Copeptin and mid-regional pro-atrial natriuretic peptide in women with suspected or confirmed pre-eclampsia: comparison with sFlt-1/PlGF ratio.

OBJECTIVES: Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) may contribute to the pathogenesis of pre-eclampsia (PE), but their role remains to be elucidated. Our aims were to evaluate the surrogates of AVP and ANP, C-terminal pro-AVP (copeptin) and mid-regional pro-ANP (MR-proANP), as biomarkers for the prediction of PE-related pregnancy complications and whether they are associated with angiogenic markers and/or clinical manifestations of PE. METHODS: This was a retrospective analysis of a prospective cohort study that enrolled pregnant women with suspected or confirmed PE, between December 2013 and April 2016. From each patient, a blood sample was obtained at study entry and serum levels of copeptin, MR-proANP, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured. We evaluated the ability of sFlt-1, PlGF, sFlt-1/PlGF ratio, copeptin and MR-proANP, assessed either alone or combined with traditional predictors (gestational age, parity, diastolic blood pressure and proteinuria), to predict maternal complications and fetal/neonatal complications. Models were compared using concordance statistic (C-index). RESULTS: A total of 526 women were evaluated in the study. Women with confirmed PE displayed elevated serum copeptin and MR-proANP levels in comparison to those with suspected PE but no hypertensive disease of pregnancy. When combined with traditional predictors, the sFlt-1/PlGF ratio displayed a higher C-index than copeptin and MR-proANP (0.76, 0.63 and 0.67, respectively, vs 0.60 for the traditional predictors alone) for the prediction of maternal complications. Similarly, for the prediction of fetal/neonatal complications, the sFlt-1/PlGF ratio displayed a higher C-index than copeptin and MR-proANP when added to the traditional model (0.83, 0.79 and 0.80, respectively, vs 0.79 for the traditional predictors alone). When subdividing women according to sFlt-1/PlGF ratio (≥ 85 vs < 85), no differences in copeptin levels were observed, while MR-proANP level was elevated in women with sFlt-1/PlGF ratio ≥ 85. Multiple regression analysis revealed that copeptin and MR-proANP were independent determinants of proteinuria. CONCLUSIONS: Copeptin and MR-proANP have limited value in predicting PE-related complications when compared with the sFlt-1/PlGF ratio. However, both copeptin and MR-proANP were associated with proteinuria, with copeptin exerting this effect independently of the sFlt-1/PlGF ratio. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Soluble fms-like tyrosine kinase-1 and placental growth factor kinetics during and after pregnancy in women with suspected or confirmed pre-eclampsia.

OBJECTIVES: To assess the evolution of the soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio in women with suspected or confirmed pre-eclampsia (PE), and to investigate the changes in sFlt-1 and PlGF levels in pre-eclamptic women after delivery. METHODS: This was an exploratory study in which secondary analysis was performed on a prospective cohort study that enrolled women with a singleton pregnancy and suspected or confirmed PE from 18 weeks' gestation, carried out between December 2013 and April 2016 at the Department of Obstetrics of the Erasmus Medical Center in Rotterdam. sFlt-1 and PlGF were determined using Roche Diagnostics Elecsys assays in two groups of patients. In the first group, patients with suspected or confirmed PE had sFlt-1 and PlGF levels measured at least twice during their pregnancy. Changes in these biomarkers over the course of pregnancy were compared for patients in this group with a baseline sFlt-1/PlGF ratio of ≤ 38 and for those with a ratio > 38. In the second group, sFlt-1 and PlGF levels of women with PE or HELLP syndrome were measured before and after delivery. For this group, pre- and postpartum sFlt-1 and PlGF levels were compared and half-lives were calculated. RESULTS: Women with suspected or confirmed PE for whom sFlt-1 and PlGF levels were measured at least twice during pregnancy (n = 46) had a median gestational age at inclusion of 26 weeks (range, 18-40 weeks). In 27 of the 30 patients with sFlt-1/PlGF ratio ≤ 38 at baseline, thereby ruling out PE, the sFlt-1/PlGF ratio remained stable for up to 100 days. In the remaining three patients with a ratio ≤ 38 and in most of the 16 patients with a ratio > 38, the ratio increased further. For women diagnosed with PE or HELLP syndrome for whom sFlt-1 and PlGF levels were measured before and after delivery (n = 26), median gestational age at inclusion was 29 weeks (range, 16-37 weeks) and median time between antepartum measurement and delivery was 2 days (range, 1-17 days). In this group, after delivery, sFlt-1 dropped to < 1% of its pre-delivery value, with a half-life of 1.4 ± 0.3 days, while PlGF dropped to ∼30% of its pre-delivery value, with a half-life of 3.7 ± 4.3 days. CONCLUSIONS: Based on this small cohort, up to 10% of pregnant women admitted with suspected or confirmed PE presenting with a sFlt-1/PlGF ratio of ≤ 38 display a rise in sFlt-1/PlGF ratio in subsequent weeks, implying that repeat determination of the sFlt-1/PlGF ratio is required to exclude definitively a diagnosis of PE. Furthermore, the rapid and pronounced decline in sFlt-1 levels after delivery in patients with PE/HELLP syndrome suggests that sFlt-1, in contrast to PlGF, is almost entirely derived from the placenta. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

