Fosinopril decreases levels of soluble vascular cell adhesion molecule-1 in Type II diabetic patients suffering from microalbuminuria.
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Albuminuria↗
Biomedical subjects
S Gasic
Publications and source records attributed to S Gasic.
Troglitazone inhibits progesterone production in porcine granulosa cells.
Troglitazone (a thiazolidinedione that improves insulin resistance) lowers elevated androgen concentrations in women with polycystic ovarian syndrome. In this study, we assessed the direct effects of troglitazone on steroidogenesis in porcine granulosa cells. Troglitazone inhibited progesterone production in a dose- and time-dependent manner (earliest effects at 4 h, maximum at 24 h) without affecting cell viability. Progesterone production was also inhibited by troglitazone in the presence of 25-hydroxycholesterol, indicating that the drug does not affect intracellular cholesterol transport. Troglitazone also inhibited FSH- and forskolin-stimulated progesterone secretion. The reduced progesterone production was accompanied by marked elevations of pregnenolone concentrations, suggesting inhibition of 3beta-hydroxysteroid dehydrogenase (3beta-HSD). The activity of 3beta-HSD in troglitazone-treated granulosa cells was decreased by more than 60%, compared with controls after 24 h. Troglitazone did not affect aromatase activity in porcine granulosa cells. In summary, troglitazone has direct effects on porcine granulosa cell steroidogenesis. The drug specifically inhibits 3beta-HSD activity, resulting in impaired progesterone production. The clinical relevance of this direct in vitro effect on steroidogenesis needs further investigation.
3-Hydroxysteroid Dehydrogenases↗
Indirect calorimetry: variability of consecutive baseline determinations of carbohydrate and fat utilization from gas exchange measurements.
During the past years, substantial methodological and interpretational limitations of indirect calorimetry, particularly concerning fuel utilisation, have been discussed. The aim of the present study was to evaluate short-time intraindividual variability of two consecutive gas exchange measurement series and of calculated data on total energy expenditure/24 h and carbohydrate and fat utilisation. 24 healthy volunteers (16 f, 8 m, 34.7 +/- 13.1 yrs) were admitted to the study. Trials were performed supine after an 12 h overnight fast. After a resting period of 30-45 min and following equilibration of respiratory values for at least 10 min prior to the test, indirect calorimetry measurements were performed using the Sensor-Medics 2.900 device (canopy). Two measurements series lasting up to 30 min each were performed 15-20 min apart. Total energy production/24 h as well as that obtained from carbohydrate and fat utilisation were calculated in both measurement series. Protein utilisation was derived from estimated urinary 24 h nitrogen excretion. O2-consumption, CO2-production, the respiratory quotient and total energy production/24 h show acceptable mean coefficients of variation of 3.7%, 4.6%, 3.5% and 3.6%, respectively. In contrast, carbohydrate and fat utilisation values demonstrate a coefficient of variation of 21.2% and 17.4%, respectively, suggesting considerable impression of estimates of fuel utilisation by indirect calorimetry. We conclude that for research purposes, particularly over short-time periods, indirect calorimetry provides sufficient accuracy only in estimating total resting energy production, while considerable uncertainty exists in using this method to assess carbohydrate and fat utilisation.
Adult↗
PR interval adaptation in the denervated transplanted heart.
In the present study, the dynamic PR response upon standardized treadmill exercise was investigated in 21 transplant recipients (recipient age 48 +/- 17 years, donor age 31 +/- 12 years, > 1 year after transplantation). HR and PR interval were measured at rest and at the end of each 25-W increase in workload till peak exercise. In 17 cases norepinephrine (NE) was assessed at rest, and at the end of each workload the HR increased from 99.3 +/- 14 to 143.4 +/- 25 beats/min at individual peak exercise, and NE increased from 1,307 +/- 1,163 to 3,688 +/- 2,036 pg/mL, while the PR interval shortened from 149.2 +/- 13 to 119.3 +/- 20 ms. On average, PR decreased by 3.4 ms for a 10-beat increase in HR, and the HR-PR interval relationship was described by a linear regression (y = 176.8-0.3469x, P = 0.0001). One patient who was unable to increase his NE levels upon exercise showed virtually no decrease in the PR interval and no HR increase. Both recipient age and donor age were moderately and significantly related to the minimum PR interval achieved at peak exercise (r = 0.6, P = 0.008 and r = 0.51. P = 0.049, respectively). These data show the following: (1) adaptation of the PH interval upon exercise does occur in the denervated transplanted heart; (2) the HR-PR relation is similar to that reported in the innervated heart; (3) the overall decline in PR interval is blunted, since denervated patients start at shorter resting PR intervals and achieve relatively longer PR intervals at peak exercise when compared to their innervated counterparts; (4) these exercise induced changes of the PR interval may be explained by circulating NE; and (5) NE levels achieved at peak exercise and the sensitivity of the AV node to NE seem to be age related.
