Biomedical subjects

S Shaw

Publications and source records attributed to S Shaw.

At least 37 records · Page 2Linked to original sources

PubMed1997

Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex.

The lymph node cortex is a critical site for encounter between recirculating T cells and their specific antigens. Due to its extreme plasticity, little is understood of the underlying functional unit of the lymph node cortex, the paracortical cord. The idealized paracortical cord (approximately 100 microns by 1000 microns) stretches from a medullary cord to the base of a B-cell follicle. In cross-section, a cord can be visualized as a set of nested cylinders consisting of spaces bounded by cells. The spaces are: i) the lumen of the high endothelial venule (HEV), ii) perivenular channels-narrow potential spaces (0.1 micron) tightly encircling the HEV, iii) corridors-broad spaces (10-15 microns) constituting the majority of the parenchyma, and iv) the cortical sinus. In addition to these spaces for cell traffic, the conduit (fifth space) is a special delivery system for the transit of soluble factors to the HEV and emigrating lymphocytes. The cellular barriers between these spaces are high endothelium, fibroblastic reticular cells, or sinus-lining cells. This review describes the spaces of the paracortical cord and their cellular boundaries, outlines the movement of cells and fluids through these spaces, and discusses how this anatomy affects the efficiency of surveillance by T cells.

Animals↗

PubMed1997

Effects of chronic ETA-receptor blockade in angiotensin II-induced hypertension.

Angiotensin II, a constrictor and mitogen of vascular smooth muscle cells, affects the release of endothelium-derived factors such as nitric oxide or endothelin-1. This study investigated the influence of endothelin-1, using the selective endothelin A receptor antagonist LU135252, on blood pressure and endothelial function in angiotensin II-induced hypertension in the rat. Two weeks of angiotensin II administration (200 ng/kg per minute) increased systolic blood pressure (+35 +/- 5 mm Hg; tail-cuff method) compared with placebo (P < .05). LU135252 alone did not affect systolic pressure but lowered the angiotensin II-induced pressure increase (P < .05). In isolated aortic rings, endothelium-dependent relaxations to acetylcholine were reduced in the angiotensin II group (P < .05 versus placebo) and improved by concomitant chronic LU135252 treatment (P < .05 versus angiotensin II). Blood pressure elevation strongly correlated with impaired endothelium-dependent relaxations to acetylcholine (r = -.967). LU135252 did not affect endothelium-independent relaxations to sodium nitroprusside, which were diminished after angiotensin II treatment (P < .05). In quiescent rings, chronic angiotensin II administration enhanced endothelium-dependent contractions to acetylcholine, which were reduced by LU135252 (P < .05). Impaired contractions to endothelin-1 and norepinephrine in the angiotensin II group were normalized after treatment with LU135252 (P < .05). Thus, chronic therapy with LU135252 partially prevents angiotensin II-induced hypertension and the alternations of the endothelial function observed in this experimental model.

Acetylcholine↗

PubMed1997

Blood pressure and vascular effects of endothelin blockade in chronic nitric oxide-deficient hypertension.

Because nitric oxide inhibits the synthesis and vasoconstrictor effect of endothelin-1, the effect of endothelin-1 may be enhanced under conditions of chronic inhibition of nitric oxide synthesis. We studied the effect of chronic therapy with bosentan, a combined endothelin-A/endothelin-B receptor antagonist, on blood pressure and vascular function and structure of small arteries as well as on the reactivity of the aorta in N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Six-week-old Wistar-Kyoto rats were randomly treated for 6 weeks with placebo (control), L-NAME (70 mg/kg per day), or L-NAME plus bosentan (100 mg/kg per day). The treatments were stopped 2 to 3 days before the in vitro experiments so that only the long-term effects of the drugs could be observed. L-NAME increased systolic blood pressure: bosentan did not prevent this effect although the initial blood pressure rise was delayed (P=NS versus L-NAME group). Bosentan administration did not modify the structural alteration of the resistance vessels induced by L-NAME, nor did it improve endothelium-dependent relaxation of resistance vessels or the aorta. However, bosentan therapy markedly increased endothelium-dependent contraction to acetylcholine, which was slightly enhanced by L-NAME. In contrast, bosentan inhibited aortic endothelium-dependent contractions when applied acutely in vitro. This observation, together with the increased maximal vasoconstriction to the thromboxane A2 receptor agonist U46619 after 2 weeks of bosentan administration, suggests that bosentan also interacts with the receptors mediating endothelium-dependent contractions. In conclusion, our experiments suggest a minor role of endothelin in chronic L-NAME-induced hypertension as well as in the concomitant alterations of vascular structure.