A human trigeminovascular biomarker for antimigraine drugs: A randomised, double-blind, placebo-controlled, crossover trial with sumatriptan.

Current antimigraine drugs are believed, besides their direct vasoconstrictive effect, to inhibit calcitonin gene-related peptide (CGRP) release from trigeminal nerve endings during migraine. Objective The objective of this report is to establish a biomarker for the CGRP-interfering effect of antimigraine drugs. Methods We quantified the effect of sumatriptan on the trigeminal nerve-mediated rise in forehead dermal blood flow (DBF), induced by capsaicin application (0.6 mg/ml) and electrical stimulation (0.2-1.0 mA), in a randomised, double-blind, placebo-controlled, crossover study in healthy male ( n = 11, age ± SD: 29 ± 8 years) and female ( n = 11, 32 ± 7 years) individuals. Results DBF responses to capsaicin were attenuated by sumatriptan (ΔDBF, mean ± SEM: 82 ± 18 AU, p = 0.0002), but not by placebo (ΔDBF: 21 ± 12 AU, p = 0.1026). Conclusion We demonstrated that sumatriptan inhibits increases in DBF, induced by the release of, most likely, CGRP. Thus, our model may be used as a biomarker to establish the trigeminovascular effects of (potential) antimigraine drugs, such as CGRP receptor antagonists or antibodies directed against CGRP or its receptor.

Arterial stiffness is not associated with bone parameters in an elderly hyperhomocysteinemic population.

Several studies have observed positive associations between bone disease and cardiovascular disease. A potential common pathway is hyperhomocysteinemia; however, to date, there is a lack of data regarding hyperhomocysteinemic populations. Therefore, we examined both cross-sectionally and longitudinally, whether there is an association between bone parameters and arterial stiffness in a hyperhomocysteinemic population, and investigated the potential common role of homocysteine (hcy) level on these associations. Cross-sectional and longitudinal data of the B-PROOF study were used (n = 519). At both baseline and 2-year follow-up we determined bone measures-incident fractures and history of fractures, bone-mineral density (BMD) and quantitative ultrasound (QUS) measurement. We also measured arterial stiffness parameters at baseline-pulse wave velocity, augmentation index and aortic pulse pressure levels with applanation tonometry. Linear regression analysis was used to examine these associations and we tested for potential interaction of hcy level. The mean age of the study population was 72.3 years and 44.3 % were female. Both cross-sectionally and longitudinally there was no association between arterial stiffness measures and BMD or QUS measurements or with incident fractures (n = 16) within the 2-3 years of follow-up. Hcy level did not modify the associations and adjustment for hcy did not change the results. Arterial stiffness was not associated with bone parameters and fractures, and hcy neither acted as a pleiotropic factor nor as a mediator. The potential association between bone and arterial stiffness is therefore not likely to be driven by hyperhomocysteinemia.

N-terminal pro-B-type natriuretic peptide and the risk of stroke and transient ischaemic attack: the Rotterdam Study.

