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Biomedical subjects

J Segal

Publications and source records attributed to J Segal.

At least 73 records · Page 4Linked to original sources
PubMed1989

3,5,3'-Triiodothyronine increases cellular adenosine 3',5'-monophosphate concentration and sugar uptake in rat thymocytes by stimulating adenylate cyclase activity: studies with the adenylate cyclase inhibitor MDL 12330A.

We have previously demonstrated that T3 increases adenylate cyclase activity in preparations of plasma membranes from rat thymocytes. On the basis of this and other evidence, we have postulated that the increased cAMP concentration and consequent increase in 2-deoxyglucose (dGlc) uptake that T3 induces in the intact thymocyte is the consequence of a similar stimulation of adenylate cyclase activity. To obtain further evidence to this point, we have now conducted experiments with MDL 12330A [N-(cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride], a compound that inhibits adenylate cyclase activity in several other tissues. In thymocyte plasma membrane preparations, MDL 12330A induced a concentration-dependent inhibition of both basal enzyme activity (activity in the absence of hormone) and the increase in activity induced by T3 and epinephrine. In the intact thymocyte, MDL 12330A greatly limited the marked increase in cellular cAMP concentration induced by maximally effective concentrations of the phosphodiesterase inhibitor 3'-isobutyl-1'-methylxanthine. This indicates that MDL 12330A inhibits adenylate cyclase activity in the intact thymocyte as it does in thymocyte plasma membrane preparations. Further, in intact thymocytes incubated with MDL 12330A, there occurred small but significant decreases in basal cAMP concentration and dGlc uptake, and the T3-induced enhancement of these functions was reduced or abolished. These data provide additional evidence that the increase in dGlc uptake in rat thymocytes that T3 induces is linked to an antecedent increase in cellular cAMP concentration, and that the latter results from a T3-induced enhancement of adenylate cyclase activity.

1-Methyl-3-isobutylxanthine↗
PubMed1989

A rapid, extranuclear effect of 3,5,3'-triiodothyronine on sugar uptake by several tissues in the rat in vivo. Evidence for a physiological role for the thyroid hormone action at the level of the plasma membrane.

T3 produced a prompt and biphasic change in the uptake of 2-deoxy-D-glucose (dGlc) by atria, ventricles, diaphragm, and fat in the rat in vivo. At the lower physiological doses T3 produced a dose-related increase in tissue dGlc uptake; the lowest effective concentration was 5-10 ng/100 g BW, and maximal effect of about 75-100% increase above control values was seen at a T3 dose of 25 (diaphragm) or 100 ng. At pharmacological doses of 5 and 50 micrograms/100 g BW T3 inhibited dGlc uptake by about 50%. Evaluation of the physiological related stimulatory effect of T3 on dGlc uptake in the four tissues revealed that it was independent of new protein synthesis, because it was not inhibited by cycloheximide which blocked [3H]leucine incorporation by more than 95%, and that it was thyroid hormone specific, as judged from the order of potency of several T3 analogs: 3'-isopropyl-L-T2 greater than or equal to L-T3 greater than L-T4 = D-T3 greater than D-T4; L-rT3, 3,5-L-T2, and DL-thyronine were without effect. Additional studies demonstrated that in the four tissues employed T3 acted to promote sugar uptake by increasing the activity of the sugar transport system located at the plasma membrane. The present study together with previous in vitro and in vivo studies, in the same and other tissues, provide a strong evidence in support of a physiological role for the action of thyroid hormone at the level of the plasma membrane to increase cellular sugar uptake.

Adipose Tissue↗
PubMed1989

Action of the thyroid hormone at the level of the plasma membrane.

In this presentation, I present evidence indicating a direct action of thyroid hormone at the level of the plasma membrane. Characteristically, the plasma membrane-mediated effects of thyroid hormones are prompt in onset, independent of new protein synthesis, and are associated with changes in the transmembrane transport of ions and substrates. The presence of specific binding sites for thyroid hormone in plasma membrane of various tissues and species, although inconclusive in itself, provides additional support for the direct action of thyroid hormone on the plasma membrane. A model for the mechanism of action of thyroid hormone at the plasma membrane level to increase sugar uptake by rat thymocytes is delineated, and the physiological role of the plasma membrane-mediated action of thyroid hormone is discussed.