Animals↗

PubMed1997

Anatomic heterogeneity of vascular aging: role of nitric oxide and endothelin.

We investigated the effects of aging, a cardiovascular risk factor, on vascular function with regard to endothelial nitric oxide synthase (eNOS), superoxide dismutase (SOD), and endothelin (ET-1) in aorta and femoral artery of the rat. Concentration-response curves to acetylcholine, calcium ionophore A23187, norepinephrine, ET-1, big endothelin, sodium nitroprusside, and exogenous SOD were obtained. Expression of eNOS mRNA was analyzed by reverse-transcription polymerase chain reaction, SOD activity was assessed using a chemiluminescence-based cytochrome c assay, and ET-1 plasma concentrations were measured by radioimmunoassay. In aorta of old rats, relaxations to acetylcholine and calcium ionophore A23187, basal NO release, and expression of eNOS mRNA in aortic endothelial cells were reduced (P<.05). In femoral arteries, relaxations to acetylcholine were preserved, whereas basal release of NO was attenuated (P<.05). Aging selectively increased contractions to norepinephrine and functional endothelin converting enzyme activity and attenuated contractions to ET-1 in aortas but not femoral arteries. Vascular SOD activity was higher in the femoral artery (P<.05) and unaffected by aging. Plasma ET-1 levels increased and plasma SOD activity decreased with age (P<.05). Aging was associated with an anatomic heterogeneity of endothelial dysfunction, functional endothelin converting enzyme activity, and vascular SOD activity. Vascular function was impaired in the aorta but not the femoral artery, which may be related to lower eNOS mRNA expression and SOD activity. These data suggest differential regulation of the vascular aging process that may contribute to the anatomic heterogeneity of atherosclerosis.

Aging↗

PubMed1997

Structure and function of small arteries in salt-induced hypertension: effects of chronic endothelin-subtype-A-receptor blockade.

The involvement of endothelin in salt-induced hypertension is unclear. In the Dahl rat model, we studied the effects of a selective endothelin-subtype A (ET[A]) receptor antagonist, LU135252, on blood pressure, vascular structure, and function. Dahl salt-sensitive and salt-resistant rats were treated for 8 weeks with 4% NaCl alone or in combination with LU135252 taken orally (60 mg/kg per day). The geometry and reactivity of basilar and mesenteric arteries were studied in vitro under perfused and pressurized conditions using a video dimension analyzer. Chronic salt administration increased systolic blood pressure by 37 +/- 3 mm Hg and media-lumen ratio of the basilar and mesenteric arteries in salt-sensitive rats (P<.05). These structural changes were caused by eutrophic remodeling in basilar and hypertrophic remodeling in mesenteric arteries. Endothelium-dependent relaxations to acetylcholine and contractions to endothelin-1 were impaired in mesenteric arteries of salt-sensitive rats on a high NaCl diet. LU135252 prevented part of the increase in systolic blood pressure and structural and functional alterations but increased plasma endothelin 1 levels (P<.05 versus salt-treated, saltsensitive rats). LU135252 had no effect on these parameters in salt-resistant rats. These findings suggest that the long-term pressor effect of salt administration is mediated in part by the action of endogenous endothelin acting via ET(A) receptors. Thus, chronic ET(A) receptor blockade may be useful therapeutically to lower arterial pressure and prevent endothelial dysfunction and hypertrophic remodeling of resistance arteries in salt-sensitive forms of hypertension.

Animals↗

PubMed1997

Role of endothelin receptor subtypes in the systemic and renal responses to endothelin-1 in humans.

