5′-nucleotidase activity suggests a rise in renal adenosine levels and in renal autoregulatory responses in order to protect the kidney against the threat presented by hypertension.

Eplerenone Suppresses Salt-Induced Vascular Endothelial Growth Factor Expression in the Kidney

Background/Aim: It is well accepted that high dietary salt intake accelerates both hypertension and target organ damage. We have previously shown that eplerenone attenuates sustained elevated systolic blood pressure in Dahl salt-sensitive (SS) rats. In the present study, we investigated the role of eplerenone on vascular endothelial growth factor (VEGF) expression because we suspected that eplerenone treatment may trigger a unique mechanism that relies on the downregulation of VEGF. Methods: Dahl SS rats were fed a high salt (8% NaCl) diet for 3 weeks and then switched to normal salt (0.3% NaCl) diet with or without treatment with eplerenone (100 mg/kg/day), enalapril (30 mg/kg/day) and their combination for an additional 3 weeks. Results: In addition to reducing blood pressure, eplerenone inhibited glomeruli sclerosis and suppressed the expression of VEGF and endothelial nitric oxide synthase mRNA as well as protein levels. Conclusions: Based on these findings, we suggest that in part, VEGF stimulation of endothelial nitric oxide synthase plays a significant role in the eplerenone-induced reversal of the renal and vascular damage caused by high dietary salt intake.

Increased long-term risk of new-onset diabetes mellitus in white-coat and masked hypertension

A sustained blood pressure elevation is associated with an increased risk of new-onset diabetes mellitus. Whether this is the case also in white-coat and masked hypertension is unknown. In 1412 individuals of the Pressioni Arteriose Monitorate E Loro Associazioni study stratified for sex and age decades, we measured office, home and 24-h ambulatory blood pressure together with fasting plasma glucose and other metabolic variables. This allowed to identify patients with white-coat, masked, sustained hypertension and true normotension. Over a 10-year period, the increase in plasma glucose and the incidence of new-onset diabetes (plasma glucose > or =126 mg/dl or use of antidiabetic drugs) was significantly greater in individuals with white-coat and masked hypertension than in those with 'true' normotension (age and sex-adjusted risk 2.9 and 2.7, respectively), the increase being similar to that of sustained hypertensive individuals. The adjusted risk showed a marked increase when development of an impaired fasting glucose condition was also considered, and the results were similar when individuals reporting antihypertensive drug treatment were excluded or white-coat and masked hypertension were identified by office versus home blood pressure. The increased risk of new-onset diabetes become no more significant when data were adjusted for initial blood glucose and BMI, which, at a multivariate analysis, were the most significant predictors of this condition, with only a small although significant contribution of the initial blood pressure. Thus, white-coat and masked hypertension are associated with a long-term greater progression of blood glucose abnormalities and an increased risk of developing diabetes. This is largely accounted for by the metabolic abnormalities that are frequent components of these conditions.

Low-dose ouabain constricts small arteries from ouabain-hypertensive rats: implications for sustained elevation of vascular resistance

Prolonged ouabain administration to normal rats causes sustained blood pressure (BP) elevation. This ouabain-induced hypertension (OH) has been attributed, in part, to the narrowing of third-order resistance arteries (approximately 320 microm internal diameter) as a result of collagen deposition in the artery media. Here we describe the structural and functional properties of fourth-order mesenteric small arteries from control and OH rats, including the effect of low-dose ouabain on myogenic tone in these arteries. Systolic BP in OH rats was 138 +/- 3 versus 124 +/- 4 mmHg in controls (P < 0.01). Pressurized (70 mmHg) control and OH arteries, with only a single layer of myocytes, both had approximately 165-microm internal diameters and approximately 20-microm wall thicknesses. Even after fixation, despite vasoconstriction, the diameters and wall thicknesses did not differ between control and OH fourth-order arteries, whereas in third-order arteries, both parameters were significantly smaller in OH than in controls. Myogenic reactivity was significantly augmented in OH fourth-order arteries. Nevertheless, phenylephrine- (1 microM) and high K(+)-induced vasoconstrictions and acetylcholine-induced vasodilation were comparable in control and OH arteries. Vasoconstrictions induced by 5 microM phenylephrine and by 10 mM caffeine in Ca(2+)-free media indicated that releasable sarcoplasmic reticulum Ca(2+) stores were normal in OH arteries. Importantly, 100 nM ouabain constricted both control and OH arteries by approximately 26 microm, indicating that this response was not downregulated in OH rats. This maximal ouabain-induced constriction corresponds to a approximately 90% increase in resistance to flow in these small arteries; thus ouabain at EC(50) of approximately 0.66 nM should raise resistance by approximately 35%. We conclude that dynamic constriction in response to circulating nanomolar ouabain in small arteries likely makes a major contribution to the increased vascular tone and BP in OH rats.