Animals↗
PubMed1988

Biphasic stimulation of cellular calcium concentration by 3,5,3'-triiodothyronine in rat thymocytes.

3,5,3'-Triiodothyronine (T3) produced a rapid and transient increase in 45Ca uptake and cytoplasmic free calcium concentration in rat thymocytes, which is the most rapid effect of T3 in this system. This effect was manifested in cells suspended in medium containing 1 mM calcium. The T3 effect on 45Ca uptake was evident at 15-30 s, reached maximum at 30-60 s, and returned to control values at 5 min. The T3 effect on cytoplasmic free calcium concentration was seen after 30 s, reached maximum at 7 min, and returned to control values after 24 min. In cells suspended in Ca2+-free medium, T3 produced a similar rapid increase in 45Ca uptake, which was sustained for at least 60 min, but T3 failed to change cytoplasmic free calcium concentration. Alprenolol (10 microM) blocked the stimulatory effects of T3 on these two functions in a similar fashion. From these results, I suggest that in rat thymocytes T3 influences cellular calcium economy through a biphasic mechanism in which T3 first increases calcium uptake which, in turn, is followed by a release of calcium from intracellular pool(s), resulting in a further increase in cytoplasmic free calcium concentration and the activation of Ca2+ -regulated systems. Moreover, the present study provides further support for the postulate that in the rat thymocyte calcium serves as the first messenger for the plasma membrane-mediated stimulatory effects of T3 on several metabolic functions.

Alprenolol↗
PubMed1988

Hormonal evaluation and autoimmune background in pruritic urticarial papules and plaques of pregnancy.

There is little insight into the pathogenesis of most of the dermatoses specifically associated with pregnancy. We evaluated the hormonal profile and the autoimmune background in 11 pregnant women with pruritic urticarial papules and plaques of pregnancy. No statistically significant difference was found between the serum levels of the beta-subunit of human chorionic gonadotropin, estradiol, cortisol, and urinary estriol of the patients and gestational age-matched control subjects. No autoantibodies were found in the patients' group. We conclude that patients with pruritic urticarial papules and plaques of pregnancy have no hormonal alterations when compared with normal pregnant women and that no known major autoimmune background plays a part in the pathogenesis of the disease.

Adult↗
PubMed1988

Aging: a non-regulated process.

Aging is a non-regulated process. This perspective on aging derives primarily from the observation that all known regulated systems are subjected to aberration, whereas aging, and its ultimate phase death, is not. Moreover, within the same species, the cause of death of an individual varies widely, which again bespeaks against a regulatory mechanism. Rejuvenation, the antidote to aging and the essence of immortality, is exercised in the lowest animals, such as protozoa, but is suppressed in the developed animal, including man, where aging is irreversible and death is inevitable. Also introduced is the exhaustion theory for the process of aging which predicts that with advancing age there occur a progressive accumulation of metabolic-derived insults which act to gradually exhaust (age) the biological systems, and consequently cause the animal's death.

Aging↗
PubMed1988

Adrenergic inhibition of the stimulatory effect of 3,5,3'-triiodothyronine on calcium accumulation and cytoplasmic free calcium concentration in rat thymocytes. Further evidence in support of the concept that calcium serves as the first messenger for the prompt action of thyroid hormone.

Thyroid hormone produces a prompt, plasma membrane-mediated increase in several metabolic functions in the rat thymocyte. These effects of thyroid hormone require calcium and are inhibited by the beta-adrenergic antagonist alprenolol. In the present study, the interrelationship between thyroid hormone and adrenergic agents, and the concept that calcium serves as the first messenger for the rapid action of thyroid hormone in the rat thymocyte are further examined. T3 produced a very rapid and dose-related increase in both 45 calcium accumulation and cytoplasmic free calcium concentration. These effects of T3, like its other calcium-dependent and prompt effects, were inhibited by beta-, but not by alpha-, adrenergic antagonists. Studies with selective beta-adrenergic agents revealed that the inhibitory effect was beta-1 in nature. In addition, beta-adrenergic agonists were found to promote additively T3 action, possibly through their beta-2 activity. Hence, the present study provides further support for the concept that calcium serves as the first messenger in the rapid, plasma membrane-mediated action of thyroid hormone in the rat thymocyte.

