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S Gasic

Publications and source records attributed to S Gasic.

At least 37 records · Page 2Linked to original sources
PubMed1995

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↗
PubMed1995

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↗
PubMed1994

[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↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

Regional effects and clearance of endothelin-1 across pulmonary and splanchnic circulation.

To determine the impact of i.v. endothelin-1 on systemic, pulmonary and splanchnic circulation, as well as the peptide's regional clearance, hepatic venous and right heart catheterization was performed in healthy volunteers. During the peptide's continuous i.v. administration (0.4 pmol x kg-1 x min-1, 60 min) its plasma concentration rose from 2.1 +/- 0.5 to 9.5 +/- 5.3 pmol/l (pulmonary artery), from 2.1 +/- 0.9 to 5.0 +/- 1.6 pmol/l (femoral artery), and from 1.5 +/- 0.6 to 2.9 +/- 1.2 pmol/l (hepatic vein). This was accompanied by an increase in mean systolic arterial pressure from 127 +/- 14 to 131 +/- 12 mmHg (P less than 0.05). Concomitantly, cardiac output and heart rate decreased from 7.0 +/- 1.1 to 5.8 +/- 1.0 l/min and from 63 +/- 6 to 56 +/- 5 beats/min, respectively, while total vascular resistance increased from 964 +/- 273 to 1204 +/- 338 dyn x cm x s-5 (P less than 0.01). No major changes in pulmonary circulation were observed, while splanchnic vascular resistance increased from 4472 +/- 1056 to 5361 +/- 1420 dyn x cm x s-5 (P less than 0.01) and estimated hepatic blood flow decreased from 1403 +/- 218 to 1218 +/- 219 ml min-1 (P less than 0.01). During endothelin-1 infusion the pulmonary vascular bed accounted for approximately 53% of the peptide's overall disposal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Sinus node dysfunction after orthotopic cardiac transplantation: postoperative incidence and long-term implications.

We investigated incidence, normalization rates, and clinical significance of sinus node (SN) dysfunction after cardiac transplantation. Thirty-nine of 90 patients systematically evaluated presented with impaired SN function in the postoperative period. Of these, 22 normalized their SN function during follow-up while 17 remained impaired after 3 months. The proportion normalized was higher in patients with prolonged SN recovery time (11/16, 68.8%) and those reverting from escape rhythm to sinus rhythm until discharge (5/8, 62.5%) when compared to patients in escape rhythm throughout the postoperative period (5/11, 45.5%) or pacemaker dependence (1/4, 25%). There was no reliable postoperative predictor of normalization and necessity of long-term pacing. A postoperative heart rate consistently less than 70 beats/min (irrespective of the native rhythm) was significantly related to outcome (P = 0.01), but revealed unacceptable sensitivity (61.5%) and specificity (81%). After all, both patients with severe symptoms (near syncopes and syncope), were derived from this group. These two patients, who had been discharged in sinus rhythm, had late pacemakers implanted. An additional 17 patients had early pacemaker placement, only seven of which were constantly paced during follow-up. Given the low normalization rates, patients with postoperative escape rhythm are those most likely to benefit from pacemaker therapy over the long term. Even those in, or reverting back to, sinus rhythm until discharge may experience severe symptoms, particularly in the setting of a postoperative rate consistently less than 70 beats/min since this indicates a relatively lower probability of recovery.

Algorithms↗
PubMed1992

Glycylglutamine: metabolism and effects on organ balances of amino acids in postabsorptive and starved subjects.

The present study was designed to investigate the metabolism of glycylglutamine and its effects on organ balances of amino acids during intravenous infusion of this dipeptide (100 mumol.h-1.kg-1) in postabsorptive and briefly starved (84-86 h) human subjects. Arterial concentrations of glycylglutamine were not significantly different in postabsorptive (265 +/- 18 microM) and starved (241 +/- 13 microM) subjects. Among the organs examined, kidney predominated in clearance of glycylglutamine from plasma. Moreover, renal clearance of glycylglutamine was reduced by starvation (87 +/- 7 vs. 52 +/- 5 mumol/min, P less than 0.01), whereas neither splanchnic nor muscle clearance was significantly affected. Infusion of glycylglutamine raised plasma concentrations of glycine and glutamine by increasing renal release of these amino acids. In postabsorptive subjects the infusion significantly increased splanchnic balances of glycine and glutamine with little or no effect on the muscle balances; the opposite was found in starved subjects. As far as other amino acids are concerned, the infusion decreased the muscle release of alanine and increased renal release of serine. We conclude that the amino acid residues of glycylglutamine are largely metabolized by the splanchnic organs in postabsorptive subjects and by peripheral organs in starved subjects. The latter results in selective inhibition of muscle release of amino acids.

Adult↗
PubMed1992

Postoperative sinus node dysfunction in the transplanted heart. Impaired automaticity but normal refractoriness.

We describe the use of the extrastimulus technique to define the range of sinus node (SN) effective refractoriness (SNERP) in the denervated transplanted human heart. SNERP could be successfully determined in 18 of 28 patients corresponding to 25 of 43 SN studies and ranged from 210 to 360 ms at a basic pacing cycle length of 500 ms (95 percent confidence limits: 252.5 to 296.2 ms), which is shorter than reported in the innervated native heart. Sixteen data sets in 12 patients showed normal SN function and nine sets of measurements in seven patients showed abnormal SN function (corrected SN recovery time greater than 520 ms). While recovery time was profoundly abnormal (279.7 +/- 94 vs 7,284.8 +/- 10,454, p less than 0.001), the SNERP did not differ significantly between the groups (274.3 +/- 40 vs 286 +/- 42 ms at 500 ms, p = 0.5) and was normal at a range of 220 to 340 ms even in those patients with grossly impaired SN recovery (SNERP in patients with normal SN function: 210 to 360 ms at 500 ms). This study demonstrates that SN refractoriness in the transplanted human heart is shorter than previously reported in innervated controls and suggests that posttransplantation SN dysfunction is characterized by impaired automaticity rather than impaired refractoriness.