First-line drugs for hypertension

Sustained elevated blood pressure, unresponsive to lifestyle measures, leads to a critically important clinical question: What class of drug to use first-line? This review answers that question. To quantify the benefits and harms of the major first-line anti-hypertensive drug classes: thiazides, beta-blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, alpha-blockers, and angiotensin II receptor blockers (ARB). Electronic search of MEDLINE (Jan. 1966-June 2008), EMBASE, CINAHL, the Cochrane clinical trial register, using standard search strategy of the hypertension review group with additional terms. Randomized trials of at least one year duration comparing one of 6 major drug classes with a placebo or no treatment. More than 70% of people must have BP >140/90 mmHg at baseline. The outcomes assessed were mortality, stroke, coronary heart disease (CHD), cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. Risk ratio (RR) and a fixed effects model were used to combine outcomes across trials. Of 57 trials identified, 24 trials with 28 arms, including 58,040 patients met the inclusion criteria. Thiazides (19 RCTs) reduced mortality (RR 0.89, 95% CI 0.83, 0.96), stroke (RR 0.63, 95% CI 0.57, 0.71), CHD (RR 0.84, 95% CI 0.75, 0.95) and CVS (RR 0.70, 95% CI 0.66, 0.76). Low-dose thiazides (8 RCTs) reduced CHD (RR 0.72, 95% CI 0.61, 0.84), but high-dose thiazides (11 RCTs) did not (RR 1.01, 95% CI 0.85, 1.20). Beta-blockers (5 RCTs) reduced stroke (RR 0.83, 95% CI 0.72, 0.97) and CVS (RR 0.89, 95% CI 0.81, 0.98) but not CHD (RR 0.90, 95% CI 0.78, 1.03) or mortality (RR 0.96, 95% CI 0.86, 1.07). ACE inhibitors (3 RCTs) reduced mortality (RR 0.83, 95% CI 0.72-0.95), stroke (RR 0.65, 95% CI 0.52-0.82), CHD (RR 0.81, 95% CI 0.70-0.94) and CVS (RR 0.76, 95% CI 0.67-0.85). Calcium-channel blocker (1 RCT) reduced stroke (RR 0.58, 95% CI 0.41, 0.84) and CVS (RR 0.71, 95% CI 0.57, 0.87) but not CHD (RR 0.77 95% CI 0.55, 1.09) or mortality (RR 0.86 95% CI 0.68, 1.09). No RCTs were found for ARBs or alpha-blockers. First-line low-dose thiazides reduce all morbidity and mortality outcomes. First-line ACE inhibitors and calcium channel blockers may be similarly effective but the evidence is less robust. First-line high-dose thiazides and first-line beta-blockers are inferior to first-line low-dose thiazides.

