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Objective: Deep vein thrombosis (DVT) is a multifactorial disease. Recently, inflammation has been suggested as a risk factor for DVT. The question is whether inflammation is a cause of venous thrombosis or rather a result of the thrombotic process. Methods: We studied the inflammatory response in the acute phase of DVT with interleukin-6, interleukin-8, and C-reactive protein (CRP) as inflammatory markers. Plasma concentrations were measured on the day of admission (day 0) in 40 patients with acute DVT confirmed with phlebography and in 33 patients with clinical suspicion of DVT but negative phlebography results (controls). In patients with DVT, inflammatory markers were also examined on five subsequent days. Results: On day 0, the median concentrations in plasma of interleukin-6, interleukin-8, and CRP were 15.0 pg/mL (range

Background — After experimental carotid sinus denervation in animals, blood pressure (BP) level and variability increase markedly but normalize to preoperative levels within 10 to 14 days. We investigated the course of arterial BP level and variability after bilateral denervation of the carotid sinus baroreceptors in humans. Methods and Results — We studied 4 women (age 41 to 63 years) who were referred for evaluation of arterial baroreflex function because of clinical suspicion of carotid sinus denervation attributable to bilateral carotid body tumor resection. The course of BP level and variability was assessed from repeated office and 24-hour ambulatory measurements (Spacelabs/Portapres) during 1 to 10 years of (retrospective) follow-up. Rapid cardiovascular reflex adjustments to active standing and Valsalva’s maneuver were assessed. Office BP level increased from 132/86 mm Hg (range, 118 to 148/80 to 92 mm Hg) before bilateral surgery to 160/105 mm Hg (range, 143 to 194/90 to 116 mm Hg) 1 to 10 years after surgery. During continuous 24-hour noninvasive BP recording (Portapres), a marked BP variability was apparent in all 4 patients. Initial symptomatic hypotension on change to the upright posture and abnormal responses to Valsalva’s maneuver were observed. Conclusions — Acute carotid sinus denervation, as a result of bilateral carotid body tumor resection, has a long-term effect on the level, variability, and rapid reflex control of arterial BP. Therefore, in contrast to earlier experimental observations, the compensatory ability of the baroreceptor areas outside the carotid sinus seems to be of limited importance in the regulation of BP in humans.

Item does not contain fulltext Iatrogenic hypoglycemias and the subsequent occurrence of hypoglycemia unawareness are well-known complications of intensive insulin therapy in type 1 diabetic patients that limit glycemic management. From a pharmacological point of view, the adenosine-receptor antagonist theophylline might be beneficial in the management of hypoglycemia unawareness. Theophylline stimulates the release of catecholamines and reduces cerebral blood flow, thereby facilitating stronger metabolic responses to and a prompter perception of decreasing glucose levels. To test the effect of theophylline on responses to hypoglycemia, we performed paired hyperinsulinemic-hypoglycemic clamp studies in 15 diabetic patients with hypoglycemia unawareness and 15 matched healthy control subjects. In random order, we concurrently infused either theophylline or placebo. Measurements included counterregulatory hormones, symptoms, hemodynamic parameters, and sweat detection using a dew-point electrode. Additionally, middle cerebral artery velocities (V(MCA)) using transcranial Doppler were monitored as an estimate of cerebral blood flow. When compared with placebo, theophylline significantly enhanced responses of plasma epinephrine, norepinephrine, and cortisol levels in both diabetic patients and control subjects. Because of the theophylline, sweat production started at approximately 0.3 mmol/l higher glucose levels in both groups (P < 0.01), and symptom scores in diabetic patients approached those in control subjects. Theophylline decreased V(MCA) in both groups (P < 0.001), but significantly greater in diabetic patients (P < 0.01), and prevented the hypoglycemia-induced increase of V(MCA) that occurred during the placebo studies. We conclude that theophylline improves counterregulatory responses to and perception of hypoglycemia in diabetic patients with impaired awareness of hypoglycemia.

OBJECTIVE—Caffeine is a central stimulant that increases the release of catecholamines. As a component of popular beverages, caffeine is widely used around the world. Its pharmacological effects are predominantly due to adenosine receptor antagonism and include release of catecholamines. We hypothesized that caffeine reduces insulin sensitivity, either due to catecholamines and/or as a result of blocking adenosine-mediated stimulation of peripheral glucose uptake. RESEARCH DESIGN AND METHODS—Hyperinsulinemic-euglycemic glucose clamps were used to assess insulin sensitivity. Caffeine or placebo was administered intravenously to 12 healthy volunteers in a randomized, double-blind, crossover design. Measurements included plasma levels of insulin, catecholamines, free fatty acids (FFAs), and hemodynamic parameters. Insulin sensitivity was calculated as whole-body glucose uptake corrected for the insulin concentration. In a second study, the adenosine reuptake inhibitor dipyridamole was tested using an identical protocol in 10 healthy subjects. RESULTS—Caffeine decreased insulin sensitivity by 15% (P < 0.05 vs. placebo). After caffeine administration, plasma FFAs increased (P < 0.05) and remained higher than during placebo. Plasma epinephrine increased fivefold (P < 0.0005), and smaller increases were recorded in plasma norepinephrine (P < 0.02) and blood pressure (P < 0.001). Dipyridamole did not alter insulin sensitivity and only increased plasma norepinephrine (P < 0.01). CONCLUSIONS—Caffeine can decrease insulin sensitivity in healthy humans, possibly as a result of elevated plasma epinephrine levels. Because dipyridamole did not affect glucose uptake, peripheral adenosine receptor antagonism does not appear to contribute to this effect.

Item does not contain fulltext The 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) isoenzymes catalyse the interconversion of cortisol and cortisone. Type 1 11 beta-HSD mainly converts cortisone into active cortisol. Type 2 11 beta-HSD inactivates cortisol in mineralocorticoid target tissues, and its activity can be inhibited by glycyrrhetinic acid (GA). Inactivation of cortisol to cortisone is impaired in a subgroup of patients with primary hypertension. To study where this defect is located, we measured cortisol and cortisone concentrations in arterial plasma, in saliva and across the forearm at baseline and after administration of GA in normotensive and hypertensive subjects. GA (500 mg) or placebo was administered orally to 20 normotensive subjects in a placebo-controlled double-blind fashion. Further, we compared the effect of GA in 20 patients with primary hypertension with that in 20 normotensive subjects. Cortisol and cortisone were measured in plasma from the brachial artery and vein and in saliva. Samples were obtained at 0, 90 and 150 min. Forearm blood flow (FBF) was measured simultaneously. Forearm production of corticosteroid hormones was assessed by multiplying the arteriovenous difference in corticosteroid concentration by FBF. The cortisol/cortisone ratio in arterial plasma remained at baseline levels after placebo (4.9 +/- 1.2; mean +/- S.D.), while after GA the ratio increased similarly in normotensive subjects (12.3 +/- 3.4) and in hypertensive patients (12.2 +/- 3.7). A similar effect of GA on the salivary cortisol/cortisone ratio was found. In both normotensive subjects and hypertensive patients no forearm production of cortisol or cortisone could be demonstrated, either at baseline or after administration of GA. Thus, both before and after GA administration, we did not find any difference in systemic and salivary 11 beta-HSD type 2 activity between subjects with primary hypertension and normotensive controls. Further, both at baseline and after GA administration we were not able to demonstrate net inactivation or re-activation of cortisol and cortisone by the 11 beta-HSD isoenzymes in the forearm in either normotensive or primary hypertensive subjects.

Item does not contain fulltext Charcot's arthropathy is a relative uncommon complication of diabetic neuropathy. The aetiology remains poorly understood. According to the neurotraumatic theory, the foot, which has become insensitive through neuropathy, is subjected to extensive (micro)trauma through continuation of use. Ultimately this leads to destruction. According to the neurovascular theory, autonomic neuropathy results in an increased blood flow in the foot with osteopenia consequently resulting due to increased osteoclastic activity and decreased osteoblastic activity. Acute Charcot's arthropathy presents with a red, warm, swollen foot, which is usually not painful and which eventually becomes ulcerated. An insidious development of the condition is also possible. The X-ray of the foot often is normal at presentation, but will later show local osteoporosis, erosions, subluxations or fractures. Technetium scintigraphy will be abnormal from the beginning, while IgG scans are usually normal. The traditional treatment is cast immobilisation with careful introduction of protected weight-bearing. After stabilisation, orthopaedic footwear is necessary to improve foot function and to prevent ulceration. Regular checkups are important.