BACKGROUND AND PURPOSE: Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a predictor of heart disease. It has also been related to stroke, but its association with transient ischaemic attacks (TIAs) is unclear. Moreover, it is unknown how clinical heart disease influences this relation. Within the prospective population-based Rotterdam Study, the association of NT-proBNP with stroke and TIA was examined and the role of heart disease on this association was investigated. METHODS: NT-proBNP was measured in 1997-2001 in 5611 participants (mean age 68.7 years; 57.7% women) without a history of stroke, TIA or heart failure. Follow-up for stroke and TIA finished in 2012. Models were adjusted for age and cardiovascular risk factors, and were stratified by sex. RESULTS: During 22 058 person-years 195 men suffered a stroke and 118 a TIA. During 31 825 person-years 230 women suffered a stroke and 187 a TIA. Higher NT-proBNP was associated with a higher risk of stroke in men [hazard ratio (HR) per SD increase 1.50; 95% confidence interval (CI) 1.29-1.76] and in women (HR 1.24; 95% CI 1.05-1.46). Associations with TIA were only present in women (HR 1.51; 95% CI 1.26-1.82) but not in men (HR 1.02; 95% CI 0.83-1.26). Excluding persons with a history of clinical coronary heart disease, heart failure or atrial fibrillation and censoring for clinical heart disease during follow-up did not change the associations. CONCLUSIONS: Higher NT-proBNP is associated with incident stroke in men and women and with incident TIA only in women. These associations are independent of clinical heart disease preceding cerebrovascular disease.

Development of an experimental model to study trigeminal nerve-mediated vasodilation on the human forehead.

BACKGROUND: During migraine, trigeminal sensory nerve terminals release calcitonin gene-related peptide (CGRP), inducing nociception and vasodilation. Applied on the skin, capsaicin activates the transient receptor potential vanilloid type 1 (TRPV1) channel and releases CGRP from sensory nerve terminals, thus increasing dermal blood flow (DBF). Using capsaicin application and electrical stimulation of the forehead skin, a trigeminal nerve-innervated dermatome, we aimed to develop a model to measure trigeminal nerve-mediated vasodilation in humans. METHODS: Using laser Doppler imaging, forehead DBF responses to application of capsaicin (0.06 mg/ml and 6.0 mg/ml) and saline, with and without iontophoresis, were studied in healthy subjects. The within-subject coefficient of variation (WCV) of repeated DBF measurements was calculated to assess reproducibility. RESULTS: Maximal DBF responses to 6.0 mg/ml capsaicin with and without iontophoresis did not differ (Emax 459 ± 32 and 424 ± 32 arbitrary units (a.u.), WCV 6 ± 4%). In contrast, DBF responses to 0.06 mg/ml capsaicin were significantly larger with than without iontophoresis (Emax 307 ± 60 versus 187 ± 21 a.u., WCV 21 ± 13%). Saline with iontophoresis significantly increased DBF (Emax: 245 ± 26 a.u, WCV 11 ± 8%), while saline application without iontophoresis did not affect DBF. CONCLUSION: Topical application of capsaicin and electrical stimulation induce reproducible forehead DBF increases and therefore are suitable to study trigeminal nerve-mediated vasodilation in humans.

Variation of urinary protein to creatinine ratio during the day in women with suspected pre-eclampsia.

OBJECTIVE: To investigate the stability throughout the day of the protein to creatinine ratio (PCR) in spot urine, to demonstrate whether the PCR is a valid alternative for 24-hour protein investigation in pregnant women. DESIGN: Prospective study. SETTING: Tertiary referral university centre. POPULATION: Women suspected of having pre-eclampsia, admitted to the Erasmus Medical Centre. METHODS: Twenty-four-hour urine collections and simultaneously three single voided 5-ml aliquots were obtained at 8 a.m., 12 a.m. (noon) and 5 p.m. A PCR was measured in each specimen and compared with the 24-hour protein excretion. MAIN OUTCOME MEASURES: The 24-hour proteinuria and PCR measured in spontaneous voids. RESULTS: The PCRs correlated strongly with each other and with the 24-hour protein excretion but did show variation throughout the day (mean coefficient of variation 36%; 95% confidence interval 31-40%). The coefficient of variation was unrelated to the degree of 24-hour proteinuria. Receiver operating characteristics curves to discriminate between values below and greater than or equal to the threshold of 0.3 g protein per 24-hour had an area under the curve of respectively 0.94 (8 a.m.), 0.96 (noon) and 0.97 (5 p.m.). Sensitivities at 8 a.m., noon and 5 p.m. were respectively 89%, 96% and 94%; specificities were 75%, 78% and 78% with the proposed PCR cut-off of 30 mg/mmol (0.26 g/g) (National Institute for Health and Care Excellence guidelines).There is no evidence of a difference between the three measurement times regarding the sensitivities and specificities. CONCLUSION: The PCR determined in spot urine varies throughout the day but is a valid alternative for 24-hour urine collections in pregnant women. It is especially useful to rapidly identify clinically relevant proteinuria.