Relationship between Blood Pressure and Nocturia in Hypertensive Patients

Objective: We investigated the relationship between the pattern of hypertension and nocturia.Methods: Seventy‐seven patients who were being treated for hypertension completed a questionnaire regarding the number of times they urinated during the day and at night, and measured their blood pressure at home immediately after rising in the morning and just before going to sleep at night. The patients' blood pressure was also measured at the clinic. The patients were divided into groups according to their blood pressure patterns. The relationship between blood pressure pattern and number of urinations during the day and at night was investigated.Results: When the patients were divided into white coat hypertension, masked hypertension, sustained hypertension, and normotension groups, the number of daytime urinations was significantly lower in the sustained hypertension group compared with the normotension and white coat hypertension groups. When the subjects were divided into morning blood pressure surge and non‐morning surge groups or into morning hypertension and non‐morning hypertension groups, the numbers of nighttime urinations was significantly higher in the morning surge group or the morning hypertension group compared with the non‐morning surge group or non‐morning hypertension group, respectively.Conclusion: Sustained hypertension and elevation of blood pressure in the early morning influence the frequency of daytime and nighttime urination, respectively. It is important to control both the blood pressure and nocturia of hypertensive patients to improve their prognosis.

Defining the Problem of Treating the Patient with Hypertension and Arthritis Pain

As osteoarthritis and hypertension coexist often in patients aged >60 years, the coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs) with hypertension therapies is common practice in clinical medicine. Clinical trials in patients with arthritis have shown that many agents within the NSAID class may induce significant increases in systolic blood pressure, particularly when patients are using renin-angiotensin–blocking agents, β-blockers, or diuretics as antihypertensives. The increases in blood pressure caused by NSAIDs are large enough to be of clinical concern. Sustained blood pressure elevations in the elderly are associated with increases in the risk of both ischemic and hemorrhagic stroke, congestive heart failure, and ischemic cardiac events. Recognition of the development of destabilization of blood pressure control in clinical practice and an awareness of those NSAIDs that place patients at risk for the development of hypertension could lead to reductions in cardiovascular morbidity.

Pedro A. Jose: Searching for genes that cause the increase in blood pressure with large salt (NaCl) intake

From a global perspective, essential hypertension has become a modern-day scourge of pandemic proportions. Essential hypertension—which manifests as an abnormal and sustained elevation of blood pressure—is a major risk factor for death and disability from heart disease, stroke and kidney failure. It represents an enormous economic burden, with the cost of health care and prevention running into billions of dollars annually. Of the estimated billion individuals afflicted worldwide, approximately half are unaware of their condition and, among those with diagnosed hypertension, less than half are properly controlled with drug therapy. Thus, the identification of environmental risk factors and elucidation of the molecular and genetic underpinnings of essential hypertension have been rigorously pursued for decades by many investigators, with Dr. Pedro A. Jose at the forefront, among others.

Modification of atrial natriuretic peptide system in cold-induced hypertensive rats

Cold exposure induces hypertension and cardiac hypertrophy via sympathetic activation. The sympathetic nervous system is fundamentally important for the regulation of cardiac atrial natriuretic peptide (ANP) secretion. The present study aimed to define changes in ANP level with renal functions during cold exposure of rats. We also measured the direct effects of adrenergic stimulation on ANP secretion in cold-induced hypertensive rat atria. Sustained elevation of blood pressure and tachycardia were observed by 2-wk cold exposure. Cold exposure increased urine volume, UNaV, UKV and positive water balance. Atrial ANP content, its mRNA level, and plasma ANP concentration increased. Plasma norepinephrine level was increased but both α 1A- and β 1-adrenoceptor (AR) mRNA levels in atrium were decreased. In isolated perfused atria from cold-exposed rats, basal ANP secretion increased and pulse pressure decreased. Phenylephrine (α 1-AR agonist)-induced stimulation of ANP secretion, and isoproterenol (β-AR agonist)-induced suppression of ANP secretion were significantly attenuated. These results suggest that an increased plasma and atrial ANP level by cold exposure may be a compensatory response to changes in hemodynamics and body fluid balance. The phenylephrine- and isoproterenol-induced attenuation of ANP secretion in cold-exposed rat atria may be due to the downregulation of α 1A- and β 1-adrenoceptors mRNA levels.