Contains fulltext : 274798.pdf (Publisher’s version ) (Closed access) BACKGROUND: Based on the data derived from the Modification of Diet in Renal Disease (MDRD) study, a new equation was developed for the estimation of glomerular filtration rate (GFR). This equation, which takes into account body weight, age, sex, serum creatinine, race, serum urea, and serum albumin, provided a more accurate estimation of GFR in patients with renal insufficiency. However, this prediction equation has not been validated in subjects with normal or supra-normal GFR. METHODS: In a cross-sectional study, we measured GFR by inulin clearance in 46 healthy controls and 46 non-complicated type 1 diabetic patients. In this study population, GFR was predicted by measured creatinine clearance, the Cockcroft-Gault formula, and the MDRD equation. RESULTS: In the healthy subjects, mean GFR (+/-SD) was 107+/-11 as compared to 122+/-18 ml/min per 1.73 m(2) in the diabetic patients. This difference in GFR was reflected by a lower serum creatinine (76+/-8 vs 71+/-8 micro mol/l) in the diabetic patients. In the healthy controls, median absolute differences (and the 50th-75th-90th percentile of percentage absolute differences) between predicted and measured GFR were 5.2 ml/min per 1.73 m(2) (4.9-9.8-18.5%) for creatinine clearance, 9.0 ml/min per 1.73 m(2) (8.6-14.3-24.6%) for the Cockcroft-Gault formula, and 10.7 ml/min per 1.73 m(2) (10.9-16.3-25.5%) for the MDRD equation. In the diabetic patients, these differences were 8.3 ml/min per 1.73 m(2) (7.6-9.3-13.0%) for creatinine clearance; 11.8 ml/min per 1.73 m(2) (10.1-16.0-22.5%) for the Cockcroft-Gault formula, and 18.8 ml/min per 1.73 m(2) (16.0-24.2-31.9%) for the MDRD equation. CONCLUSIONS: In subjects with a normal or increased GFR, the new MDRD-prediction equation of GFR is less accurate than creatinine clearance or the Cockcroft-Gault formula, and offers no advantage.

Item does not contain fulltext Three patients diagnosed with primary hypertension suddenly developed hard-to-treat blood pressure after several years of stable blood pressure. One patient, a man aged 48 years, had developed a renal artery stenosis, which had not been present five years earlier. The other two patients, a man aged 57 years and a woman aged 27 years, were diagnosed with an aldosterone-producing adenoma of the left adrenal gland and a pheochromocytoma, respectively. In patients with previously stable blood pressure, sudden derangement may be due to secondary hypertension on top of the pre-existing primary hypertension. A thorough history and physical examination together with limited laboratory investigations usually leads the way to the correct diagnosis.

Item does not contain fulltext Characterized by the behavioral response to apomorphine, two outbred lines of Wistar rats can be recognized with constitutionally determined high (apomorphine susceptible, APO-SUS) or low (apomorphine unsusceptible, APO-UNSUS) adrenal responses to similar environmental stress. Within the accumbens nucleus, the APO-SUS and APO-UNSUS rats differ in alpha -adrenergic receptor responsiveness. This study explored whether these differences in adrenergic receptor sensitivity also exist in mesenteric resistance arteries. A Mulvany myograph was used to study the vasomotor responses of isolated mesenteric resistance arteries to adrenergic receptor stimulation. Phenylephrine (alpha1-agonist)-induced vasoconstriction did not differ between the two lines (pEC : 5.8 +/- 0.05 microM versus 5.8 +/- 0.04 microM and Emax: 36 +/- 2 kPa versus 33 +/- 1 kPa for APO-SUS, n = 9, and APO-UNSUS, n = 11, respectively, p > 0.1). After precontraction with phenylephrine, salbutamol (beta -agonist)-induced relaxation was less in APO-SUS rats (pEC50 4.9 +/- 0.06 versus 5.3 +/- 0.06M for APO-SUS, n = 9, and APO-UNSUS, n = 7, respectively, p < 0.001). Likewise, clonidine (alpha2-agonist)-induced relaxation was reduced in APO-SUS rats (pEC50: 6.7 +/- 0.07 versus 7.0 +/- 0.04, for APO-SUS, n = 9, and APO-UNSUS, n = 8, respectively; p < 0.01). In conclusion, constitutionally determined high susceptibility to stress is accompanied by an impaired vasorelaxation to adrenergic stimuli whereas vasoconstriction is unaffected. An unopposed vasoconstrictor action of norepinephrine may place the APO-SUS rats at increased risk for the development of hypertension, insulin resistance, and atherosclerosis.

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Item does not contain fulltext In 3 patients, 2 women aged 21 and 34 years and a man aged 56 years, with complaints related to wide-ranging and extensive vascular conditions, an organ-specific diagnostic approach and treatment did not lead to the correct diagnosis of the underlying clinical condition. Hereafter a structured, partly protocol-based approach was started which considered the entire vascular system and risk factors for vascular disease. The youngest women died a few years later due to ventricular fibrillation, while the two other patients were assisted in reducing those risk factors that could be influenced. As a result, the planned bypass operation was no longer necessary for the male patient. A structured evaluation by a multidisciplinary team can optimise the care of these patients. The basis of such a team consists of a vascular specialist and vascular nurse-practitioner, both of whom should have specific knowledge of risk factors, aetiology, life style intervention and treatment of these disorders.

Contains fulltext : 178496.pdf (Publisher’s version ) (Open Access) Protection against ischemic kidney injury is afforded by 24 h of ureteral obstruction (UO) applied 6 or 8 days prior to the ischemia. Uremia or humoral factors are not responsible for the protection, since unilateral UO confers protection on that kidney but not the contralateral kidney. Prior UO results in reduced postischemic outer medullary congestion and leukocyte infiltration. Prior UO results in reduced postischemic phosphorylation of c-Jun N-terminal stress-activated protein kinase 1/2 (JNK1/2), p38, mitogen-activated protein kinase (MAPK) kinase 4 (MKK4), and MKK3/6. Very few cells stain positively for proliferating cell nuclear antigen after obstruction, indicating that subsequent protection against ischemia is not related to proliferation with increased numbers of newly formed daughter cells more resistant to injury. UO increases the expression of heat shock protein (HSP)-25 and HSP-72. The increased HSP-25 expression persists for 6 or 8 days, whereas HSP-72 does not. HSP-25 expression is increased in the proximal tubule cells in the outer stripe of the outer medulla postobstruction, prior to, and 24 h after ischemia. In LLC-PK(1) renal epithelial cells, adenovirus-expressed human HSP-27 confers resistance to chemical anoxia and oxidative stress. Increased HSP-27 expression in LLC-PK(1) cells results in reduced H(2)O(2)-induced phosphorylation of JNK1/2 and p38. In conclusion, prior transient UO renders the kidney resistant to ischemia. This resistance to functional consequences of ischemia is associated with reduced postischemic activation of JNK, p38 MAP kinases, and their upstream MAPK kinases. The persistent increase in HSP-25 that occurs as a result of UO may contribute to the reduction in phosphorylation of MAPKs that have been implicated in adhesion molecule up-regulation and cell death.

Item does not contain fulltext Multiple System Atrophy (MSA) and idiopathic Parkinson's disease (PD) can be difficult to distinguish. There is an ongoing debate about the diagnostic value of the growth-hormone response to clonidine (CGH-test) in PD and MSA. We investigated whether the CGH-test can identify individual patients in the early stages of PD (n = 21) and Striatonigral Degeneration (SND, n = 11), a particular variety of MSA. Patients were diagnosed on the basis of clinical criteria and IBZM-SPECT. Clonidine induced a greater total serum growth-hormone production in PD than in SND (p = 0.01). However, taking the difference in prevalence of PD and SND into account, and because of the low likelihood ratios of the test, an increase of GH after clonidine increases the pre-test probability for PD by about only 5 %, while an absent response of GH also increases the pre-test probability for SND by about 5 %. We conclude that the CGH-test discriminates between groups of patients with PD and SND, but has little practical diagnostic value for identifying individual patients.