The authors recently reported that infusion of endothelin-1 in humans to obtain pathophysiological plasma levels causes profound renal vasoconstriction and sodium retention. The relative roles of the ETA- and ETB-receptor subtypes in these effects in humans is unknown. Such information is essential in view of the recent introduction of endothelin-receptor blockers in clinical medicine. The study presented here was designed to define the role of the ETA- and ETB-receptor subtypes in the renal actions of endothelin-1 in humans. Systemic infusion of endothelin-1, a nonselective receptor agonist, was compared with infusion of equimolar dosages of the ETB-selective agonist endothelin-3 in healthy volunteers. Endothelin-1 infusion was associated with an approximate 2.5-fold increase in plasma levels of endothelin-1. This was accompanied by an increase in blood pressure by approximately 6 mm Hg (P < 0.05). During endothelin-1 infusion, RPF decreased from 642 +/- 42 to 480 +/- 36 mL/min (P < 0.05) and GFR from 121 +/- 4 to 109 +/- 7 mL/min (P < 0.05). Sodium excretion rate decreased during endothelin-1 infusion, from a baseline value of 182 +/- 33 to 84 +/- 28 mumol/min at the end of the endothelin-1 infusion. Endothelin-3 infusion also resulted in a approximate 2.5-fold increase of plasma levels of endothelin-3. However, in contrast to the endothelin-1 infusion, endothelin-3 had no effect on blood pressure, renal hemodynamics, and electrolyte excretion. These results suggest that the systemic and renal vasoconstrictor effects of endothelin-1 in humans are predominantly mediated by the ETA receptors.

Adult↗

PubMed1996

Regulation of chemokine gene expression in human endothelial cells by proinflammatory cytokines and Borrelia burgdorferi.

Chemokines play a central role in the process of leukocyte recruitment to tissues. By their chemotactic activity they guide leukocytes to the site of infection/injury. Chemokines have been suggested to trigger firm adhesion of leukocytes to activated endothelial cells as well as the subsequent diapedesis. For these functions, chemokines produced by EC are particularly well suited. Our experiments with proinflammatory stimuli demonstrate that chemokines are induced in EC by a variety of stimuli including inflammatory cytokines and bacterial structures such as LPS and preparations of B. burgdorferi. The induction of chemokines by all of these agents occurs rapidly and does not require new protein synthesis. Two chemokines, MCP-1 and IL-8, respond to very low doses (0.1-1 U/ml) of proinflammatory cytokines which is important at the beginning of an immune response when soluble inflammatory mediators might still be limiting. The chemokines RANTES, IP-10, and mig show synergistic induction by low doses (1 U/ml) of several inflammatory mediators, which again is important when only limiting amounts of inflammatory stimuli are present. The upregulation of six chemokine genes as well as genes encoding adhesion molecules in two cell types, EC and fibroblasts, by B. burgdorferi suggests that chemokines might play a central role in the regulation of spirochete-induced inflammatory responses and the subsequent immune responses. Recent evidence suggests that T cells with pathogenic potential contribute to chronic inflammation at the late stage of Lyme disease. Therefore, the use of therapeutic agents that block chemokine activity might be useful in treating chronic Lyme arthritis.

Borrelia burgdorferi Group↗

PubMed1996

Sophisticated strategies for information encounter in the lymph node: the reticular network as a conduit of soluble information and a highway for cell traffic.

The lymph node is the crossroad in which soluble signals and cells carried by lymph meet lymphocytes emigrating from blood. Efficient interactions among these elements depend on the reticular network, which comprises reticular fibers, related extracellular matrix components, and associated fibroblastic reticular cells. This network provides a three-dimensional scaffold for attachment of APCs and pathways for the migration of T cells to these APCs. In addition, the network constitutes a miniature conduit system for bulk flow delivery of soluble molecules to distinct sites in the paracortex, particularly the high endothelial venule. The delivered mediators, such as chemokines, regulate the phenotype of the high endothelial venule, the recruitment of lymphocytes, and the behavior of the recruited lymphocytes. Thus, the reticular network is a multifunctional infrastructure that facilitates encounters of cells with other cells and factors necessary for effective and efficient immune surveillance.

Cell Communication↗

PubMed1996

A fluorogenic assay of endogenous phosphatase for assessment of cell adhesion.