B-vitamin levels and genetics of hyperhomocysteinemia are not associated with arterial stiffness.

BACKGROUND AND AIMS: Hyperhomocysteinemia is associated with arterial stiffness, but underlying pathophysiological mechanisms explaining this association are to be revealed. This study was aimed to explore two potential pathways concerning the one-carbon metabolism. A potential causal effect of homocysteine was explored using a genetic risk score reflecting an individual's risk of having a long-term elevated plasma homocysteine level and also associations with B-vitamin levels were investigated. METHODS AND RESULTS: Baseline cross-sectional data of the B-PROOF study were used. In the cardiovascular subgroup (n = 567, 56% male, age 72.6 ± 5.6 yrs) pulse wave velocity (PWV) was determined using applanation tonometry. Plasma concentrations of vitamin B12, folate, methylmalonic acid (MMA) and holo transcobalamin (holoTC) were assessed and the genetic risk score was based on 13 SNPs being associated with elevated plasma homocysteine. Associations were examined using multivariable linear regression analysis. B-vitamin levels were not associated with PWV. The genetic risk score was also not associated with PWV. However, the homocysteine-gene interaction was significant (p < 0.001) in the association of the genetic risk score and PWV. Participants with the lowest genetic risk of having long-term elevated homocysteine levels, but with higher measured homocysteine levels, had the highest PWV levels. CONCLUSION: Homocysteine is unlikely to be causally related to arterial stiffness, because there was no association with genetic variants causing hyperhomocysteinemia, whereas non-genetically determined hyperhomocysteinemia was associated with arterial stiffness. Moreover, the association between homocysteine and arterial stiffness was not mediated by B-vitamins. Possibly, high plasma homocysteine levels reflect an unidentified factor, that causes increased arterial stiffness.

Components of the renin-angiotensin-aldosterone system in plasma and ascites in hepatic cirrhosis.

BACKGROUND: Decompensated liver cirrhosis is characterized by activation of the renin-angiotensin-aldosterone system (RAAS). We investigated whether compartmentalization of these components occurs in ascitic fluid. METHODS: In 26 patients with cirrhosis RAAS components and albumin were quantified in simultaneously obtained plasma and ascitic fluid samples. Renin degradation was determined in vitro in plasma and ascites. RESULTS: Plasma angiotensinogen was below normal reference values in all but two patients and correlated inversely with plasma renin (r = -0.73, P < 0.001). Plasma renin activity was elevated in most subjects. The plasma and ascites concentrations of renin, prorenin, angiotensinogen and aldosterone were closely (P < 0.001) correlated. Expressed as a percentage of plasma levels, the angiotensinogen level (18 +/- 11%) was slightly lower than the albumin level (23 +/- 8%), whereas the aldosterone level (43 +/- 18%) was considerably higher (P < 0.0001). For renin and prorenin these percentages were much lower (P < 0.0001), despite the fact that their molecular weight is lower than that of albumin and angiotensinogen. This was not due to a more rapid degradation of renin in ascites fluid, since the in-vitro degradation rates of renin in plasma and ascitic fluid were identical. CONCLUSION: In hepatic cirrhosis ascites can be regarded as an ultrafiltrate of plasma RAAS components. Since differences in molecular weight or metabolic rate cannot explain the low ascites-to-plasma ratio of renin and prorenin, either their transcapillary transport is impaired and/or they selectively bind to (pro)renin binding sites.

Aldosterone-to-renin ratio as a screening test for primary aldosteronism--the Dutch ARRAT Study.