Adrenergic alpha-Antagonists↗
PubMed1988

Effect of hypothyroidism on the in-vivo and in-vitro uptake of sugar by rat thymocytes and on the stimulatory response to 3,5,3'-tri-L-iodothyronine.

We have previously demonstrated, both in vivo and in vitro, that 3,5,3'-tri-L-iodothyronine (T3) increases the uptake of the glucose analogue 2-deoxy-D-glucose (2-DG) in rat thymocytes by acting at the level of the plasma membrane. In the present study, the effect of hypothyroidism on the basal uptake of 2-DG by rat thymocytes and their response to T3 was examined. Rats were rendered hypothyroid by thyroidectomy at 21 days of age, and experiments performed with 31- and 56-day-old animals. Uptake of 2-DG by thymocytes from hypothyroid rats, both in vivo and in vitro, was greater in 31-day-old animals and less in 56-day-old animals than that in euthyroid rats. In both age-groups, hypothyroidism increased cellular responsiveness to T3, shifting the dose-response curve to the left. Similar results were obtained in experiments in which animals were rendered hypothyroid by KCIO4. Injection of thyroid hormones into rats treated with KCIO4 reversed the effects of hypothyroidism on uptake of [3H]2-DG by thymocytes and their response to T3. From these observations it was concluded that hypothyroidism produces a time-dependent change in basal sugar uptake by rat thymocytes, and increases cellular responsiveness to the effect of T3 at the level of the plasma membrane.

Animals↗
PubMed1987

The effect of trypsin on sugar uptake in rat thymocytes. Modulation of cellular cyclic AMP concentration and the sugar-transport system.

I have shown that cyclic AMP stimulates sugar uptake in rat thymocytes. However, trypsin treatment, which increases rat thymocyte cyclic AMP concentration, fails to increase sugar uptake. The purpose of the present study is to examine this seeming inconsistency, and to evaluate further the function of trypsin. Mild trypsin treatment of rat thymocytes produced a dose-related increase in cellular cyclic AMP concentration. Trypsin produced the same proportionate increase in cyclic AMP concentration in the presence or absence of optimal concentrations of the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine, which suggests that trypsin acts to increase thymocyte cyclic AMP concentration by stimulating adenylate cyclase activity. Trypsin at concentrations of 0.3 mg/ml and less had no effect on the uptake of the glucose analogue 2-deoxy-D-glucose (2-DG), whereas at concentrations of 1 mg/ml and higher trypsin produced a small, dose-related, decrease in basal 2-DG uptake, becoming significantly lower than control values only at 5 mg/ml (-22.7%, P less than 0.05). Thymocyte sugar transporters, characterized by means of cytochalasin B binding, consist of a single class of sites with an apparent KD of 0.15 microM and maximum binding capacity of 2.73 pmol/20 x 10(6) cells (8.4 x 10(4) sites/thymocyte). Trypsin produced a dose-related decrease in the sugar-displaceable binding of cytochalasin B, so that at 5 mg of trypsin/ml the number of sugar transporters was decreased by approx. 50%. Thus trypsin treatment of rat thymocytes on the one hand increases cellular cyclic AMP concentration, which itself potentiates 2-DG uptake, and on the other hand decreases the number of sugar transporters, which itself decreases cellular sugar uptake, indicating that the apparent effect of trypsin on thymocyte 2-DG uptake is the result of the balance of its effects on these two systems.

Animals↗
PubMed1987

When should Doppler-determined valve area be better than the Gorlin formula?: Variation in hydraulic constants in low flow states.