Assays of cell adhesion generally require prelabeling of cells with radioactive or fluorescent probes. A new fluorogenic phosphatase assay requiring no prelabeling has been developed to quantitate cell number, which can thus serve as the basis for quantitating cell adhesion or migration. The assay uses the non-fluorescent substrate 3,6-fluorescein diphosphate (FDP) whose dephosphorylation generates fluorescein. The fluorescence generated is linear with incubation time and cell number until substrate becomes limiting; the assay easily quantitates cells over a range from 10(3) to 10(6) for a variety of cell types, including resting T cells. It is as sensitive as the 51Cr assay, but has the many advantages of a non-radioactive assay, making more convenient the removal of nonadherent cells by simple 1 x g sedimentation. Unlike most other non-radioactive assays, it requires no pre-incubation; this: (1) reduces cell manipulation; (2) eliminates problems of spontaneous release; and (3) avoids potential dye toxicity. This technique of cell quantitation has been adopted as standard in our laboratory for routine adhesion and migration assays.

Buffers↗

PubMed1996

Career changes among Saskatchewan physicians.

OBJECTIVE: To determine how often Saskatchewan physicians changed career paths during medical training and practice. DESIGN: Population survey (mailed questionnaire). SETTING: Saskatchewan. PARTICIPANTS: All 1077 active members of the Saskatchewan Medical Association were sent a questionnaire; 493 (45.8%) responded. OUTCOME MEASURES: Long-term career goal or plan in next-to-last year of undergraduate medical school, probable choice of career if forced to choose at that time, and number of physicians who changed their field of training or practice at any time since graduation. RESULTS: In all, 57.8% (237/410) of the respondents were currently practising in a field different from that planned in their next-to-last year of medical school, 63.5% (275/436) were not practising in the field they would have chosen if forced to at that time, and 42.9% (211/492) had changed their field of training or practice at some time since graduation. Older physicians, those who graduated outside of Canada and specialists were the most likely to have changed career paths, family physicians, and those who graduated in Saskatchewan were the least likely to have changed. CONCLUSION: The current system of postgraduate training in Canada does not permit career changes of the sort made by most of the practising Saskatchewan physicians in the survey sample. The implications of this new system are as yet unknown but require careful monitoring.

Adult↗

PubMed1996

Hepatic expression of macrophage inflammatory protein-1 alpha and macrophage inflammatory protein-1 beta after liver transplantation.

Two local events that are crucial for T cell emigration into tissue are (1) activation of T cell integrins to permit binding to endothelial counter-receptors and (2) directed migration through the endothelium and into tissue in response to chemotactic factors. Because the chemokines macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta can activate adhesion and induce migration of T cells in vitro, we investigated their expression in human liver allografts to determine whether they might be involved in regulating the recruitment of T cells to allografts in vivo. Both chemokines were expressed strongly by infiltrating leukocytes during rejection and could be detected immunohistochemically on biliary epithelium, an important target for T cell mediated graft damage. Both chemokines, but particularly MIP-1 beta, were detected on the vascular and sinusoidal endothelium of rejecting liver allografts, where they were coexpressed with the T cell beta 1-integrin receptor vascular cell adhesion molecule-1. In situ hybridization with complementary ribonucleic acid probes showed no MIP-1 alpha or MIP-1 beta mRNA in normal liver but dramatic expression of both chemokines in infiltrating leukocytes and graft endothelium during rejection. Expression was reduced after successful corticosteroid treatment of rejection but persisted in patients progressing to chronic rejection. Increased MIP-1 alpha and MIP-1 beta mRNA expression was already found in biopsies taken at the end of the transplant operation, suggesting that early induction of chemokines, possibly in response to graft reperfusion, might promote the subsequent development of graft rejection. These data demonstrate for the first time that MIP-1 alpha and MIP-1 beta are (1) expressed in human liver allografts, (2) produced by endothelial cells in vivo, and (3) induced early after transplantation. They suggest that MIP-1 alpha and MIP-1 beta produced by graft infiltrating leukocytes and graft endothelium might play a crucial role in regulating T cell recruitment to liver allografts in vivo.