Item does not contain fulltext BACKGROUND: Data on the prevalence of orthostatic intolerance (OI) in patients with chronic fatigue syndrome (CFS) are limited and controversial. We tested the hypothesis that a majority of CFS patients exhibit OI during head-up tilt. METHODS: Hemodynamic and neurohumoral responses to 40 minutes of head-up tilt were studied in 36 CFS patients and 36 healthy controls. Changes in stroke volume, cardiac output and peripheral vascular resistance were estimated from finger arterial pressure waveform analysis (Modelflow). Blood samples were drawn before and at the end of head-up tilt for measurement of plasma catecholamines. RESULTS: At baseline, supine heart rate was higher in CFS patients (CFS: 66.4 +/- 8.4 bpm; controls: 57.4 +/- 6.6 bpm; p < 0.001) as was the plasma epinephrine level (CFS: 0.11 +/- 0.07 nmol/l; controls: 0.08 +/- 0.07 nmol/l: p = 0.015). An abnormal blood pressure and/or heart rate response to head-up tilt was seen in 10 (27.8 %) CFS patients (6 presyncope, 2 postural tachycardia, 2 tachycardia and presyncope) and 6 (16.7 %, p = 0.26) controls (5 presyncope, 1 tachycardia, 2 tachycardia and presyncope). Head-up tilt-negative CFS patients showed a larger decrease in stroke volume during tilt (-46.9 +/- 10.6) than head-up tilt-negative controls (-40.3 +/- 13.6 %, p = 0.008). Plasma catecholamine responses to head-up tilt did not differ between these groups. CONCLUSION: Head-up tilt evokes postural tachycardia or (pre)syncope in a minority of CFS patients. The observations in head-up tilt-negative CFS patients of a higher heart rate at baseline together with a marked decrease in stroke volume in response to head-up tilt may point to deconditioning.

Item does not contain fulltext Pheochromocytomas are dangerous tumors that, although a rare cause of hypertension, require consideration among large numbers of patients. The resulting low prevalence of the tumor among tested populations and the inadequacies of commonly used biochemical tests make excluding or confirming the tumor an often difficult and time-consuming task. Recognition that catecholamines are metabolized to free metanephrines within pheochromocytoma tumor cells, and that this process is independent of catecholamine release, provides a rationale for use of these metabolites in the biochemical diagnosis of pheochromocytoma. Here we briefly review the history of biochemical diagnosis of pheochromocytoma in relation to recent data about the diagnostic utility of plasma free metanephrines for detection of these tumors. Measurements of urinary or plasma catecholamines have reasonable sensitivity for detection of most pheochromocytomas, particularly those in patients with sustained hypertension. False-negative test results can, however, occur in asymptomatic patients tested because of an adrenal incidentaloma or a familial predisposition for pheochromocytoma, or when sampling is carried out between episodes of paroxysmal hypertension. Measurements of urinary total metanephrines or vanillylmandelic acid are less reliable and are of little value as initial screening tests. In contrast, measurements of plasma concentrations or free metanephrines or 24-hour urinary outputs of fractionated normetanephrine and metanephrine almost always reveal the tumor. Although, both tests have similarly high sensitivity, the relatively low specificity of urinary fractionated metanephrines means that pheochromocytomas can be more efficiently excluded or confirmed using measurements of plasma free metanephrines.

Item does not contain fulltext This study was performed to test two hypotheses: (1) ischaemic preconditioning (development of tolerance to ischaemia) influences muscle fibre conduction velocity (MFCV) during repeated ischaemic isometric exercise and (2) the increase in MFCV to supranormal levels during recovery from ischaemic exercise is caused by activation of Na(+)-K(+)-ATPase. For this purpose, MFCV was measured with surface electromyography (sEMG) during repeated ischaemic isometric exercise of the brachioradial muscle (2 min at 30 % of maximal voluntary contraction). The involvement of ischaemic preconditioning was tested by changing the duration of ischaemia and by intra-arterial infusion of adenosine (brachial artery, 50 microg min(-1) dl(-1)). The role of Na(+)-K(+)-ATPase was explored using ouabain (0.2 microg min(-1) dl(-1)). During the exercise, MFCV decreased from 4.4 +/- 0.2 m s(-1) to 3.7 +/- 0.2 m s(-1) (P < 0.01, n = 13). Similar reductions in MFCV were observed during repeated exercise, irrespective of the reperfusion time (10 min vs. 18 min) or duration of the ischaemia (2 vs. 10 min). However, initial MFCV gradually increased for each subsequent contraction when contractions were repeated at 10 min intervals (4.4 +/- 0.2 m s(-1) vs. 4.9 +/- 0.2 m s(-1) for the first and fourth contraction respectively; P < 0.01; n = 13). This increase was not observed when contractions were performed at 18 min intervals, nor when additional ischaemia was applied. Intra-arterial adenosine did not affect MFCV. Intra-arterial ouabain did not affect the reduction in MFCV during exercise but completely prevented the increase in MFCV during recovery: from 4.7 +/- 0.2 m s(-1) to 5.2 +/- 0.2 m s(-1) vs. 4.5 +/- 0.1 m s(-1) to 4.5 +/- 0.1 m s(-1) in the absence and presence of ouabain respectively (P < 0.05 for ouabain effect; n = 6). In conclusion, ischaemic preconditioning is not involved in changes in MFCV during repeated ischaemic isometric exercise. The increase in MFCV during recovery from repeated ischaemic isometric exercise is caused by rapid activation of Na(+)-K(+)-ATPase.

Background Vascular (interstitial) anglotensin (ANG) II production depends on circulating renin-angiotensin system (RAS) components. Mannose 6-phosphate (man-6-P) receptors and angiotensin II type 1 (AT,) receptors, via binding and internalization of (pro)renin and ANG II, respectively, could contribute to the transportation of these components across the endothelium. Objective To investigate the mechanism(s) contributing to transendothelial RAS component transport. Methods Human umbilical vein endothelial cells were cultured on transwell polycarbonate filters, and incubated with RAS components in the absence or presence of man-6-P, eprosartan or PD123319, to block man-6-P, AT, and angiotensin II type 2 (AT(2)) receptors, respectively. Results Apically applied (pro)renin and angiotensinogen slowly entered the basolateral compartment, in a similar manner as horseradish peroxidase, a molecule of comparable size that reaches the interstitium via diffusion only. Prorenin transport was unaffected by man-6-P. Apical ANG I and ANG II rapidly reached the basolateral fluid independent of AT(1) and AT(2) receptors. Basolateral ANG II during apical ANG I application was as high as apical ANG II, whereas during apical ANG II application it was lower, During basolateral ANG I application, ANG II generation occurred basolaterally only, in an angiotensin-converting enzyme (ACE)-dependent manner. Conclusions Circulating (pro)renin, angiotensinogen, ANG I and ANG II enter the interstitium via diffusion, and interstitial ANG II generation is mediated, at least in part, by basolaterally located endothelial ACE. J Hypertens 20:2029-2037 (C) 2002 Lippincott Williams Wilkins.

Item does not contain fulltext Cardiovascular disease (CVD) is rapidly becoming an important public health problem in sub-Saharan Africa, yet the response so far is often minimal and inadequate. While there is, undoubtedly, a 'double burden of disease' (persisting infectious diseases co-existing with emerging non-communicable disease), this is hardly reflected in current health planning, possibly due to a limited appreciation of the changing pattern of CVD and CVD risk factor exposure. In a situation where there are also considerable budget constraints and well-established infectious disease priorities, it is difficult to implement effective interventions for prevention or treatment of CVD. Yet such planning is urgently needed and a template for a comprehensive programme, adaptable to local situations, is presented here. The first step is to raise awareness and create evidence-based commitment among policy-makers, which could lead to the establishment of a multi-sectoral CVD unit at national level. Programmes need to focus on prevention of modifiable risk factors at population level, involving a wide range of institutions and individuals. Recommended strategies include decentralizing the design and implementation of programmes, with appropriate standardized surveillance of major risk factors, all complemented by operational, epidemiological and basic research.