In low flow states, underestimation errors occur when the Gorlin formula is used to calculate valve area. A model of valvular stenosis designed to examine changes in the hydraulic discharge coefficient (Cd) and coefficient of orifice contraction (Cc) may explain these errors. Unsteady flow was examined in a pulsatile pump model and in a dog model. Valve areas were calculated from pressure and flow data using: a modified form of the Gorlin formula (assuming constant values for Cd and Cc) and a corrected formula (with values of Cd and Cc obtained from steady state data). Valve area was also calculated using the continuity equation with velocity and flow data (constant Cc). Flow velocities were measured using a newly designed ultrasound Doppler catheter capable of resolving flow velocities of up to 5.5 m/s. Both the corrected formula and continuity equation were highly predictive of actual valve area (r = 0.99, slope or M = 0.96 and r = 0.99, M = 1.06, respectively). The modified Gorlin equation was less accurate and tended to underestimate valve areas (r = 0.87, M = 0.83). This underestimation was most notable at low rates of flow (Gorlin: r = 0.94, M = 0.53; continuity: r = 0.93, M = 0.81 and r = 0.94, M = 0.89, respectively) more accurately than the modified Gorlin formula (r = 0.69, M = 0.49). In patients with low cardiac output, hemodynamic formulas, such as the Gorlin formula, which assume a constant value for the hydraulic discharge coefficient (Cd), may be less accurate than formulas using either a corrected value of Cd or Doppler-determined flow velocity and mean systolic flow.

Animals↗
PubMed1987

Opposite regulatory effects of cAMP and cGMP on sugar uptake in rat thymocytes.

The present study provides several lines of evidence which indicate that in the rat thymocyte adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5-cyclic monophosphate (cGMP) induce opposing regulatory effects on 2-deoxyglucose (2-DG) uptake; cAMP is stimulatory, whereas cGMP is inhibitory. First, the cyclic nucleotide analogues dibutyryl cAMP (dBcAMP) and dibutyryl cGMP (dBcGMP) produced a dose-related increase and decrease in thymocyte 2-DG uptake, respectively. Second, 3,5,3'-triiodo-L-thyronine (T3) and epinephrine, which increased cellular cAMP concentration but had no effect on cellular cGMP concentration, increased 2-DG uptake in the rat thymocyte. Third, dBcGMP inhibited the stimulatory effects of dBcAMP, T3, and epinephrine on thymocyte 2-DG uptake. Fourth, prostaglandin E1 and the inhibitors of the cyclic nucleotide phosphodiesterases, 3-isobutyl-1-methylxanthine, theophylline, and caffeine, all increased both cellular cAMP and cGMP concentration but had no effect on 2-DG uptake. Insulin did not change cellular cAMP and cGMP concentration, but produced a dose-related increase in 2-DG uptake by the rat thymocyte. From these results I have concluded that in the rat thymocyte cAMP and cGMP produce opposite effects on sugar uptake and that the effect of certain, but not all, agents on thymocyte sugar uptake results from their modulation of cellular cAMP and cGMP concentration.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Trypsin-induced increase in cyclic AMP concentration in rat thymocytes. An effect independent of calcium and calmodulin.

Trypsin produces a dose-related increase in cellular cyclic AMP concentration in rat thymocytes [Shneyour, Patt & Trainin (1976) J. Immunol. 117, 2143-2149; Segal & Ingbar (1983) Clin. Res. 31, 277A]. In the present study, I examined whether this effect of trypsin requires Ca2+ and whether it is modified by calmodulin. In fresh thymocytes suspended in standard medium (containing 1 mM-Ca2+), trypsin produced a concentration-dependent increase in cytoplasmic free Ca2+ concentration, which was evident at a concentration of 50 micrograms of trypsin/ml and reached maximal values at about 1 mg/ml. This effect of trypsin was very prompt in onset, almost immediate, and reached maximal values within 2-3 min. But in cells suspended in essentially Ca2+-free medium (6 nM free Ca2+), trypsin had no effect on cytoplasmic free Ca2+ concentration, which indicates that trypsin acted by increasing Ca2+ uptake rather than Ca2+ release from an intracellular pool. However, the increase in thymocyte cyclic AMP concentration produced by trypsin was independent of extracellular Ca2+ and was not influenced by calmodulin, because it was the same in the presence or absence of Ca2+ and was not changed by the calmodulin inhibitor trifluoperazine. I therefore suggest that in rat thymocytes the trypsin-induced increase in cyclic AMP concentration does not require Ca2+ and is not influenced by calmodulin.