Since the introduction of the aldosterone-to-renin ratio (ARR ) as a screening tool for primary aldosteronism (PA), there has been a marked increase in the reported prevalence of this condition among hypertensive subjects. A meta-analysis from the literature shows a PA prevalence of almost 8% among hypertensive patients, with a twofold higher prevalence in referred patients as compared with primary care patients (9.0 vs 4.3%). However, the usefulness of the ARR remains subject of debate, because of doubts on its validity, and the many factors affecting the ARR , including posture, time of day of blood sampling, and use of antihypertensive medication. Furthermore, there is no clear cut-off value and it is unknown what population should be screened. Recently, The Dutch ARR AT Study was initiated. This is a multicentre, prospective trial aiming to evaluate the test characteristics of the ARR within a Dutch population of therapy-resistant hypertensive patients. The effect of antihypertensive medication on the ARR will be studied. Furthermore, from this study the prevalence of PA in this population will follow. Last, the blood pressure response to the selective aldosterone-receptor-antagonist eplerenone will be evaluated. The Dutch ARR AT Study will run until the end of 2009 and will contribute to the formulation of uniform guidelines for the screening for PA in the Netherlands.

Paraganglioma of the urinary bladder.

Since paragangliomas of the urinary bladder are rare and not easily recognised, histological examination is often the only leading key to diagnosis. We report on a patient with a paraganglioma of the urinary bladder. Although the patient presented with classical signs and symptoms, these were only appreciated after histological examination of a transurethral resection specimen had elucidated the correct diagnosis.

[No advantage of the combination of ACE-inhibition and angiotensin receptor blockade in patients with high cardiovascular risk]. / Geen voordeel van de combinatie van ACE-remming en angiotensinereceptorblokkade bij patiënten met een hoog cardiovasculair risico.

The results of the 'Ongoing telmisartan alone and in combination with ramipril global eendpoint trial' (ONTARGET) have recently been published. In this trial, which was performed in patients with a high cardiovascular risk, it was investigated whether angiotensin II receptor blockade with telmisartan is equally effective as angiotensin converting enzyme (ACE) inhibition with ramipril and whether the combination oftelmisartan and ramipril (dual blockade) is more effective than ACE-inhibition alone to reduce cardiovascular morbidity and mortality and hospitalization for heart failure. On the basis of the ONTARGET results it can be concluded that dual blockade has no place in the treatment of high cardiovascular risk patients without heart failure, because this approach gives no additional reduction of cardiovascular risk and may even be associated with increased mortality. It also has more side effects. Since telmisartan was equally effective and safe as ramipril, one can choose from both agents in the treatment of patients with a high cardiovascular risk.

Causes and consequences of a non-dipping blood pressure profile.

The development and clinical application of ambulatory blood pressure monitoring (ABP M) has brought several of the main features of the circadian blood pressure (BP) rhythm to light. ABP M has shown to be a very useful method in cardiovascular risk assessment and remains the only method of diagnosing a non-dipping blood pressure profile. A 'non-dipping' BP profile is currently regarded as a risk factor in its own right for cardiovascular (CV) events and target organ damage. Nevertheless, the reliability of ABP M in assessing dipping status is still being questioned. Furthermore, a clear-cut definition of 'non-dipping' has not been established so far. The pathophysiological mechanism(s) of a non-dipping profile might involve abnormalities in extracellular volume and/or vascular resistance regulation. In addition, differences in daytime and nighttime activity, sleep quality and body position during sleep are involved as well. A reduction in cardiovascular risk by a pharmacologically induced switch from a non-dipper to a dipper status might be expected, but remains to be proven.

[Diagnostic and prognostic value of B-type natriuretic peptides in heart failure or signs of heart failure]. / Diagnostische en prognostische waarde van B-type-natriuretische peptiden bij hartfalen of bij aanwijzingen daarvoor.

Biologically active B-type natriuretic peptide or brain natriuretic peptide (BNP) and biologically inactive N-terminal proBNP (NT-proBNP) are secreted into the bloodstream by the heart and provide primarily information regarding the filling pressures in the heart. The accuracy of plasma BNP levels in the diagnosis of heart failure is comparable to that of plasma NT-proBNP levels. Reliable assays have been developed for both peptides, some of which can be used for rapid diagnosis in the emergency clinic. In both groups of patients with heart failure and the general population, there is a relationship between the plasma BNP and NT-proBNP levels and the risk of cardiovascular death, after correction for the traditional risk factors. Screening studies using the determination of BNP or NT-proBNP levels in order to detect patients with heart failure at an early stage cannot be recommended because their specificity is too low: in addition to heart failure, the plasma BNP or NT-proBNP level is affected by age, gender, body mass index, renal function, and pulmonary capacity. There are indications that the introduction ofa rapid BNP determination for patients that present to the emergency clinic with acute dyspnoea will lead to more effective diagnosis and treatment. Sequential determinations ofthe plasma BNP or NT-proBNP levels in inpatients and outpatients with heart failure can help to optimise the treatment, thus decreasing the morbidity and mortality that are associated with heart failure.