Item does not contain fulltext Hypertension has become an important public health problem for sub-Sahara Africa. In a previous nationwide study, we observed a high degree of geographical variation in the prevalence of diastolic hypertension. Geographical variation provides essential background information for the development of community randomised trials could suggest aetiological mechanisms, inform control strategies and prompt further research questions. We designed a follow-up study from the nine high-prevalence communities, and from 18 communities where hypertension was found least prevalent (controls). In each community, 50 households were randomly selected. In each household, an (unrelated) man and woman were enrolled. The risk for hypertension (blood pressure > or =160/95 mm Hg) was higher in the high prevalence communities compared to the control villages (adjusted OR = 1.7, 95% CI 1.3-2.2). The observed coefficient of variation in hypertension prevalence, k, was 0.30. Thus we confirmed significant geographical variation in prevalence of hypertension over time, which has implications for planning of interventions.

Background: Hypertension is an established risk factor for cardiovascular disease. Risk factor patterns for various cardiovascular complications are different. We studied the relationship between increasing diastolic blood pressure and arterial wall dynamics of various peripheral arteries in hypertensives to increase insight in the variability of properties within the arterial tree. Methods: Eighty-six untreated hypertensives participated in this cross-sectional study. The study-population was divided into quartiles with increasing diastolic office blood pressure. Cross-sectional compliance and distensibility coefficients of the carotid and femoral arteries were determined, using a vessel wall movement detector system (Wall Track System®). Results: Diameters of both common carotid arteries enlarged (right: from 7.4 ± 0.2 to 7.9 ± 0.2 mm) while cross-sectional compliance (right: from 0.61 ± 0.04 to 0.42 ± 0.04 mm2/kPa) and distensibility coefficients (right: from 14.2 ± 1.0 to 9.0 ± 1.0 10−3/kPa) gradually dropped with increasing diastolic blood pressure. Cross-sectional compliance and diameter of the right common femoral artery remained unchanged while distensibility coefficient decreased although less gradually when compared with the carotid arteries. Conclusions: In untreated hypertensives gradual arterial wall stiffening of the carotid arteries occurred with increasing diastolic blood pressure. Gradual changes were less clear in the common femoral artery which points to the heterogeneity of the arterial tree.

Item does not contain fulltext Overactivity of the hexosamine biosynthetic pathway may underlie hyperglycemia-associated insulin resistance, but to date human studies are lacking. Hexosamine pathway activation can be mimicked by glucosamine (GlcN). In the present placebo-controlled study we determined whether GlcN infusion affects insulin resistance in vivo. In 18 healthy subjects, we applied the double forearm balance technique (infused arm vs. control arm) combined with the euglycemic hyperinsulinemic clamp (60 mU/m(2).min insulin) for at least 300 min. During the clamp, subjects received infusions in the brachial artery of 4 micromol/dL.min GlcN from 90-240 min (n = 6) or from 0-300 min (n = 6) or saline (placebo; n = 6). We studied the effects of GlcN on forearm glucose uptake (FGU; infused arm vs. control arm, and vs. placebo experiments) and on whole body glucose uptake. GlcN infusion raised the plasma GlcN concentration in the infusion arms to 0.42 0.14 and 0.81 0.46 mmol/L; plasma GlcN remained very low (< 0.07 mmol/L) in the control arms and in the placebo group. GlcN infusion did not change forearm blood flow. During insulin, FGU increased more than 10-fold. At all time points, FGU was similar in the GlcN-infused arm compared with the control arm and was not different from FGU in the placebo experiments. Similar results were obtained for forearm arteriovenous glucose differences or extraction and for whole body glucose uptake. Thus, despite relevant GlcN concentrations for 5 h in the infused forearm, GlcN had no effect on insulin-induced glucose uptake. These results do not support involvement of the hexosamine pathway in the regulation of insulin sensitivity in humans, at least not in the short-term setting.

Item does not contain fulltext Two patients, a man and a woman aged 36 and 40 years, respectively, were found to have disturbed blood pressure regulation after medical intervention in the jugular area. The man had undergone radiation therapy of the neck due to regional lymph node involvement of a nasopharyngeal carcinoma. Six years later he developed episodic complaints of headache accompanied by labile hypo- and hypertension. Mental and physical stimuli resulted in excessive sympathetic activation. In the woman, a carotid body tumour was resected bilaterally. There was an immediate onset of hypertension after surgery. In both patients, the clinical syndrome was attributed to afferent baroreflex failure due to carotid sinus denervation.

Item does not contain fulltext BACKGROUND: High LDL-cholesterol is a risk factor for atherosclerosis. We aimed to determine whether aggressive cholesterol lowering with statins was more effective than conventional statin treatment in this disease. We investigated the effect of high-dose atorvastatin on carotid atherosclerosis progression. METHOD: We did a randomised, double-blind clinical trial in 325 patients with familial hypercholesterolaemia. Patients were given either atorvastatin 80 mg (n=160) or simvastatin 40 mg (n=165) daily, on an intent-to-treat basis. The primary endpoint was the change of carotid intima media thickness (IMT), as measured by quantitative B-mode ultrasound, over 2 years. FINDINGS: The overall baseline IMT, combining the measurements of the common and internal carotid artery and the carotid bifurcation on both sides, was 0.93 mm (SD 0.22) and 0.92 mm (0.21) in the atorvastatin and simvastatin groups, respectively. After treatment with atorvastatin for 2 years, IMT decreased (-0.031 mm [95% CI -0.007 to -0.055]; p=0.0017), whereas in the simvastatin group it increased (0.036 [0.014-0.058]; p=0.0005). The change in thickness differed significantly between the two groups (p=0.0001). Atorvastatin showed greater reductions in cholesterol concentrations than did simvastatin. HDL-cholesterol concentrations increased in both groups. Both drugs were equally well tolerated. INTERPRETATION: Our results show that aggressive LDL-cholesterol reduction by atorvastatin was accompanied by regression of carotid intima media thickness in patients with familial hypercholesterolaemia, whereas conventional LDL lowering was not.

Item does not contain fulltext The reproducibility of capillaroscopic measurements of capillary blood cell velocity (CBV) in human nailfolds was investigated by use of the computerized system CapiFlow. Therefore, CBV measurements of two capillaries of each of three fingers together with laser Doppler fluxmetry (LDF) and skin temperature measurements were performed three times in five healthy volunteers. Short-term (1.5 h) intra-individual coefficient of variation (CV) of CBV was 18.4%. Long-term (7 days) CV amounted to 55.8%. Inter-individual CV was 55.9%. Short- and long-term intra-individual CVs of LDF were 25.4% and 37.3%. Inter-individual variation was 36.0%. Skin temperature showed short- and long-term CVs of 3.7% and 5.5% and inter-individual CV of 5.8%. In conclusion, measurement of CBV using CapiFlow is a suitable method to assess acute effects, but has limited value in investigating long-term effects. Because of the wide interindividual variability in both CBV and LDF, power calculations will reveal large numbers to investigate. Skin temperature has a relatively small intra- and inter-individual variation and is more suitable for long-term studies.