Intravenous Intralipid-Induced Blood Pressure Elevation and Endothelial Dysfunction in Obese African-Americans with Type 2 Diabetes

Increased free fatty acids (FFAs) are leading candidates in the pathogenesis of insulin resistance and hypertension in obese subjects. We evaluated the effect of sustained elevations of FFA on blood pressure, endothelial function, insulin secretion, inflammatory markers, and renin-angiotensin system. Twenty-four obese, African-American, normotensive diabetic subjects received a sequential 48-h infusion of Intralipid (20%, 40 ml/h) plus heparin (250 units/h) or normal saline (40 ml/h) plus heparin (250 units/h). Blood pressure was significantly increased within 4 h of lipid infusion and reached a peak increment of 13 mm Hg in systolic and 5 mm Hg in diastolic blood pressure at 24 h (P < 0.01). Compared to baseline, lipid infusion reduced flow-mediated dilatation by 11% at 24 h and 18% at 48 h (P < 0.001). FFA and triglyceride levels increased from a baseline of 0.5 +/- 0.2 mmol/liter and 135 +/- 76 mg/dl to 1.8 +/- 1.0 mmol/liter and 376 +/- 314 mg/dl at 48 h, respectively (P < 0.01). C-Reactive protein increased by 35% at 24 h and by 110% at 48 h of lipid infusion. There were no significant changes in plasma renin and aldosterone levels during lipid or saline infusions. Increased FFA levels result in a rapid and sustained elevation in blood pressure, impaired endothelial function, and increased inflammatory markers in obese subjects with type 2 diabetes. The model of FFA-induced hypertension may be useful in examining disease mechanisms associated with the development of hypertension in obese subjects.

Hypertension in Transgenic Mice With Brain-Selective Overexpression of the 2B-Adrenoceptor

Previous studies have shown that the presynaptic alpha(2B)-adrenoceptor subtype in the central nervous system has a sympathoexcitatory function and its activation leads to a hyperadrenergic hypertensive state. The purpose of this project was to develop a novel hyperadrenergic model, a transgenic (TG) mouse model with brain-selective overexpression of the alpha(2B)-adrenergic receptor (alpha(2B)-AR). We used Southern blot analysis to confirm transgene, real-time PCR to assess gene expression, western Blot analysis and immunohistology to assess protein expression and localization in brain areas. Indirect blood pressure (BP) and heart rate were recorded. In TG mice there was a 1.8-fold increase in alpha(2B)-AR protein expression compared to wild-type (WT) mice. Immunostaining of brain sections revealed that concentration of alpha(2B)-AR was much more pronounced in TG than in WT mice. Systolic BP at 8 weeks of age was significantly elevated in TG 130 +/- 6 mm Hg, compared with WT control nontransgenic littermates of the same age 107 +/- 7 mm Hg, (P < 0.05), indicating that the TG mice had indeed developed hypertension. We have therefore documented that overexpression of the alpha(2B)-AR gene leads to increased production of alpha(2B)-AR protein in brain regions known to regulate central sympathetic outflow, thus resulting in sustained BP elevation. This is a unique model of experimental hypertension driven purely by overexpression of the alpha(2B)-AR that would result in an overactive sympathetic system and would be suitable for testing the pharmacologic properties of potential therapeutic agents.

