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S Gasic

Publications and source records attributed to S Gasic.

At least 19 recordsLinked to original sources
PubMed2001

Troglitazone is a competitive inhibitor of 3beta-hydroxysteroid dehydrogenase enzyme in the ovary.

OBJECTIVE: Troglitazone is a potent inhibitor of progesterone release from porcine granulosa cells. This is associated with a marked increase in pregnenolone secretion, implicating inhibition of the 3beta-hydroxysteroid dehydrogenase enzyme. This study determined whether troglitazone is a direct inhibitor of 3beta-hydroxysteroid dehydrogenase activity. STUDY DESIGN: Homogenates of porcine granulosa cells underwent classic enzyme kinetic analysis through Lineweaver-Burke and Dixon plotting. Human ovarian homogenates were also assayed for the effects of troglitazone on 3beta-hydroxysteroid dehydrogenase enzyme activity. Enzyme kinetics data were analyzed by the HyperKinetics software program. Analysis of variance was used to determine statistical significance for human ovarian homogenate experiments. RESULTS: In porcine granulosa cells Lineweaver-Burke analysis found that troglitazone inhibition of 3beta-hydroxysteroid dehydrogenase enzyme activity was competitive in nature, with 5 microg/mL troglitazone increasing the apparent Michaelis constant from 1.3 to 4.3 micromol/L (no change in maximum velocity). Dixon plot analysis demonstrated that the inhibition constant for troglitazone of 3beta-hydroxysteroid dehydrogenase is approximately 6.5 microg/mL, which is in the same order of magnitude as its therapeutic concentration in blood. Troglitazone also significantly decreased the activity of 3beta-hydroxysteroid dehydrogenase in homogenates of human ovarian tissue. CONCLUSION: We conclude that troglitazone can inhibit steroidogenesis in the ovary by direct competitive inhibition of 3beta-hydroxysteroid dehydrogenase.

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

Quantification of unconjugated metanephrines in human plasma without interference by acetaminophen.

BACKGROUND: Pheochromocytoma is a rare cause of hypertension resulting from increased catecholamine secretion. We aimed to develop a method to measure unconjugated plasma normetanephrine (NMN) and metanephrine (MN) without interference from acetaminophen, a widely prescribed drug for headaches. METHODS: Plasma samples were obtained from 48 subjects (23 males, 25 females; mean age, 49 +/- 14 years; hypertension, n = 37) under resting conditions. Following extraction on solid-phase cation-exchange columns, unconjugated metanephrines were analyzed by HPLC with electrochemical detection and with 4-hydroxy-3-methoxybenzylamine as an internal standard. Catecholamines were measured by HPLC. RESULTS: The assays were linear up to 2000 pg for NMN and for MN. Intraassay imprecisions (CVs) were 4.7% for NMN and 7.0% for MN, and the interassay CV was 12% for both NMN and MN. The limit of detection was 11 fmol for NMN and 17 fmol for MN. Ingestion of acetaminophen or its addition to plasma did not interfere with the MN peaks. Plasma NMN and MN were positively correlated (r = 0.52 and 0.49, respectively; P <0.01 for both) with the respective catecholamines. Plasma NMN (r = 0.27; P = 0.02) but not MN positively correlated with age, whereas only plasma catecholamines (and not metanephrines) were positively correlated (P <0.05) with diastolic blood pressure. CONCLUSIONS: This sensitive MN assay is not affected by simultaneous acetaminophen medication, and reveals a correlation of metanephrines with plasma and urinary catecholamines and age but not with blood pressure.

Acetaminophen↗
PubMed2000

Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma.

BACKGROUND: Recently, measurement of plasma metanephrines was suggested to improve the detection of pheochromocytoma compared with the other common biochemical tests. OBJECTIVE: To examine the diagnostic precision of measurements of plasma metanephrines, plasma catecholamines, and urinary catecholamines and to assess their variability. METHODS: Plasma metanephrine as well as plasma and urinary catecholamine concentrations were measured by high-performance liquid chromatography with electrochemical detection. Before surgery, responses of plasma metanephrines and catecholamines to change of posture were determined. Intraoperatively, metanephrines and catecholamines were measured before skin incision, during maximal mechanical tumor manipulation, and repetitively after the tumor was separated from the circulation. Patients were reexamined 1 and 3 months after surgery. Patients with pheochromocytoma (n = 17) and with histologically proved other adrenal tumors (n = 14) were studied before, during, and after surgery. RESULTS: Measurement of plasma metanephrines and plasma and urinary catecholamines provided 100% and 82% sensitivity, respectively, for the detection of pheochromocytoma (P<.001). Levels of plasma catecholamines but not metanephrines increased in response to change of posture (norepinephrine, P =.03; epinephrine, P =.07) and intraoperative stress (norepinephrine, P =.002; epinephrine, P =.009). CONCLUSIONS: Plasma metanephrines offer improved efficacy for the diagnosis of pheochromocytoma. Less variability in response to external factors may favor plasma metanephrines in the screening for this disease. Arch Intern Med. 2000;160:2957-2963