Item does not contain fulltext BACKGROUND: Renal artery stenosis is among the most common curable causes of hypertension. The definitive diagnosis is made by renal angiography, an invasive and costly procedure. The prevalence of renal artery stenosis is less than 1% in non-selected hypertensive patients but is higher when hypertension is resistant to drugs. OBJECTIVE: To study the usefulness of standardised two-drug regimens for identifying drug-resistant hypertension as a predictor of renal artery stenosis. DESIGN AND SETTING: Prospective cohort study carried out in 26 hospitals in The Netherlands. PATIENTS: Patients had been referred for analysis of possible secondary hypertension or because hypertension was difficult to treat. Patients < or =40 years of age were assigned to either amlodipine 10 mg or enalapril 20 mg, and patients >40 years to either amlodipine 10 mg combined with atenolol 50 mg or to enalapril 20 mg combined with hydrochlorothiazide 25 mg. Renal angiography was performed: (1) if hypertension was drug-resistant, ie if diastolic pressure remained > or =95 mm Hg at three visits 1-3 weeks apart or an extra drug was required, and/or (2) if serum creatinine rose by > or =20 micromol/L (> or =0.23 mg/dL) during ACE inhibitor treatment. RESULTS: Of the 1106 patients with complete follow-up, 1022 had been assigned to either the amlodipine- or enalapril-based regimens, 772 by randomisation. Drug-resistant hypertension, as defined above, was identified in 41% of the patients, and 20% of these had renal artery stenosis. Renal function impairment was observed in 8% of the patients on ACE inhibitor, and this was associated with a 46% prevalence of renal artery stenosis. In the randomised patients, the prevalence of renal artery stenosis did not differ between the amlodipine- and enalapril-based regimens. CONCLUSIONS: In the diagnostic work-up for renovascular hypertension the use of standardised medication regimens of maximally two drugs, to identify patients with drug-resistant hypertension, is a rational first step to increase the a priori chance of renal artery stenosis. Amlodipine- or enalapril-based regimens are equally effective for this purpose.

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Item does not contain fulltext The proinflammatory cytokines TNFalpha and IL-1beta are thought to play a role in the mechanism of septic vasodilatory shock. Most evidence indicate that the vascular effects these cytokines are mediated through increased expression of inducible nitric oxide synthase, whereas several animal studies report a more rapid vasorelaxant effect. We studied the direct vascular effects of TNFalpha and IL-1beta in human isolated resistance arteries (n=9) using a microvascular myograph.After precontraction with noradrenaline or a depolarising high potassium solution, TNFalpha and IL-1beta (up to 10(-8) M, alone or in combination) did not exert any relevant vasoactive effect. We conclude that, in contrast with some animal experiments, these cytokines exert no direct vasoactivity in human resistance arteries.

Item does not contain fulltext OBJECTIVE: To show that different methods of data analysis affect the grading that blood pressure measuring devices achieve according to the British Hypertension Society (BHS)-protocol. METHODS: Based on the somewhat unclear description of the exact method of data analysis in the BHS-protocol four different methods can be discerned. The effect on the grading-results is calculated for these four different options. RESULTS AND CONCLUSIONS: It is shown that using these four different options the achieved grade can range for diastolic blood pressure from C (option 1) to almost A (option 4) and for systolic blood pressure from D (option 1) to B (option 4). Different researchers may well have used different methods. Option 1 is the method that should be used. Also it is stated that the systematic error and the standard deviation of differences (SDD) are measures that give more insight to describe a device's performance. Calculating the grades after correction for the systematic error shows its influence and that of the SDD on the reported accuracy of a blood pressure measuring device.

Item does not contain fulltext The objective of this study was to determine the quantitative intravascular ultrasound (IVUS) and angiographic changes that occur during 1 year follow-up after renal artery stent placement, given that restenosis continues to be a limitation of renal artery stent placement. 38 consecutive patients with symptomatic renal artery stenosis treated with Palmaz stent placement were studied prospectively. IVUS and angiography were performed at the time of stent placement and at 1 year follow-up. At follow-up, angiographic restenosis was seen in 14% of patients. The lumen area in the stent, seen with IVUS, was significantly decreased from 24+/-5.6 mm(2) to 17+/-5.6 mm(2) (p

Item does not contain fulltext Animal studies suggest that overactivity of the hexosamine pathway, resulting in increased UDP-hexosamines [UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc)] is an important mechanism by which hyperglycemia causes insulin resistance. This study was performed to test this hypothesis in patients with type 2 diabetes mellitus (DM). Eight obese patients with uncontrolled DM type 2 and severe insulin resistance were treated with iv insulin for 28 +/- 6 d aimed at euglycemia. Before and after iv insulin treatment, insulin sensitivity was measured using a hyperinsulinemic euglycemic clamp, and a muscle biopsy was taken for measurement of UDP-GlcNAc, UDP-GalNAc, UDP-glucose, and UDP-galactose levels. Also, isoelectric focusing patterns of serum transferrin and the urinary excretion of glycosaminoglycans as measures of final products of the hexosamine pathway were examined. After euglycemia, insulin resistance improved, as demonstrated by an increase in the glucose infusion rate during the clamp from 12.7 +/- 5.6 to 22.4 +/- 8.8 micro mol/kg.min (P < 0.0005) and a decrease in insulin requirement from 1.7 +/- 0.9 to 1.1 +/- 0.6 U/kg.d (P < 0.005), whereas metabolic control improved. Surprisingly, both UDP-GlcNAc, from 8.81 +/- 1.21 to 12.31 +/- 2.52 nmol/g tissue (P < 0.005), and UDP-GalNAc concentrations, from 4.49 +/- 0.85 to 5.89 +/- 1.55 nmol/g tissue (P < 0.05) increased. Isoelectric focusing patterns of serum transferrin and excretion of glycosaminoglycans were similar before and after euglycemia. In conclusion, after amelioration of hyperglycemia- induced insulin resistance, UDP-hexosamines increased in skeletal muscle of patients with type 2 DM. These results do not support the hypothesis that accumulation of products of the hexosamine pathway plays a major role in hyperglycemia-induced insulin resistance.

Purpose: To determine pretreatment variables that may predict 1-year clinical outcome of stent placement for renal artery stenosis. Methods: In a prospective study, 40 consecutive patients (29 men; mean age 60 ± 9.1 years) with angiographically proven atherosclerotic renal artery stenosis were treated with stent placement because of drug resistant hypertension (n=14), renal function impairment (n=14), or both (n=12). Clinical success at 1 year was defined as a decrease of diastolic blood pressure ≥10 mmHg or a decrease in serum creatinine ≥20%, depending on the indication for treatment. Regression analysis was performed using anatomical parameters from angiography and intravascular ultrasound, estimates of renal blood flow from renal scintigraphy, and single-kidney renal function measurements. Results: Patients treated for hypertension had better outcome than those treated for renal function impairment, with clinical success rates of 85% and 35%, respectively. Preserved renal function, with low serum creatinine and high 2-kidney glomerular filtration rate at baseline, was associated with clinical success in the entire patient group at follow-up (p=0.02 and p=0.03, respectively). An elevated vein-to-artery renin ratio on the affected side was borderline predictive (p=0.06). In patients treated for renal impairment, lateralization to the affected kidney (affected kidney—to–2-kidney count ratio ≤0.45) on the scintigram emerged as a significant predictor for clinical success, with an odds ratio of 15 (p=0.048). Conclusions: Clinical success of renal artery stent placement is better for the treatment of hypertension than for preserving renal function. In patients with renal function impairment, lateralization to the affected kidney on the scintigram appears to be a predictor of clinical success.

Item does not contain fulltext BACKGROUND: In response to stressors and pathophysiologic conditions, sympathetic neuronal outflows can change heterogeneously among body organs and tissues. This study examined the validity of microdialysis and measurements of microdialysate concentrations of catechols, to assess local sympathetic function in skeletal muscle and adipose tissue in humans. METHODS: Based on preliminary experiments, a microdialysate perfusion rate of 3 microl/min and collection duration of 30 minutes were chosen. To assess responses to a stimulus that increases sympathetic outflow to skeletal muscle, microdialysate norepinephrine and dihydroxyphenylglycol concentrations in quadriceps muscle, abdominal subcutaneous adipose tissue, and plasma were measured during orthostasis in 8 healthy normal volunteers. To assess responses to decreased postganglionic sympathetic nerve traffic, norepinephrine and dihydroxyphenylglycol concentrations were measured during i. v. infusion of trimethaphan in 5 volunteers. RESULTS: All subjects had detectable norepinephrine and dihydroxyphenylglycol in microdialysate from both skeletal muscle and adipose tissue. Orthostasis significantly increased microdialysate norepinephrine in skeletal muscle (0.38 +/- (SEM) 0.07 nmol/L supine to 1.48+/-0.24 nmol/L standing, p < 0.01) and in adipose tissue (0.31+/-0.02 nmol/L supine to 0.68+/-0.11 nmol/L standing, p < 0.01). Orthostasis also increased microdialysate dihydroxyphenylglycol in both tissues (1.76+/-0.30 nmol/L to 3.08+/-0.43 nmol/L, p < 0.01; 1.37+/-0.15 nmol/L supine to 1.99+/-0.34 nmol/L standing, p < 0.01). Trimethaphan decreased norepinephrine concentrations in skeletal muscle microdialysate by 50%, adipose tissue by 70%, and antecubital venous plasma 50%, with non-significant decreases in dihydroxyphenylglycol concentrations at each site. CONCLUSIONS: Microdialysate concentrations of norepinephrine and dihydroxyphenylglycol can be detected reliably and respond appropriately during manipulations that increase or decrease the sympathetically mediated release and turnover of norepinephrine. This approach may provide a means to assess sympathetic neuronal function in skeletal muscle and adipose tissue in humans with known or suspected dysautonomias.