Adaptation, Physiological↗
Thromboxane A2 does not mediate angiotensin II-dependent nonischemic peripheral vasoconstriction in healthy men: a pilot study.
It has been suggested that angiotensin II-dependent hemodynamic effects are in part mediated by thromboxane A2 (TXA2). The present study investigates in 6 healthy normotensive men whether prostaglandin H2-TXA2 receptor blockade with 100 mg of linotroban (5(2-(phenylsulfonylamino)ethyl)-thienyloxy-acetic acid) p.o. influences angiotensin II-dependent peripheral regional vasoconstriction. Moreover, the regional balance of thromboxane B2 (TXB2), a stable metabolite of TXA2, across the leg vascular bed was assessed at baseline conditions as well as during exogenous infusion (0.2 microgram/min) of angiotensin II. Net transfemoral TXB2 balance was calculated from the respective arteriovenous plasma concentration differences and the corresponding regional plasma flow, the latter being determined by indocyanine-green dye, using appropriate catheterization techniques. Angiotensin II (0.2 microgram/min) induced a 66% increase in leg vascular resistance (p < 0.01) without affecting systemic hemodynamics. These regional hemodynamic effects of angiotensin II were not influenced by prostaglandin H2-TXA2 receptor blockade. Baseline TXB2 balance across the femoral vascular bed was equilibrated at slight extraction rates or around zero and remained unchanged during angiotensin II infusion. These results suggest that, in healthy man, angiotensin II-dependent, nonischemic peripheral vasoconstriction is not mediated by TXA2. Possible benefits of prostaglandin H2-TXA2 receptor blockade in pathological conditions with tissue malperfusion or ischemia are discussed.
Adult↗
Effect of weight loss on whole body and cellular lipid metabolism in severely obese humans.
We evaluated the effect of diet-induced weight loss on whole body and cellular lipid metabolism in persons with severe upper body obesity in two study protocols. In protocol 1, palmitate and glycerol rates of appearance (Ra) in plasma were determined during basal conditions in seven subjects [initial body mass index (BMI) = 41.3 +/- 2.2 kg/m2] before and after 20.4 +/- 3.0 kg weight loss. Total glycerol and palmitate Ra decreased from 231.0 +/- 19.4 and 166.2 +/- 16.6 mumol/min, respectively, before weight loss to 162.7 +/- 9.5 and 105.0 +/- 9.7 mumol/min, respectively, after weight loss (P < 0.01). However, glycerol and palmitate Ra expressed per kilogram fat mass were similar both before and after weight loss. In protocol 2, subcutaneous abdominal adipose tissue was obtained before and after 14.4 +/- 2.1 kg weight loss in five subjects (initial BMI = 41.6 +/- 2.6 kg/m2). Weight loss caused a 38 +/- 8% decrease in adipocyte hormone-sensitive lipase concentration (P < 0.05) but was not associated with any consistent changes in the concentrations of GTP-dependent regulatory proteins, Gi1 alpha, Gi2 alpha, and G3 alpha. We conclude that diet-induced weight loss ameliorates the increase in basal lipolytic rates in persons with severe upper body obesity. These alterations are associated with changes in cellular hormone-sensitive lipase but not GTP-dependent regulatory protein concentrations.
Adult↗
Influence of angiotensin II on circulating adhesion molecules and blood leukocyte count in vivo.
The mechanism of the beneficial effect of angiotensin converting enzyme inhibitors in patients with myocardial infarction is not clear. Recent in vitro data indicate that angiotensin II (AII) stimulates the expression of adhesion molecules and thus activates leukocyte endothelial interactions. In eight healthy volunteers we investigated the influence of exogenous AII on circulating adhesion molecules and on the blood leukocyte count. A systemically effective and a systemically ineffective dose of AII were administered intravenously over 4 h in a single blind crossover design. Examination of the time course of circulating intercellular and vascular adhesion molecules and E-selectin (cICAM-1, cVCAM-1, cE-selectin-1) in response to the AII infusion revealed increases of up to 11% (especially in cVCAM-1 levels) at single time points, but no significant sustained elevation or trend that can be interpreted as a drug-induced effect. The systemically effective dose, which induced an increase in mean arterial blood pressure from 80 to 108 mmHg (1 mmHg = 133.3 Pa), resulted in a significant increase in blood leukocytes, from 4.8 +/- 0.3 to 5.5 +/- 0.3 g/L (p < 0.05); the systemically ineffective AII dose did not alter blood leukocyte count significantly. Although we did not find an influence of AII on circulating adhesion molecules in vivo, we observed an increase in the blood leukocyte count; thus it may be intriguing to assess whether renin-angiotensin system modulating drugs might exert their favorable effect in ischemic diseases at least in part via an influence on leukocytes.