[The most recent study into blood pressure lowering by amlodipine: the beginning of the end for the beta-blockers]. / De nieuwste studie naar bloeddrukverlaging door amlodipine: begin van de aftocht van beta-blokkers.

In the 'Anglo-Scandinavian cardiac outcomes trial-blood pressure lowering arm' (ASCOT-BPLA), a regimen ofamlodipine and perindopril was compared with a classic regimen of atenolol and bendroflumethiazide in over 19,000 hypertensive subjects. Most likely related to a lower systolic blood pressure, a better metabolic profile and inferiority of the comparator atenolol, the trial showed better outcomes for total and cardiovascular mortality, fatal and nonfatal stroke and cardiovascular events and procedures for the combination of newer agents. Additionally, the newer combination was associated with a 30% reduction in new-onset diabetes mellitus. It is expected that these newer drugs will quickly replace the beta-blockers as the medication for patients with high blood pressure.

Safety and long-term effects of renal denervation: Rationale and design of the Dutch registry.

BACKGROUND: Percutaneous renal denervation (RDN) has recently been introduced as a treatment for therapy-resistant hypertension. Also, it has been suggested that RDN may be beneficial for other conditions characterised by increased sympathetic nerve activity. There are still many uncertainties with regard to efficacy, safety, predictors for success and long-term effects. To answer these important questions, we initiated a Dutch RDN registry aiming to collect data from all RDN procedures performed in the Netherlands. METHODS: The Dutch RDN registry is an ongoing investigator-initiated, prospective, multicentre cohort study. Twenty-six Dutch hospitals agreed to participate in this registry. All patients who undergo RDN, regardless of the clinical indication or device that is used, will be included. Data are currently being collected on eligibility and screening, treatment and follow-up. RESULTS: Procedures have been performed since August 2010. At present, data from 306 patients have been entered into the database. The main indication for RDN was hypertension (n = 302, 99%). Patients had a mean office blood pressure of 177/100 (±29/16) mmHg with a median use of three (range 0-8) blood pressure lowering drugs. Mean 24-hour blood pressure before RDN was 157/93 (±18/13) mmHg. RDN was performed with different devices, with the Simplicity™ catheter currently used most frequently. CONCLUSION: Here we report on the rationale and design of the Dutch RDN registry. Enrolment in this investigator-initiated study is ongoing. We present baseline characteristics of the first 306 participants.

Endothelin-1 and blood pressure after inhibition of nitric oxide synthesis in human septic shock.

BACKGROUND: The systemic hypotension during human sepsis has been ascribed to increased production of nitric oxide (NO). Therefore, inhibitors of NO synthesis have been used in the treatment of hypotension in patients with septic shock. In addition, NO production may inhibit the synthesis and vasoconstrictor effects of endothelin-1 (ET-1). In this study, we tested whether ET-1 contributed to the vasopressor action of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in patients with severe septic shock. METHODS AND RESULTS: Compared with healthy volunteers, patients with septic shock had increased plasma levels of nitrite/nitrate (37+/-5 [SEM] versus 12+/-5 mmol/L, P<0.01), the stable end products of NO metabolism, and ET-1 (45+/-7 versus 3+/-2 pg/mL, P<0.001). Plasma ET-1 concentration was not related to plasma nitrite/nitrate concentration or blood pressure. Continuous infusion of L-NAME (1 mg. kg-1. h-1 IV) for 12 hours increased mean arterial pressure by 43+/-5% and systemic vascular resistance by 64+/-10% (both P<0.01). The increase in blood pressure and systemic vascular resistance correlated positively with the level of ET-1 (both P<0. 005) but not with plasma nitrite/nitrate level. L-NAME infusion did not result in significant changes in the plasma concentrations of ET-1 or nitrite/nitrate. CONCLUSIONS: NO and ET-1 may both play a role in the cardiovascular derangements of human sepsis. Although L-NAME does not increase ET-1 concentration in patients with septic shock, the vasopressor response induced by L-NAME depends on the plasma level of ET-1. These findings may indicate that inhibitors of NO synthesis unmask a tonic pressor response of ET-1 in human septic shock.