Item does not contain fulltext BACKGROUND: Microalbuminuria reflects widespread vascular dysfunction in type 1 diabetes mellitus and results from increased glomerular sieving caused by changes in transglomerular pressure and/or permselectivity characteristics of the glomerular basement membrane. Increased tubular reabsorption or degradation of albumin will offset an early increase in albuminuria. We hypothesized that the infusion of atrial natriuretic peptide (ANP) as a tool to increase glomerular permeability might uncover changes in permselectivity in patients with uncomplicated type 1 diabetes. METHODS: We investigated whether these patients were characterized by endothelial and/or vascular dysfunction. We therefore studied 46 normoalbuminuric patients (urinary albumin excretion [UAE] < 10 microg/min) with type 1 diabetes and 44 healthy controls. Measurements of renal hemodynamics and albuminuria were performed before (baseline) and during the infusion of ANP (0.01 microg/kg/min). On a separate occasion, endothelial function was assessed by the intra-arterial infusion of acetylcholine (ACh), an endothelial-dependent vasodilator. RESULTS: At baseline, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were greater in patients with diabetes (GFR, 121 +/- 3 versus 106 +/- 2 mL/min/1.73 m(2); ERPF, 558 +/- 16 versus 527 +/- 13 mL/min/1.73 m(2); P < 0.001). The infusion of ANP increased filtration fraction. There were no differences in these responses between groups. UAE was significantly greater in patients with diabetes after the ANP infusion (15.8 +/- 1.4 [+183%] versus 9.5 +/- 1.3 microg/min [+96%]; P < 0.01). A subgroup of patients with diabetes with an enhanced albuminuric response (change in UAE > 2 SD of controls) to ANP infusion (mean UAE, 30.3 +/- 1.0 microg/min; 425% +/- 61%) was characterized by a diminished vasodilatory response to ACh (maximal forearm blood flow, 17.2 +/- 2.9 [+563%] versus 26.3 +/- 2.3 mL/min/dL [+800%] in patients with diabetes with a normal albuminuric response; P < 0.05). CONCLUSIONS: In a subgroup of patients with uncomplicated type 1 diabetes, an increase in glomerular permselectivity can be unmasked by the infusion of ANP. These patients are characterized by a diminished vascular response to ACh.

Renoprotective effects of losartan in diabetic nephropathy: Interaction with ACE insertion/deletion genotype?BackgroundThe beneficial short- and long-term renoprotective effects of angiotensin I-converting enzyme (ACE) inhibition are lower in albuminuric diabetic patients homozygous for the deletion compared to the insertion polymorphism of the ACE gene. In an attempt to overcome this interaction, we evaluated the short-term renoprotective effect in diabetic nephropathy of the angiotensin II receptor antagonist losartan in patients homozygous for the insertion or the deletion allele.MethodsFifty-four hypertensive type 1 diabetic patients with diabetic nephropathy homozygous for the insertion (I; N = 26) or the deletion (D; N = 28) allele of the ACE/ID polymorphism were included. After four weeks of washout, the patients received losartan 50 mg daily followed by 100 mg in two treatment periods each lasting two months. Patients and investigators were blinded to ACE genotypes. At baseline and in the end of the treatment periods, 24-hour blood pressure, albuminuria and glomerular filtration rate values were determined.ResultsAt baseline, blood pressure, albuminuria and glomerular filtration rate (GFR) values were similar in the two genotype groups [II vs. DD, 1134 (238 to 5302) vs. 1451 (227 to 8129) mg/24 h, median (range); 156/82 (17/9) vs. 153/80 (17/11) mm Hg, mean (SD); and 86 (22) vs. 88 (24) mL/min/1.73 m2, respectively]. Both doses of losartan significantly lowered blood pressure, albuminuria, and GFR (P < 0.05 vs. baseline). Losartan 100 mg was more effective than 50 mg in reducing albuminuria, 51% (95% CI; 40 to 61) versus 33% (23 to 42), respectively (P < 0.01). No differences in the impact of losartan between the II and DD groups were observed: Losartan 100 mg lowered systolic/diastolic blood pressure by 12/6 and 10/4 mm Hg, whereas albuminuria decreased by 55% (35 to 68) and 46% (28 to 61), in the II and DD groups, respectively (P = NS).ConclusionOur data suggest that losartan offers similar short-term renoprotective and blood pressure lowering effects in albuminuric hypertensive type 1 diabetic patients with the ACE II and DD genotypes. However, the long-term renoprotective effects remain to be evaluated.

Item does not contain fulltext We describe 2 immunocompetent adolescents with fulminant infectious mononucleosis and virus-associated hemophagocytosis. A new quantitative polymerase chain reaction revealed high serum Epstein-Barr virus DNA levels in these patients. One patient died with an increasing viral load not responding to corticosteroids followed by antiviral and intensified immunomodulatory treatment. The other patient received corticosteroids and acyclovir at diagnosis; her rapid recovery was heralded by a steep decline of viral load. We propose monitoring the clinical course of fulminant infectious mononucleosis in immunocompetent patients by Epstein-Barr virus DNA quantification and prompt corticosteroid and antiviral therapy when viral load is high.

Background In rats, diadenosine pentaphosphate (AP5A) has been implicated in the pathogenesis of essential hypertension. This study describes for the first time the vasomotor action of AP5A in humans by means of the “perfused forearm technique.” Results AP5A evoked a dose-dependent forearm vasodilator response equal to that of adenosine but less than that of adenosine triphosphate (ATP) at equimolar doses. The P1-purinoceptor antagonist theophylline (0.28 μmol/min per deciliter) reduced the percentage decrease in forearm vascular resistance (FVR) to AP5A (0.6, 6, and 20 nmol/min/dL): −8% ± 6%, −50% ± 6%, and −68% ± 4% during saline solution versus −7% ± 4%, −33% ± 5%, and −45% ± 6% during theophylline (mean ± standard error [SE]; ANOVA for repeated measures; P < .05 for the interaction between purine dose and theophylline; n = 10). An inhibitor of equilibrative nucleoside transport, dipyridamole (7.4 nmol/min per deciliter), augmented the AP5A (0.6 and 6 nmol/min per deciliter)-induced reduction in FVR as follows: −34% ± 6% and −67% ± 5% during saline versus −49% ± 5% and −80% ± 3% during dipyridamole (P < .05 for the effect of dipyridamole; n = 6). The bivalent cation chelator ethylenediaminetetra-acetic acid (EDTA) inhibited the rapid degradation of AP5A in vitro. In vivo, the highest tolerated intra-arterial EDTA dose was not sufficient to inhibit AP5A metabolism. Conclusion Intra-arterial AP5A caused a dose-dependent reduction in FVR. This is, at least in part, mediated by its degradation product adenosine. The data do not support an in vivo vasoconstrictor action of AP5A, and as such AP5A does not seem likely to contribute to the pathogenesis of primary hypertension in humans. Clinical Pharmacology & Therapeutics (2002) 71, 448–456; doi: 10.1067/mcp.2002.124469

Item does not contain fulltext This study determined whether insulin at pre- (fasting) and post-prandial concentrations increases coronary blood flow and improves cardiac function after acute ischemia during a situation of myocardial stunning. The experiments were performed using an isolated, erythrocyte perfused, working rat heart model. To the perfusate we added erythrocytes and 1.5% bovine serum albumin to improve clinical relevance. The following protocol was used: 8 min baseline performance assessment, 10 min pre-ischemic treatment, 12 min global ischemia, 20 min post-ischemic treatment and 8 min recovery assessment. Vehicle, 10 mIU l(-1) and 100 mIU l(-1) human insulin were tested (all n=6). No significant vasodilator response to insulin was observed either pre- or post-ischemically. After the 12-min ischemic insult, cardiac function returned dose-dependently to pre-ischemic values (function loss with 100 mIU l(-1) insulin: -0.2+/-0.4% vs. vehicle: 10.7+/-0.8%). This study clearly shows that in our clinically relevant model of moderate ischemia (stunning), insulin is highly cardioprotective at physiological concentrations. This may be explained primarily by higher glucose uptake, improving the myocardial energetic state during ischemia. Therefore, insulin should be considered for use when the myocardium is at acute risk for ischemic incidents.