A role for the thromboxane receptor in l-NAME hypertension

Actions of the lipid mediator thromboxane (Tx) A2 acting through the TP receptor contribute to the pathogenesis of cardiovascular disease. To further explore the role of TxA2 in hypertension, we examined the consequences of deficiency of the TP receptor on the course of hypertension associated with endothelial dysfunction and salt sensitivity. To this end, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was administered to TP-deficient (Tp-/-) and wild-type (Tp+/+) control mice in drinking water for 21 wk along with a high-salt (HS; 6% NaCl) diet. Administration of L-NAME increased urinary excretion of TxB2 to a similar extent in both Tp+/+ and Tp-/- animals. L-NAME also caused significant and sustained elevations in blood pressure that reached a maximum between weeks 3 and 6. However, the severity of hypertension was attenuated in the Tp-/- mice throughout the study period (P<0.001). At the end of the study, the wild-type mice developed significant cardiac hypertrophy (23.6+/-2% increase in heart-to-body weight ratio). The severity of cardiac hypertrophy was attenuated in the TP-deficient group (11.1+/-2.6%; P<0.05). In contrast, kidney hypertrophy was exaggerated in the Tp-/- mice compared with controls (37.1+/-5.4 vs. 12.3+/-2.3%; P<0.01). Moreover, the severity of glomerulosclerosis, tubule vacuolization, and interstitial chronic inflammation was also enhanced in the Tp-/- group (P<0.01). Thus, in L-NAME hypertension, TP receptors contribute to elevated blood pressure and cardiac hypertrophy. In this model, TP receptors also provided unexpected protection against kidney injury.

Does psychosocial stress cause hypertension? A systematic review of observational studies

Acute stress promotes transient elevation of blood pressure, but there is no consistent evidence that this effect results in hypertension. In this systematic review of cohort and case-control studies that investigated the association between psychosocial stress and hypertension, we conducted a complete search up to February 2007 in MEDLINE, EMBASE, PSYCINFO and LILACS, through a search strategy that included eight terms to describe the exposure, six related to the design of the studies and one term for outcome. The quality was assessed by the Newcastle-Ottawa Quality Assessment Scale. The selection was done in duplicate by two teams of independent reviewers. Among 82 studies selected in the second phase, only 14 (10 cohort studies and 4 case-control studies), totalling 52,049 individuals, fulfilled the selection criteria. The average quality of the studies was 6.6+/-1.3 in a 9-point scale. Acute life events were associated with hypertension in one and were not associated in two studies. Five out of seven studies found a significant and positive association between measures of chronic stress and hypertension, with risk ratios ranging from 0.8 to 11.1. Three out of five studies reported high and significant risks of affective response to stress for hypertension, one a significant risk close to a unit and one reported absence of risk. Acute stress is probably not a risk factor for hypertension. Chronic stress and particularly the non-adaptive response to stress are more likely causes of sustained elevation of blood pressure. Studies with better quality are warranted.

Pooled analysis of the safety and tolerability of desvenlafaxine Succinate compared with placebo in the treatment of major depressive disorder

Objective:To characterize the safety and tolerability of desvenlafaxine succinate (DVS) in patients with major depressive disorder (MDD).Methods:Pooled data from 7 double-blind, placebo-controlled studies were analyzed. Adult outpatients with DSM-IV MDD received DVS or placebo for 8 weeks. Four studies employed flexible dosing of DVS (100-200mg/d [1 study]; 200-400mg/d [3 studies]); 3 studies evaluated fixed doses (100/200/400mg/d [1 study]; 200/400mg/d [2 studies]). Vital signs and treatment-emergent adverse events (TEAEs) were evaluated. In the fixed-dose subset of studies, dose-related effects were analyzed.Results:The overall safety population consisted of 2014 patients (DVS: n=1211; placebo: n=803); 60% were women. Adverse events were responsible for discontinuations in 4% of placebo-treated patients and 15% of DVS-treated patients. Discontinuation rates increased with dose (10% with 100mg/d to 17% with 400mg/d) in the subset of fixed-dose studies. TEAEs were consistent with the serotonin-norepinephrine reuptake inhibitor (SNRI) class. Nausea was generally mild to moderate with a median duration less than or = to 6 days; the incidence decreased to placebo-like rates after week 1. With all doses of DVS, small but statistically significant changes in mean blood pressure were observed. Mean changes in pulse rate and the proportion of potentially clinically important increases in sustained elevations in supine diastolic blood pressure were higher for patients receiving 200/400mg/d than among placebo-treated subjects; values for these parameters with the 100mg/d dose did not differ from placebo.Conclusions:DVS treatment exhibited a safety and tolerability profile that was generally consistent with the SNRI class.