Adult↗
Gi down-regulation and heterologous desensitization in adipocytes after treatment with the alpha 2-agonist UK 14304.
Prolonged treatment of rat adipocytes with the A1-adenosine receptor agonist [-]N(6)-phenylisopropyl adenosine (PIA) or prostaglandin E1 down-regulates Gi and induces heterologous desensitization. alpha 2-Adrenergic receptors also inhibit adenylyl cyclase through Gi, but whether alpha 2-receptors are present on rat adipocytes has been controversial. We have investigated the effects of the highly specific alpha 2-adrenergic agonist UK 14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline) on rat adipocytes. In previous studies on young rats, we were unable to demonstrate an effect of the alpha 2-agonist. We now report that, in cells isolated from older, more obese rats (300-400 g), UK 14304 inhibited lipolysis (measured as the rate of glycerol release) by approximately 40% (EC50 approximately 40 nM). To determine whether UK 14304 would induce heterologous desensitization, we incubated adipocytes with or without 1 microM UK 14304 for 4 days in primary culture. The cells were then washed, and the rate of lipolysis was determined during a 30-min incubation in the presence of various concentrations of PIA. The concentration-response curve for PIA-induced inhibition of lipolysis was shifted to the right, with the EC50 for UK 14304-treated cells about 2-fold higher than in the control cells. This finding demonstrates that the alpha 2-agonist can desensitize the response to PIA and indicates heterologous desensitization. To investigate the mechanism of this phenomenon, we isolated crude membrane fractions from the cells and analyzed them on Western blots using antibodies against Gi alpha 1, 2 and 3. In cells treated with UK 14304 for 4 days, Gi1 alpha and Gi2 alpha were down-regulated to about 15% of the control level, and Gi3 alpha was decreased to 30% of control. We conclude that prolonged treatment of adipocytes with the alpha 2-agonist induces heterologous desensitization of lipolysis and causes down-regulation of Gi. The findings suggest that G-protein down-regulation is a mechanism for heterologous desensitization.
Adipocytes↗
Increased concentrations of proteins Gi1 and Gi2 in adipocytes from aged rats alter the sensitivity of adenylyl cyclase to inhibitory and stimulatory agonists.
We used a series of antipeptide antisera to estimate the relative amounts of G proteins in adipocytes from young lean versus aged obese Sprague-Dawley rats. Western blots were analyzed using antisera that recognize (1) the alpha-subunits of Gi1 and Gi2 (serum SG1), (2) the alpha-subunit of Gi3 (serum I3B) (3) two forms of the alpha-subunit of Gs (serum CS1), and (4) forms of the beta-subunits common to all the G proteins (serum BN2). Adipocyte membranes from aged rats contained approximately fivefold to sixfold more alpha i1 and alpha i2 than those from young rats, but almost equal amounts of alpha i3. Membranes from aged rats had a modestly higher (50%) amount of a 43-kd and normal amounts of a 47-kd form of alpha s. Membranes from old rats also had approximately a threefold higher amount of beta-subunits, consistent with increased concentrations of some of the G proteins but not others. Finally, the functional consequences of these differences in G proteins was investigated by measuring the effect of N6-phenylisopropyl adenosine ([PIA] an A1-adenosine receptor agonist) and isoproterenol on adenylyl cyclase activity. Adenylyl cyclase was more sensitive to inhibition by PIA in membranes from old rats than from young rats, but was less sensitive to stimulation by isoproterenol, suggesting that the differences we observed are functionally active G proteins. These findings may account for the altered sensitivity of adipocytes from old rats to antilipolytic and lipolytic hormones.
Adenylyl Cyclase Inhibitors↗
[Therapeutic possibilities in cardiac arrhythmias].
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Anti-Arrhythmia Agents↗
[Classification and mechanism of action of anti-arrhythmia drugs].