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Item does not contain fulltext BACKGROUND: Angiotensin II subtype-1 receptor antagonists represent a valuable new class of drugs in the treatment of diabetic nephropathy. The aim of our study was to evaluate the optimal dose of losartan for renoprotection and blood pressure reduction in diabetic nephropathy. METHODS: Fifty consecutive hypertensive type 1 diabetic patients with diabetic nephropathy received increasing doses of losartan, 50, 100, and 150 mg once daily in three periods each lasting 2 months. At baseline and at the end of each treatment period, albuminuria, 24-h blood pressure (TM2420 A&D), and glomerular filtration rate (GFR) ([(51)Cr]EDTA plasma clearance) were determined. RESULTS: Baseline values of albuminuria (geometric mean (95% CI)) and GFR (means+/-SEM) were 1138 (904-1432) mg/24 h and 91+/-3 ml/min/1.73 m(2), respectively. The blood pressure at baseline was 155/81+/-3/2 mmHg. All doses of losartan reduced albuminuria and blood pressure. Albuminuria was reduced by 30% (95% CI (15-41)) on losartan 50 mg, 48% (35-57) by losartan 100 mg, and 44% (32-56) by losartan 150 mg (all P values

Item does not contain fulltext OBJECTIVE : Brain natriuretic peptide (BNP) causes vasodilatation but the mechanisms by which this is accomplished are not fully known. The aim of the present study was to determine whether, besides K+Ca2+-channels, nitric oxide (NO) is involved in BNP-induced vasodilatation. METHODS : We studied 10 healthy males twice, in random order, at an interval of 2 weeks. Experiments always started with infusion of BNP (8-16-32-64 pmol/dl per min) into the brachial artery. On the first day this infusion was followed by a second BNP infusion combined with the K+Ca2+-channel-blocker, tetraethylammonium (TEA, 0.1 mg/dl per min), and on the other day by BNP infusion combined with the NO-synthase inhibitor, l-NG-monomethyl arginine (l-NMMA, 0.8 mumol/dl per min). The latter was then followed by a combined infusion of BNP, l-NMMA and TEA. All infusions were separated by a 1 h washout period. Forearm blood flow (FBF) was determined by venous occlusion plethysmography. RESULTS : Mean arterial pressure and heart rate did not change during any of the experiments. BNP alone induced a dose-dependent dilatation, which was similar on both days. TEA, l-NMMA, and their combination all reduced the BNP-induced dilatation (P < 0.05). The combined infusion had a significantly greater effect than TEA alone (P = 0.005). BNP infusions were associated with a significant increase in plasma cyclic guanosine monophosphate (cGMP) and C-type natriuretic peptide (CNP) (P < 0.05). CONCLUSIONS : BNP induces arterial vasodilatation not only by opening K+Ca2+-channels, but also via stimulation of NO production. In addition, BNP stimulates net CNP increase.

Item does not contain fulltext The mechanism of insulin-induced vasodilation has not been completely clarified, but could be important in future treatment strategies of insulin resistance. Recently, a role for calcium-dependent and ATP-dependent potassium (K(Ca) and K(ATP)) channels in insulin-induced vasodilation has been demonstrated in in vitro studies. A role for these channels has never been confirmed in humans in vivo. Therefore, we investigated the role of these channels in insulin-induced vasodilation in humans in vivo. A hyperinsulinemic euglycemic clamp was combined with intra-arterial infusion of placebo, tetraethylammonium (blocker of K(Ca) channels) or glibenclamide (blocker of K(ATP) channels) in three groups of 12 healthy volunteers. Bilateral forearm blood flow was measured with venous occlusion plethysmography. Systemic hyperinsulinemia induced a 20+/-9% vasodilation (p=0.001). Neither tetraethylammonium nor glibenclamide reduced this vasodilation as compared to placebo. According to the results of the present study, insulin-induced vasodilation seems not to be mediated by the opening of K(Ca) and K(ATP) channels in humans in vivo.

Item does not contain fulltext AIMS: Glibenclamide attenuates the protective responses to opening of vascular ATP-sensitive potassium (K(ATP)) channels during ischaemia. Therefore, glibenclamide treatment of Type 2 diabetes mellitus may have hazardous cardiovascular effects when used under conditions of ischaemia. Glimepiride and metformin seem to lack such characteristics. Based on these data, we hypothesized that, in contrast to glibenclamide, chronic treatment of Type 2 diabetic patients with glimepiride or metformin will not impair the vasodilator function of K(ATP) opening in vivo. METHODS: Two groups of 12 Type 2 diabetes mellitus patients participated in a double-blind randomized cross-over study consisting of two 8-week periods, in which treatment with orally administered glibenclamide (15 mg/day) was compared with either glimepiride or metformin (6 mg and 1500 mg/day, respectively). At the end of each treatment period, the increase in forearm blood flow (FBF, venous occlusion plethysmography) in response to intra-arterial administered diazoxide (K(ATP) opener), acetylcholine (endothelium-dependent vasodilator) and dipyridamole (adenosine-uptake blocker) and to forearm ischaemia was measured. RESULTS: There were no significant differences in vasodilator responses to diazoxide, acetylcholine, dipyridamole and forearm ischaemia after glibenclamide compared with glimepiride and metformin. CONCLUSIONS: Chronic treatment of Type 2 diabetes mellitus with glimepiride or metformin has similar effects on vascular K(ATP) channels compared with chronic glibenclamide treatment.

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Item does not contain fulltext The accuracy of the Welch Allyn Vital Signs Monitor, a compact device for the oscillometric measurement of blood pressure, was determined according to the British Hypertension Society protocol. The monitor achieved a grade C for diastolic and a grade D for systolic blood pressure. The device is suitable for monitoring a patient, for example post-operatively, in the emergency department or during an intervention. The device cannot, however, be recommended for an exact determination of blood pressure when compared with the mercury sphygmomanometer. In an earlier validation report, the Welch Allyn Vital Signs Monitor achieved a grade A for both diastolic and systolic blood pressure. After adjusting for the difference in method of calculating the grades used in the two studies, there remained a considerable difference in grading results, for which no clear reason could be found.

Familial combined hyperlipidemia (FCH) is characterized by a variable expression of hypercholesterolemia and/or hypertriglyceridemia. We evaluated the variability in lipid phenotype expression over a 5-year period and studied factors affecting the lipid phenotype expression. A total of 32 families (299 subjects) were studied in 1994 and in 1999. Subjects were classified as having FCH when total cholesterol and/or triglyceride levels exceeded the 90th percentile adjusted for age and sex. In 1994, 93 (31%) of the 299 subjects were affected, whereas 206 (69%) of the subjects were unaffected relatives. In 1999, a diagnosis of FCH was consistent in 69 (74%) of the 93 subjects. So, 26% of the FCH subjects in 1994 showed a sporadic normolipidemic pattern (ie, total cholesterol and/or triglycerides P =0.03) and body mass index (odds ratio 1.14, 95% CI 1.05 to 1.24; P K (apoB 1461±305 versus 997±249 mg/L, respectively [ P K value −0.22±0.19 versus −0.02±0.19, respectively [ P K value show less variability in time and are more consistently associated with FCH, inasmuch as affected FCH subjects, compared with the unaffected relatives, persistently show a higher apoB level and a lower value of parameter K , reflecting small dense LDL, even when they present a sporadic normolipidemic pattern. In conclusion, our results emphasize the need for reevaluation of the diagnostic criteria for FCH. We demonstrate that apoB and small dense LDL are attractive new candidates for defining FCH. Further studies are indicated to evaluate the role of apoB and small dense LDL as diagnostic criteria for FCH.