Adult↗
PubMed1991

Effect of stress hormones on transsplanchnic balance of exogenous amino acid in healthy man.

The effect of stress hormones on transsplanchnic balance of basal and infused amino acids (AA: Val,Met,Ile,Leu,Phe,Lys,His) was investigated in healthy men without and with added epinephrine (EPI) and dexamethasone (DEX). Concentrations of AA and blood glucose were measured in arterial and hepatic venous blood before and after primed-continuous (t = 120 minutes) AA infusion without (group I: controls; n = 6, 24 +/- 3 years), and with intravenous (IV) EPI infusion (group II: 6 micrograms/min, t = -75 to 120 minutes; n = 6, 26 +/- 5 years) or oral DEX pretreatment (group III: 6 mg/d for 2 days; n = 7, 26 +/- 3 years). In the absence of exogenous AA, EPI was demonstrated to increase estimated hepatic plasma flow (EHPF, mL/min: 1,019 +/- 133 [mean +/- SD] v 737 +/- 153; P less than .01), splanchnic output of glucose (SGO), and splanchnic uptake of total AA (nmol/kg.min: 4,657 +/- 2,014 v 2,802 +/- 704; P less than .05), of Gln (+78%) and of Gly (+100%). DEX did not affect EHPF or SGO, but doubled basal splanchnic AA uptake (5,446 +/- 3,635 nmol/kg.min) and increased that of Gln by 110%. Following AA administration, total splanchnic AA uptake was consistently increased (group I, 8,577 +/- 2,380; II, 8,957 +/- 3,714; III, 10,757 +/- 2,689 nmol/kg.min) as was splanchnic Gln uptake, both of which did not differ versus controls following EPI or DEX exposure. However, metabolic clearance rate (MCR, L/min) of infused AA was elevated by 40% (Met) to 85% (Leu) versus controls in subjects receiving EPI, but unchanged in those receiving oral DEX.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1991

Contribution of splanchnic and peripheral vascular tissues to the disposal of angiotensin-II and to regional conversion rates of angiotensin-I: a pilot study in humans.

The present study investigates angiotensin-II (A-II) balance across the splanchnic vascular bed and leg vascular tissues in humans, at baseline conditions and following a systemically ineffective femoral arterial angiotensin-I (A-I) infusion, both before and during inhibition of angiotensin-converting enzyme (ACE) with enalaprilat. In six healthy men, net regional A-II balance was calculated from the transfemoral or transsplanchnic arteriovenous differences in plasma concentrations and the corresponding regional plasma flow. Systemic and splanchnic hemodynamics remained unchanged throughout the trial, indicating an absence of major hemodynamic effects during A-I infusion or concomitant ACE inhibition. In contrast, regional leg plasma flow significantly decreased following A-I infusion (165.2 +/- 15.7 vs. 304.7 +/- 43.7; p less than 0.01) and again gradually returned to about baseline values after ACE inhibition. Baseline net transfemoral A-II balance was equilibrated at slight formation rates in four subjects and at minimal extraction rates in two of the six subjects. Following A-I infusion, a shift toward net femoral A-II formation (average increase 2,774% above baseline) was observed in all subjects (p less than 0.01). After concomitant ACE inhibition, femoral A-II balance again returned to baseline levels. Across the splanchnic vascular bed a net baseline. A-II extraction was observed in all subjects. Following A-I infusion an average increase by 285% (p less than 0.05) in splanchnic A-II extraction was observed. During concomitant ACE inhibition splanchnic A-II extraction tended to decrease toward baseline values in four subjects, and remained rather unchanged in two subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Demographic and perioperative factors associated with initial and prolonged sinus node dysfunction after orthotopic heart transplantation. The impact of ischemic time.

The etiology of sinus node (SN) dysfunction after orthotopic heart transplantation as assessed by the origin of rhythm, heart rate (HR), and, provided the origin of rhythm was sinus, by corrected sinus node recovery time (CSNRT) was studied in 50 patients. The possible influences on postoperative donor SN function of donor age, recipient age, underlying pretransplant heart disease, pretransplant amiodarone (AMIO) treatment, date of surgery, ischemic time, surgical technique of atrial incision, the use of different cardioplegic solutions during the study period, and rejection were evaluated. The results thus obtained indicate that SN dysfunction is common after cardiac transplantation and pinpoint to a different etiology of transient (restoration of normal SN function within 4 postoperative weeks) and persistent (SN function still impaired at 3 months) SN dysfunction. Of the several demographic and perioperative variables evaluated, only ischemic time had an influence on postoperative SN function in that ischemic times were significantly longer in patients with impaired SN function when compared with patients exhibiting normal SN function (148 +/- 39 min vs. 110.5 +/- 36 min, respectively, P = 0.001). Further stratification according to the duration of SN dysfunction revealed significantly longer ischemic times in patients with transiently impaired SN function only (156.3 +/- 35 min vs. 110.5 +/- 36 min, P = 0.0026). No relation to persistent SN dysfunction of ischemic time (130.5 +/- 36 min vs. 110.5 +/- 36 min, P = ns) or any other factor investigated was found.

Amiodarone↗