The knowledge of basic electrophysiologic functions and of ion fluxes across the cell membrane of excitable tissues seems essential for the understanding of the action mode of antiarrhythmic drugs. Therefore, the rather complex physiological interconnections at the membrane site are briefly reviewed. Moreover, the interaction mechanisms of antiarrhythmic drugs with transmembraneous ion movements are discussed. The classification of antiarrhythmic agents as proposed by Vaughan-Williams is critically discussed, emphasizing that each drug has a particular electrophysiologic action.
Anti-Arrhythmia Agents↗
Immediate normalization of profound sinus node dysfunction by aminophylline after cardiac transplantation.
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Adult↗
Increase in skeletal muscle blood flow but not in renal blood flow during euglycemic hyperinsulinemia in man.
In order to investigate the effect of euglycemic hyperinsulinemia on skeletal muscle blood flow and renal blood flow, catheters were inserted into both femoral arteries, one femoral vein and one renal vein of 7 healthy men. Constant infusions of indocyanine-green dye (intraarterial) and of p-aminohippuric acid (intra-venous) were used to estimate leg plasma flow (ELPF) and renal blood flow (ERPF), respectively, prior to and during a euglycemic, hyperinsulinemic clamp (1.0 mU/kg.min of human insulin, serum concentrations of insulin before and during the clamp: 4.6 +/- 0.9 microU/ml and 65.5 +/- 20.6 microU/ml, respectively, t = 120 min). ERPF (basal: 1220 +/- 320 ml/min) remained unchanged throughout the period of induced hyperinsulinemia in each volunteer (mean: 1135 +/- 490 ml/min), whereas mean leg plasma flow (ELPF) rose from basal 206 +/- 99 ml/min up to 275 ml/min 90 minutes after the beginning of the euglycemic clamp study (p < 0.01). This was due to the marked rise in ELPF from 149 +/- 24 ml/min up to 243 +/- 25 ml/min (p < 0.01) seen in 5 subjects. In two men, who presented a markedly higher basal ELPF (332 and 365 ml/min, respectively), no further rise in ELPF was seen during induced hyperinsulinemia. Fractional renal extraction of insulin was unchanged during induced hyperinsulinemia (28 +/- 5%; basal: 22 +/- 18%), as was fractional extraction of insulin by the leg (10 +/- 5%; basal: 13 +/- 11%). The observed dissociation of ERPF and ELPF suggests a differential response to insulin in renal vs. leg vasculature which possibly is due to increased peripheral glucose metabolism.
Adult↗
Normal AV node function in patients with sinus node dysfunction after cardiac transplantation.
Postoperative atrioventricular nodal (AVN) function was compared in 55 patients with normal and 50 patients with impaired sinus node (SN) function after cardiac transplantation (corrected SN recovery time > 520 msec or sinus arrest +/- escape rhythm). Fifty-two patients had fixed atrial pacing at cycle lengths between 600 and 430 msec, and 53 patients at cycle lengths from 600 to 300 msec between postoperative weeks 1 to 3. Relative (stimulus-R interval; AVNRRP) and effective AVN refractory period (AVNERP) were determined in 53 patients at a cycle length of 500 msec. Only one of 105 recipients had high degree AVN conduction disturbance characterized by a Wenckebach phenomenon at cycle length < 630 msec in the first postoperative week. Three patients with normal and two patients with impaired SN function had Wenckebach cycle lengths > 430 msec while the Wenckebach cycle lengths were < or = 430 msec in the remainder (p = NS). Resting PQ interval (146 +/- 18 vs 162 +/- 32; p = 0.09), Wenckebach cycle length (350 +/- 53 vs 362 +/- 50 msec), AVNRRP (356 +/- 38 vs 367 +/- 37 msec), and AVNERP (217 +/- 48 vs 244 +/- 49 msec) did not differ significantly between patients with normal and impaired SN function. AVN conduction did not deteriorate during 318 +/- 130 days of follow-up (PQ at follow-up 154 +/- 17 and 158 +/- 22 msec, patients with normal and impaired SN function, respectively). One DDD pacemaker was placed for AVN conduction disturbance while 22 pacemakers were implanted for SN deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Endothelin-1 in adult respiratory distress syndrome.