Adrenal Gland Neoplasms↗
PubMed2000

Polypyrimidine tract-binding protein-associated splicing factor is a negative regulator of transcriptional activity of the porcine p450scc insulin-like growth factor response element.

The porcine P-450 cholesterol side-chain cleavage enzyme gene (P450scc) contains a 30-bp region [insulin-like growth factor response element (IGFRE)] that mediates insulin-like growth factor I (IGF-I)-stimulated gene expression and binds Sp1. In this study, we showed that polypyrimidine tract-binding protein (PTB)-associated splicing factor (PSF), an RNA-binding component of spliceosomes, binds to the IGFRE. Southwestern analysis with an IGFRE oligonucleotide showed that a protein (from Sp1-immunodepleted HeLa extract) fractionated on SDS-PAGE at 100 kDa. Microsequence analysis of 100-kDa band HeLa proteins detected PSF. DNA affinity chromatography, using an IGFRE mutant oligonucleotide that does not bind Sp1, isolated a protein that immunoreacted with PSF antibody. Deoxyribonuclease I (DNase I) footprint analysis showed recombinant PSF binds 5' of the Sp1-binding GC box of the IGFRE, and mutant oligonucleotides further delineated this region to a palindrome, CTGAGTC. Functional analysis of these mutants by transfection experiments in a cell line overexpressing the IGF-I receptor (NWTb3) found that an inability to bind PSF significantly increased the IGFRE transcriptional activity, while retaining responsiveness to IGF-I. Moreover, transfection of expression vectors for Sp1 and PSF in porcine granulosa cells found that Sp1 expression stimulated IGFRE transcriptional activity while PSF inhibited activity even with coexpression of Sp1. In conclusion, we identified PSF as an independent, inhibitory regulator of the transcriptional activity of the porcine P450scc IGFRE.

Animals↗
PubMed1999

Tumor necrosis factor alpha stimulates lipolysis in adipocytes by decreasing Gi protein concentrations.

Prolonged treatment (12-24 h) of adipocytes with tumor necrosis factor alpha (TNFalpha) stimulates lipolysis. We have investigated the hypothesis that TNFalpha stimulates lipolysis by blocking the action of endogenous adenosine. Adipocytes were incubated for 48 h with TNFalpha, and lipolysis was measured in the absence or presence of adenosine deaminase. Without adenosine deaminase, the rate of glycerol release was 2-3-fold higher in the TNFalpha-treated cells, but with adenosine deaminase lipolysis increased in the controls to approximately that in the TNFalpha-treated cells. This suggests that TNFalpha blocks adenosine release or prevents its antilipolytic effect. Both N6-phenylisopropyl adenosine and nicotinic acid were less potent and efficacious inhibitors of lipolysis in treated cells. A decrease in the concentration of alpha-subunits of all three Gi subtypes was detected by Western blotting without a change in Gs proteins or beta-subunits. Gi2alpha was about 50% of control, whereas Gi1alpha and Gi3alpha were about 20 and 40% of control values, respectively. The time course of Gi down-regulation correlated with the stimulation of lipolysis. Furthermore, down-regulation of Gi by an alternative approach (prolonged incubation with N6-phenylisopropyl adenosine) stimulated lipolysis. These findings indicate that TNFalpha stimulates lipolysis by blunting endogenous inhibition of lipolysis. The mechanism appears to be a Gi protein down-regulation.

Adipocytes↗
PubMed1999

Fosinopril decreases levels of soluble vascular cell adhesion molecule-1 in borderline hypertensive type II diabetic patients with microalbuminuria.