Time course and mechanism of myocardial catecholamine release during transient ischemia in vivo.

BACKGROUND: Elevated concentrations of norepinephrine (NE) have been observed in ischemic myocardium. We investigated the magnitude and mechanism of catecholamine release in the myocardial interstitial fluid (MIF) during ischemia and reperfusion in vivo through the use of microdialysis. METHODS AND RESULTS: In 9 anesthetized pigs, interstitial catecholamine concentrations were measured in the perfusion areas of the left anterior descending coronary artery (LAD) and the left circumflex coronary artery. After stabilization, the LAD was occluded for 60 minutes and reperfused for 150 minutes. During the final 30 minutes, tyramine (154 nmol. kg(-1). min(-1)) was infused into the LAD. During LAD occlusion, MIF NE concentrations in the ischemic region increased progressively from 1. 0+/-0.1 to 524+/-125 nmol/L. MIF concentrations of dopamine and epinephrine rose from 0.4+/-0.1 to 43.9+/-9.5 nmol/L and from <0.2 (detection limit) to 4.7+/-0.7 nmol/L, respectively. Local uptake-1 blockade attenuated release of all 3 catecholamines by >50%. During reperfusion, MIF catecholamine concentrations returned to baseline within 120 minutes. At that time, the tyramine-induced NE release was similar to that seen in nonischemic control animals despite massive infarction. Arterial and MIF catecholamine concentrations in the left circumflex coronary artery region remained unchanged. CONCLUSIONS: Myocardial ischemia is associated with a pronounced increase of MIF catecholamines, which is at least in part mediated by a reversed neuronal reuptake mechanism. The increase of MIF epinephrine implies a (probably neuronal) cardiac source, whereas the preserved catecholamine response to tyramine in postischemic necrotic myocardium indicates functional integrity of sympathetic nerve terminals.

Hypotension during hemodialysis results from an impairment of arteriolar tone and left ventricular function.

AIMS: Hypotensive episodes are a major complication of hemodialysis. Hypotension during dialysis could be directly related to a reduction in blood volume or to a decrease in cardiovascular activation as a response to decreased cardiac filling. A decreased cardiovascular activation could be due to patient-related or to dialysis-related factors. In order to study the isolated effect of a reduction in filling pressure, lower body negative pressure (LBNP) causes activation of the cardiovascular reactivity with a decrease in cardiac filling, but without the influence of the dialysis procedure that could affect cardiovascular reactivity. METHODS: We studied the relationship between relative blood volume (RBV), central venous pressure (CVP), systolic arterial pressure, heart rate, stroke volume index (SI), and total peripheral resistance index (TPRI) during a combined dialysis/ultrafiltration and during LBNP to -40 mmHg in 21 hemodialysis patients with a high incidence of hypotension. Systolic arterial pressure, heart rate, SI and TPRI were measured by Finapres. CVP was measured after cannulation of the jugular vein. During dialysis RBV was measured by a blood volume monitor (BVM). In order to study the conditions in which hypotension occurred after dialysis, we divided the patients into 2 groups: hypotensive (H) and non-hypotensive (NH) during dialysis. RESULTS: Baseline levels did not show any significant differences. During dialysis systolic arterial pressure declined gradually in the H group from 30 minutes before the onset of hypotension. There was a similar decrease of RBV and increase of heart rate in both groups with a large interindividual variation. At hypotension, H patients showed a significantly smaller increase in TPRI as compared to NH patients. The reduction in SI tended to be greater at hypotension, while CVP decreased to a similar extent in both groups. Moreover, during LBNP, a similar reduction in CVP resulted in a much smaller decrease in SI. Systolic arterial pressure was only slightly lowered due to a much greater increase in TPRI. CONCLUSION: We conclude that dialysis-related hypotension in our patient group did not result from an inability to maintain blood volume or from decreased cardiac filling. Hypotension appeared to result from the inability to adequately increase arteriolar tone and a reduction in left ventricular function. Both vascular tone and left ventricular function appeared to be impaired by the dialysis procedure.