Bile Ducts↗

PubMed1996

Increased activation of sympathetic nervous system and endothelin by mental stress in normotensive offspring of hypertensive parents.

BACKGROUND: The pathogenesis of essential hypertension is still uncertain, but genetic factors and the sympathetic nervous system are likely to be involved. Sympathetic nerve activity and hormonal circulatory control mechanisms, however, are affected by blood pressure itself. Hence, early functional changes are best investigated in normotensive subjects at risk to develop hypertension, such as normotensive offspring of hypertensive parents. METHODS AND RESULTS: Muscle sympathetic nerve activity (MSA) was measured in the peroneal nerve of 10 normotensive offspring of parents with essential hypertension and 8 offspring of normotensive parents. Measurements were performed under resting conditions, during a 10-minute period of hypoxia (12.5% O2/87.5% N2) and during a 3-minute mental stress test. The tests were separated by a 30-minute resting period. Plasma samples for determination of norepinephrine and endothelin were collected before and after the tests. Baseline values of MSA were comparable in offspring of hypertensive and normotensive parents. During hypoxia, MSA, heart rate, and norepinephrine and endothelin plasma levels increased in offspring of hypertensive and normotensive parents to a comparable degree, whereas no significant changes in blood pressure and plasma norepinephrine levels were observed in either group. During mental stress, MSA and plasma norepinephrine and endothelin increased only in offspring of hypertensive parents (P < .001 to .01). In parallel, blood pressure increased significantly only in offspring of hypertensive parents (P < .001 to .05) but heart rate increased in both groups (P < .001 to .05). CONCLUSIONS: The activity of the sympathetic nervous system and plasma norepinephrine and endothelin levels are increased during mental stress only in offspring of hypertensive parents, whereas the response to hypoxia was similar in offspring of hypertensive and normotensive parents, suggesting a genetically determined abnormal regulation of the sympathetic nervous system to certain stressful stimuli in offspring of hypertensive parents. This may play a role in the pathogenesis of essential hypertension.

Adult↗

PubMed1996

Long-term treatment with lansoprazole for patients with Zollinger-Ellison syndrome.

BACKGROUND: Normalization of gastric secretion and cure of associated upper gastrointestinal lesions by resection of gastrinoma is possible in approximately 20% of patients with Zollinger-Ellison syndrome, leaving approximately 80% dependent on medical treatment with proton pump inhibitors for acid suppression. METHODS: Lansoprazole was given for 3-48 months (median 28 months) to 26 Zollinger-Ellison syndrome patients with peptic ulcer manifestations in all and oesophagitis in 13. Starting with 60 mg/day. the dose was individualized to lower basal acid output to less than 5 mmol/h for those with intact stomachs and less than 1 mmol/h in those who had prior gastrectomy or with oesophagitis. The patients were studied every 3 months for 1 year and then every 6 months with gastric analysis (basal and maximal acid and pepsin output) and endoscopy with biopsy for enterochromaffin-like (ECL) cells. RESULTS: Lansoprazole inhibited basal acid output by 95%, pepsin output by 65% and remained effective at the initial mean (66 +/- 4.3 mg/day) or smaller doses (56 +/- 12 mg/day) at 48 months. Mucosal lesions healed and symptoms (ulcer-type pain, diarrhoea, heartburn, weight loss) resolved rapidly, usually within a few weeks. Serum gastrin and ECL cell populations, which were elevated before treatment, remained statistically unchanged but one of the three multiple endocrine neoplasia I (MEN-I) patients developed a small carcinoid. Of the three patients with metastatic gastrinoma at diagnosis one has died and one has progressed, while the third has had stable liver metastases for 26 years. Ulcer-type relapses occurred in three of the five post-gastrectomy patients, one with fatal jejunal ulcer perforation despite adequate acid suppression. No biochemical or clinical adverse events due to lansoprazole were encountered. CONCLUSION: Lansoprazole effectively inhibits acid and pepsin secretion in Zollinger-Ellison syndrome patients without any demonstrated side-effects. Despite strict acid control, post-gastrectomy Zollinger-Ellison syndrome patients were more liable to ulcer relapse, while oesophagitis was not a marker for therapeutic difficulty.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Long-term treatment with lansoprazole of patients with duodenal ulcer and basal acid output of more than 15 mmol/h.