Endothelin-1 (ET-1), a potent vasoconstrictor peptide produced by endothelial cells and degraded predominantly in the pulmonary vasculature, has been implicated in the development of various organ dysfunctions. To determine the pathophysiologic role of ET-1 in adult respiratory distress syndrome (ARDS) and the impact of impaired lung function on transpulmonary peptide handling, we compared plasma levels and pulmonary ET-1 balance in 14 patients with ARDS and in seven healthy control subjects. To obtain comparable conditions in both groups, the ET-1 level was raised in the control group by exogenous infusion (0.4 pmol/kg/min) to 9.4 +/- 0.8 pmol/L. ARDS was accompanied by a hyperdynamic circulatory pattern with increased cardiac output and depressed total vascular resistance but, simultaneously, pulmonary hypertension. Venous ET-1 concentration was massively increased in ARDS (9.8 +/- 1.2 versus 2.1 +/- 0.2 pmol/L, p < 0.001). In control subjects, the lung cleared the major fraction of ET-1 (fractional extraction 43 +/- 8.8%, uptake 12.5 +/- 2.5 pmol/min). In contrast, in ARDS there was a pronounced pulmonary releases into the circulation (32.8 +/- 10.3 pmol/min). We conclude that ET-1 concentrations are elevated in ARDS as the result of both increased formation and decreased disposal. Lung failure affects not only gas exchange but also nonrespiratory, metabolic pulmonary functions.
Adolescent↗
Studies on the effect of two angiotensin-converting enzyme inhibitors, captopril and cilazapril, on platelet and vascular prostaglandin metabolism in vivo.
We have studied in 12 healthy volunteers the effects of two angiotensin-converting enzyme (ACE) inhibitors, captopril and cilazapril, on vascular and platelet prostaglandin metabolism, in a double-blind, placebo-controlled, randomized cross-over study. Formation of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2) was measured locally at the site of a microvascular injury. Similar amounts of TxB2 and 6-keto-PGF1 alpha were generated following administration of either ACE inhibitor as compared to placebo. It is concluded that neither captopril nor cilazapril significantly influence vascular and platelet prostaglandin metabolism.
6-Ketoprostaglandin F1 alpha↗
Bioavailability and biological activity of wheat-bound chlorpyrifos-methyl residues in rats.
Wheat grain was treated with 14C-chlorpyrifos-methyl to generate bound residues for determining their bioavailability to rats. In a parallel experiment, bound residues were prepared with non-labelled chlorpyrifos-methyl to determine possible adverse effects in rats fed the grain-bound residue for 28 and 90 days. Two dose levels of 10 and 50 ppm were initially used on the grain. The 10 ppm led to the formation of 25.1% bound residues (2.51 ppm) after 6 months as determined by radiomeasurement. The higher dose was assumed to form 12.55 ppm bound residues. When 14C-bound residues were fed to male rats for 24 hours, the animals eliminated 75% of the radioactivity in urine, 7% in expired air and 8% in faeces after 3 days, indicating that the bound residues were highly bioavailable. A further "bioavailable" amount (4%) was found in selected organs.
Alanine Transaminase↗
Regional hemodynamic effects and clearance of endothelin-1 in humans: renal and peripheral tissues may contribute to the overall disposal of the peptide.
We investigated the regional balance of endothelin-1 across the renal and leg vascular bed as well as the hemodynamic effects of exogenously administered endothelin-1 in six healthy men. Net regional endothelin-1 balance was calculated from the respective arteriovenous differences in plasma concentrations and the corresponding plasma flow, the latter being determined by para-aminohippurate or indocyanine-green dye using appropriate catheter techniques. During constant intravenous (i.v.) infusion of endothelin-1 (0.4 pmol/kg/min), a slight increase in diastolic blood pressure (p less than 0.05) and a decrease in heart rate (p less than 0.01) were observed. In contrast, no significant changes in leg hemodynamics were noted. Renal plasma flow decreased by approximately 30%, and renal vascular resistance increased by 50% as compared with the control (placebo) period (p less than 0.01). Renin plasma concentrations did not change substantially during endothelin-1 infusion. During the control (placebo) period, arterial endothelin-1 plasma concentrations averaged 2.1 +/- 1.0 pM. An equilibrated peptide balance across the leg and a slight renal uptake of endothelin-1 was observed. After endothelin-1 infusion, arterial plasma concentrations of the peptide increased to 4.9 +/- 1.3 pM (p less than 0.01), and a net overall renal and limb uptake of endothelin-1 accounted for approximately 9 and 6% of the infused endothelin-1 amount, respectively. Results showed that at systemic endothelin-1 plasma concentrations, comparable to those which occur in a variety of pathologic conditions such as hypertension or cardiogenic shock, besides pulmonary clearance, renal and limb uptake of the peptide may also contribute to the short half-life (t1/2) of endothelin-1 in humans.
Adult↗