Item does not contain fulltext BACKGROUND: It has been reported that sodium-lithium countertransport (Na/Li CT) activity is increased in patients with diabetes mellitus and that this increased Na/Li CT activity is associated with the development of diabetic nephropathy. It is unclear however, whether Na/Li CT is related to other pathophysiological factors in diabetic patients. We studied kinetic parameters of Na/Li CT activity together with other putative risk factors for microangiopathy in normoalbuminuric type 1 diabetic patients and matched control subjects. SUBJECTS AND METHODS: We measured maximum velocity (Vmax) and sodium affinity (Km) of Na/Li CT in 53 diabetic patients and 45 healthy controls. Endothelial function was assessed by monitoring forearm vascular response to intrabrachial infusion of acetylcholine. Blood samples were collected for measurement of HbA1c, glucose, insulin and lipids. Blood pressure was measured intra-arterially. Renal haemodynamics were measured by inulin/p-aminohippurate clearance. Urinary albumin was measured by enzyme-linked immunosorbent assay. Transcapillary escape of albumin (TERalb) was calculated by the disappearance curve of 125I-labelled albumin. RESULTS: Vmax was increased in diabetic patients (779 +/- 36 micromol Li+ h-1 L-1 erythrocytes vs. 623 +/- 35 in controls, P < 0.01), whereas Km was decreased (64 +/- 16 mmol L-1 vs. 76 +/- 27 in controls, P = 0.03). The ratio of Vmax : Km was 12.4 +/- 0.6 in diabetic patients and 8.9 +/- 0.9 in controls (P < 0.001). When comparing diabetic patients in the lowest and highest quartile of Vmax or Km there were no differences in blood pressure, renal haemodynamics, urinary albumin excretion, TERalb, endothelial function, HbA1c, glucose, insulin, or lipid profile. CONCLUSION: Na/Li CT is increased in uncomplicated type 1 diabetes and characterized by an increase in Vmax and a decrease in Km. The increase in Na/Li CT is not associated with changes in endothelial function, degree of metabolic control, blood pressure or renal haemodynamics.

Item does not contain fulltext PURPOSE: Denervation of the carotid sinus causes baroreflex and chemoreflex failure, resulting in labile hypertension and loss of hypoxic responsiveness. We investigated whether radiation therapy for laryngeal or pharyngeal cancer affects baroreflex and chemoreflex function. METHODS AND MATERIALS: Twelve patients were studied after radiation therapy for locally advanced laryngeal or pharyngeal cancer (11 male, 1 female, age: 56.0 +/- 7.9 years), 3.3 years (median; range 1.0-4.7) after radiotherapy and 15 healthy controls (11 male, 4 female, 53.4 +/- 9.2 years). We measured baroreflex sensitivity (phenylephrine), blood pressure level and variability (24-h Spacelabs and 5-h Portapres recordings), responses to cardiovascular reflex tests, and the ventilatory responses to normocapnic and hypercapnic hypoxia. RESULTS: Baroreflex sensitivity was lower in patients (9.7 +/- 7.8 ms/mm Hg) than in controls (17.5 +/- 10.3 ms/mm Hg, p = 0.011). Mean office blood pressure was significantly higher in patients (141.5 +/- 27.8/89.2 +/- 10.6 mm Hg, 63.3 +/- 12.3 bpm) than in controls (117.3 +/- 10.1/75.1 +/- 6.8 mm Hg, 61.8 +/- 10.8 bpm). Blood pressure variability was not different between groups, nor were the responses to reflex tests. The normo/hypercapnic ventilatory response to hypoxia was similar in patients (0.21 +/- 0.10/1.37 +/- 0.60 L/min/%) and controls (0.22 +/- 0.16/1.19 +/- 0.78 L/min/%). CONCLUSIONS: Radiation therapy for laryngeal or pharyngeal carcinoma does not affect chemoreflex function, but results in an attenuated baroreflex sensitivity. Clinically relevant blood pressure lability is absent however.

Item does not contain fulltext BACKGROUND: Cortisol is known to increase blood pressure. One possible mechanism is the reported increase in renal vascular resistance (RVR). It is unknown whether this is due to a direct effect of cortisol on the kidneys. OBJECTIVE: To study the effect of infusion of cortisol directly into the renal artery on renal blood flow (RBF) and on renal 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-mediated conversion of cortisol to cortisone in patients with primary hypertension. DESIGN AND METHODS: Twenty-seven patients with primary hypertension participated in this study. Fifteen received placebo and 12 received glycyrrhetinic acid (GRA; 500 mg) orally 2.5 h before the study. After a 10 min infusion of 5% glucose, cortisol was infused in stepwise increasing doses (0.625, 1.25 and 2.5 microg/kg per min), for 10 min each dose. At the end of each infusion step, RBF was measured using the xenon-133 washout technique. Plasma samples from the femoral artery and renal vein were taken for measurement of cortisol and cortisone. Urine was collected for measurement of steroid concentrations for 6 h on the day before the infusion and for 6 h after the infusion. RESULTS: After placebo or GRA, cortisol infusion did not change RVR, RBF or blood pressure. RVR values were 0.72 (0.45-0.89) mmHg/ml per min per 100 ml tissue [median (first and third quartiles)] and 0.71 (0.64-0.91) mmHg/ml per min per 100 ml tissue during infusion of 5% glucose and infusion of the highest dose of cortisol, respectively ( P= NS). Cortisol infusion increased the venous-arterial difference in plasma cortisone concentration across the kidney from 76 (40-115) nmol/l to 138 (100-186) nmol/l (P< 0.05) and increased the cortisol : cortisone ratios in the renal vein and in urine (both P< 0.05). As compared with placebo, administration of GRA increased the cortisol : cortisone ratios in peripheral and renal veins and in the urine. CONCLUSION: Acute infusion of cortisol in high doses directly into the renal artery in patients with primary hypertension did not affect RBF or RVR. Infusion of cortisol resulted in increased cortisol-cortisone conversion by renal 11beta-HSD2, but the concurrent increase in renal and urinary cortisol : cortisone ratio suggests a relative insufficiency of renal 11beta-HSD2 activity as a result of enzyme saturation. This may enhance mineralocorticoid receptor stimulation by cortisol.

Item does not contain fulltext Previous research has shown that the sulfonylurea derivative glibenclamide may improve post-ischemic cardiac functional recovery. Although K(ATP) channel blockade is a possible explanation for this observation, alternative mechanisms exist. Therefore, we simultaneously recorded cardiac function and the intracellular concentration of ATP, phosphocreatine, Pi and pH before and after ischemia in the presence of glibenclamide or vehicle. (31)Phosphorus magnetic resonance (MS) spectroscopy on erythrocyte-perfused, isolated working rat hearts was performed. Glibenclamide 4 micromol l(-1) or vehicle alone was tested (both n=5). The following protocol was used: 8 min performance assessment, 10 min drug treatment, 12 min global ischemia, 20 min reperfusion with drug treatment and 8 min functional recovery assessment. Compared with vehicle, glibenclamide significantly decreased coronary blood flow (59.5+/-7.0% vs. 94.3+/-1.3%, P=0.008), ischemia-induced cardiac functional loss (7.4+/-1.3% vs. 18.8+/-3.3%; P=0.019) as well as the ischemia-induced intracellular acidosis (6.75+/-0.01 vs. 6.43+/-0.03 for vehicle, P=0.03).In conclusion, glibenclamide is able to reduce the myocardial functional loss after ischemia while preserving pH but not ATP levels during ischemia. This suggests that the beneficial response to glibenclamide is probably not the result of myocardial K(ATP) channel blockade, but may be explained by inhibition of glycolysis.