BACKGROUND: About 10% of patients with duodenal ulcers have marked gastric acid hypersecretion with basal acid output (BAO) of more than 15 mmol/h, which is in the range found in Zollinger-Ellison syndrome. PATIENTS AND STUDY DESIGN: We report long-term, up to 4 years, prospective treatment using lansoprazole in nine male patients with duodenal ulcers and a BAO of more than 15 mmol/h whose results are compared with those in 10 male Zollinger-Ellison syndrome patients with intact stomachs reported in detail in an accompanying paper. RESULTS: All 19 subjects, except one Zollinger-Ellison syndrome patient who had gastric and oesophageal ulcers, had a history of duodenal ulcers; 22% of those with gastric acid hypersecretion had oesophagitis compared with 60% of those with Zollinger-Ellison syndrome. Each subject had the dose of lansoprazole adjusted to give a BAO of less than 5 mmol/h. At 3-month intervals to 1 year, and then at 6-monthly intervals, basal and pentagastrin stimulated secretions were studied, in addition to gastroscopy with biopsy for gastric mucosal morphology. Basal and maximal acid and pepsin secretions were not different between gastric acid hypersecretion and Zollinger-Ellison syndrome patients before treatment. During treatment, BAO was reduced by over 90% to less than 2 mmol/h, while peak acid output was reduced by 70% in those with gastric acid hypersecretion and 90% in Zollinger-Ellison syndrome patients. Four gastric acid hypersecretion patients had relapses during treatment, three times in one patient and twice in another patient, but all responded to continued treatment with lansoprazole. Of the seven ulcer-related relapses in the gastric acid hypersecretion patients, four occurred with a BAO of less than 2 mmol/h and three with a BAO of 7.1-7.3 mmol/h; five of the seven relapses occurred in the absence of Helicobacter pylori. Lansoprazole remained effective at an average dose of approximately 70 mg/day, without causing any side-effects. CONCLUSION: Lansoprazole is apparently safe and effective for treating hypersecretion, whether due to hypergastrinaemia (Zollinger-Ellison syndrome) or not (non-Zollinger-Ellison syndrome hypersecretors).

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Vitamin C-driven free radical generation from iron.

Circulating free iron is lethal. Humans have two circulating iron binding proteins to soak up free iron to prevent it from generating toxic quantities of free radicals. These proteins are transferrin, a high-affinity, low-capacity protein (2 atoms of iron per molecule of transferrin) for which there are receptors on the surface of every iron-requiring cell; and ferritin, a lower-affinity, high-capacity protein (maximum of 4500 atoms of iron per molecule of ferritin) for which there are receptors only on the surface of iron-storage cells such as RE (reticulo-endothelial) cells. Iron is trapped inside the ferritin protein shell as harmless Fe3. When there is a high serum level of reduced ascorbic acid, it drives through the pores of the ferritin protein shell to the inside surface, where it converts the Fe3 to catalytic Fe2, which then leaks out of the pores of the ferritin protein shell and generates billions of free radicals. In normal individuals, per milliliter of serum, there are approximately 300,000 molecules of transferrin per molecule of ferritin. Ferritin protein is an acute phase reactant that sharply rises in the presence of inflammation of any kind, whereas transferrin is a reverse acute phase reactant that falls in the presence of inflammation of any kind.

Ascorbic Acid↗

PubMed1996

Metabolic neutrality of combined verapamil-trandolapril treatment in contrast to beta-blocker-low-dose chlortalidone treatment in hypertensive type 2 diabetes.