Angiotensin converting enzyme inhibitors (ACE-I) are a mainstay for the treatment of heart failure, and of diabetic microalbuminuria. Recently ACE-I have been found to decrease plasma levels of circulating vascular cell adhesion molecule-1 (cVCAM-1) in patients with congestive heart failure. As increased cVCAM-1 levels are pathognomonic for diabetics with microangiopathy, we investigated the effects of ACE-I on plasma levels of cVCAM-1, intercellular adhesion molecule (cICAM-1), and cE-selectin in microalbuminuric diabetics. In addition, the effects of ACE-I on plasma levels of plasminogen activator inhibitor (PAI-1) and of tissue plasminogen activator (TPA) were studied. Fosinopril (10 mg/day) was administered over 12 weeks to 11 microalbuminuric patients with non-insulin-dependent diabetes mellitus (NIDDM). As expected, baseline plasma concentrations of cE-selectin, cICAM-1, and cVCAM-1 were markedly higher in patients than in healthy control subjects (n = 82; P < .001). PAI-1 levels in NIDDM were similar to those in control subjects, whereas TPA levels were about 25% lower in patients than in control subjects (P = .013). Serum levels of cVCAM-1 decreased by -19% (CI: -25% to -13%) after treatment with fosinopril (P = .003) and were no longer different from those of the control group. In contrast, plasma levels of cE-selectin, cICAM-1, PAI-1, and TPA were unaffected. As expected microalbuminuria decreased by -44% (CI: -65 to -22; P = .004). In conclusion, fosinopril lowered cVCAM-1 levels along with microalbuminuria in NIDDM. This may represent a novel mechanism of action of ACE-I in diabetes-associated endothelial dysfunction. Whether decreased VCAM-1 expression is responsible for the observed reduction in microalbuminuria, deserves further investigation.

Adult↗
PubMed1999

Alterations in angiotensin II release and vascular reactivity in hypertensive men: a pilot study.

Cold- and insulin-mediated release of angiotensin II (AII) and endothelin-1 (ET-1), as well as vascular reactivity to exogenous ET-1 and to insulin, were compared in hypertensive and normotensive subjects. Peripheral vascular release of AII and of ET-1 was investigated in 10 hypertensive (H; 29.2+/-5.8 years) and 12 normotensive (N; 29.1+/-4.6 years) men in two separate trials. Net transfemoral balance of AII and of ET-1 was calculated from the respective Arterio-Venous (A-V) differences in plasma concentrations (PC) of the peptides and the regional plasma flow (indocyanine-green dye method), both at baseline conditions and after a cold stimulus (immersion of one hand into ice water) in 7H and 6N, or during short-time hyperinsulinemia (hyperinsulinemic euglycemic clamp: biosynthetic human insulin, 1 mU/kg/min) in 7H and 7N. Moreover, hemodynamic changes to sequential exogenous ET-1 infusion (1, 2.5, 5, 10, 20, 40 ng/min) or during hyperinsulinemic clamp were studied in 7H and 6N and 7H and 7N, respectively. Baseline net-transfemoral balance of ET-1 and of AII were similar in the two subject groups. The cold stimulus provoked a similar increase in transfemoral ET-1 release in H and N (H: 257.0+/-31.7 to 526.2+/-393.7 pg/min; N: 280.2+/-112.7 to 524.0+/-393.7 pg/min, mean +/- SD, P<.05). In contrast, the cold-induced increase in transfemoral AII release was somewhat more pronounced in H than in N (H: 162.2+/-304.6 to 1081.7+/-1037.7 pg/ min, P<.05; N: 83.9+/-166.3 to 317.6+/-187.8 pg/ min, P<.02; maximum value H v. N P<.05). During the hyperinsulinemic clamp the PC of insulin increased from 5.8+/-2.8 to 69.1+/-15.5 microU/ mL in H and from 4.6+/-1.7 to 67.5+/-9,5 microU/mL in N; P<.0005. Hyperinsulinemia induced a similar elevation of norepinephrine PC in H and N, but an increase in transfemoral ET-1 release in N only (219.7+/-161.2 to 512.2+/-279.0 pg/min, P<.02). In contrast, hyperinsulinemia increased transfemoral AII formation in H (730.4+/-554.3 to 1088.6+/-597.9 pg/min, P<.05), but not in N. Insulin-mediated vasodilation was observed only in N, whereas ET-1-induced vasoconstriction was blunted in H. We conclude that the cold-induced increase in peripheral vascular release of AII is more pronounced in H than in N, whereas insulin provokes an increase in AII formation in hypertensives only. Moreover, insulin-mediated vasodilation and ET-1-dependent vasoconstriction are blunted in hypertensive subjects.

Adult↗
PubMed1998

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↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1996

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↗
PubMed1996

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↗
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↗