OBJECTIVE: To investigate the metabolic, antihypertensive and albuminuria-modifying effects of a heart rate-modulating calcium antagonist-angiotensin converting enzyme inhibitor combination compared with those of a beta-blocker-low-dose diuretic combination in non-insulin-dependent diabetic hypertensives. DESIGN: A prospective randomized double-blind study. SUBJECTS AND METHODS: Twenty-four diabetics with diastolic blood pressure 90-115 mmHg without azotemia (plasma creatinine level < 150 mumol/l) were evaluated after 4 weeks receiving placebo and 12 weeks receiving treatment either with combined slow-release verapamil (retard formulation) and trandolapril (mean maintenance doses, 180 and 1.6 mg daily) or with atenolol and chlortalidone (71 and 18 mg daily). Insulin sensitivity (by the minimal model method of Bergman), additional metabolic variables, clinic blood pressure, ambulatory blood pressure profile and renal indices were assessed at the end of the placebo and active treatment phases. RESULTS: Compared with placebo, the two therapies produced similar decreases in mean supine clinic blood pressure [10 +/- 3 versus 11 +/- 3% (means +/- SEM)], upright clinic blood pressure (10 +/- 4 versus 11 +/- 4%) and ambulatory daytime blood pressure (9 +/- 2 versus 12 +/- 3%). However, although the verapamil-trandolapril combination was found to be metabolically neutral, the atenolol-chlortalidone combination aggravated insulin resistance [insulin sensitivity index, from (0.8 +/- 0.2) to (0.3 +/- 0.1) x 10(-4)/min per U per ml], increased the serum triglycerides level and decreased the high-density lipoprotein cholesterol and plasma potassium levels. Although both therapies tended to reduce 24 h albuminuria, this was significant for the verapamil-trandolapril treatment only. CONCLUSIONS: Because the effect of any antihypertensive drug, including diuretics and beta-blockers, on cardiovascular morbidity and on mortality in non-insulin-dependent diabetic patients is not known, rational treatment selection can presently be based only on surrogate end-points. Therefore, the triad of metabolic neutrality with antihypertensive and antiproteinuric efficacy supports combined verapamil-trandolapril as a potentially valuable therapy for hypertension accompanying diabetes mellitus.

Adrenergic beta-Antagonists↗

PubMed1996

Metabolic neutrality of perindopril: focus on insulin sensitivity in overweight patients with essential hypertension.

To assess the effects of antihypertensive treatment with the angiotensin-converting enzyme (ACE) inhibitor perindopril on insulin sensitivity, plasma insulin, and lipoprotein metabolism in overweight hypertensive patients, we measured the insulin sensitivity index (SI, determined according to the minimal model method of Bergman), fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure (BP) in 30 overweight [mean body mass index (BMI) 30.9 kg/m2], nondiabetic patients with essential hypertension after a 4-week run-in period and after 6 weeks of perindopril (n = 20) or placebo (n = 10) administered in a double-blind fashion. Furthermore, we estimated their state of physical fitness using the Conconi bicycle ergometer test before and after perindopril or placebo administration. SI was low in our study population (3.2 vs. 13.3 10(-4) ml.microU-1.min-1 in normal lean control subjects). It did not differ between the perindopril and placebo group after the placebo run-in period (3.1 vs. 3.3 x 10(-4) ml.microU-1.min-1) and was not influenced by perindopril (3.3 x 10(-4) ml.microU-1.min-1) or placebo (3.6 x 10(-4) ml.microU-1.min-1) treatment. Moreover, no significant changes were apparent in fasting plasma insulin and glucose, the areas under the glucose and insulin curves, the glucose disappearance rates, serum total triglycerides (TG), or cholesterol or lipoprotein cholesterol fractions between run-in and active treatment phases in the perindopril or the placebo group, respectively. Heart rate (HR), body weight, and anaerobic threshold remained stable in both groups. Compliance, assessed by pill counting was > 90% in both groups at all visits. Therefore, the ACE inhibitor perindopril is neutral with regard to insulin sensitivity, plasma insulin and glucose, and lipoprotein metabolism in overweight, nondiabetic patients with essential hypertension.

Adult↗

PubMed1996

Evaluation of the Upsherscope. A new rigid fibrescope.

A new, rigid intubating fibrescope, the Upsherscope, was evaluated in clinical practice. Intubation was attempted in 200 adult patients and was successful in 191, with a median intubation time of 38 s, range 14-154 s. Intubation was straightforward in just under half of the patients. Difficulties were encountered in picking up the epiglottis, in passing the tracheal tube between the vocal cords and with secretions interfering with the view. In two patients known to be difficult to intubate, the Upsherscope was successful in one patient using an awake technique and failed in the other.

Adolescent↗