Adenylyl Cyclases↗
PubMed1986

Lanthanum increases the rat thymocyte cytoplasmic free calcium concentration by enhancing calcium influx.

In the present study, I have examined the effect of lanthanum (La3+) on cytoplasmic free calcium concentration in isolated rat thymocytes employing the quin2 technique. As with its effect on 15Ca accumulation in rat thymocytes (Segal, J. and Ingbar, S.H. (1984) Endocrinology, 115, 160-166), La3+ produced a concentration-related increase in thymocyte cytoplasmic free calcium concentration. This effect of La3+ was very prompt in onset, evident within about 30 s from the time of addition of La3+. The lowest effective concentration of La3+ was 6 microM (+22.7% above control), and it increased progressively to reach maximal values at 25 microM (+100% above control). La3+ added to quin2-loaded thymocytes suspended in a calcium-free medium was without effect. In addition, La3+ had no significant effect on 45Ca efflux, and La3+ did not inhibit calcium-ATPase activity in the rat thymocytes. These results demonstrate that in rat thymocytes La3+ increases cytoplasmic free calcium concentration by increasing the extracellular calcium influx into the cell rather than the release of calcium from an intracellular pool.

Aminoquinolines↗
PubMed1986

Selective osmoreceptor dysfunction presenting as intermittent hypernatremia following surgery for a pituitary chromophobe adenoma.

Intermittent hypernatremia following hypothalamic surgery or trauma is usually attributed to the triphasic dysfunction of vasopressin release (diabetes insipidus, inappropriate vasopressin release, and diabetes insipidus). A 39-year-old patient had hypodipsia and intermittent hypernatremia following hypothalamic surgery for a chromophobe adenoma. Mean arterial pressure fell by 25 percent during orthostasis testing and was associated with an increase in vasopressin levels from 1.3 microU/ml to 12 microU/ml. Plasma renin activity and aldosterone increased from 1.1 to 16 ng/ml per hour and from 6.7 to 39 ng/dl, respectively, and remained elevated for three and a half hours after tilt testing. Hypertonic saline infusion, on the other hand, increased serum osmolality from 290 to 304 mOsm/kg but did not result in a significant rise in vasopressin levels (all were less than 1 microU/ml). These results are consistent with a selective dysfunction of the osmoreceptor pathways of vasopressin release and intact volume receptor-mediated pathways. Patients with intermittent hypernatremia following hypothalamic surgery or trauma should be questioned specifically regarding thirst. If it is impaired or absent, these patients should be watched carefully, not only for the development of triphasic dysfunction of vasopressin release, but also for a selective osmoreceptor dysfunction associated with thirst deficits as found in patients with "essential hypernatremia."

Adult↗
PubMed1986

Studies on the age-related decline in the response of lymphoid cells to mitogens: measurements of concanavalin A binding and stimulation of calcium and sugar uptake in thymocytes from rats of varying ages.

We have previously demonstrated that mitogenic response of rat thymocytes to concanavalin A (Con A) declines with age (Segal, Troen and Ingbar, Thymus, in press). To elucidate the mechanism underlying this process, we have examined the effect of age on Con A binding and stimulation of calcium and sugar uptake in thymocytes from rats varying in age from 10 to 360 days. Binding of Con A by thymocytes remained unchanged with advancing age. Basal uptake of the glucose analogue 2-[3H]deoxyglucose (2-DG) by rat thymocytes declined with age, becoming significantly lower than maximal values (26 days) at 4 months of age. While the proportionate increase in thymocyte 2-DG uptake produced by Con A remained essentially unchanged. However, because of the decline in basal 2-DG uptake, total uptake of 2-DG in the presence of Con A decreased with age becoming significantly lower than maximal values at 4 months. Basal calcium-45 uptake by thymocytes was practically the same in all the age-groups studied, except at 21 days, where, as with basal 2-DG uptake, it was markedly smaller, But the stimulatory effect of Con A on 45Ca uptake declined progressively with age and was nil at 360 days. From these observations I suggest that the age-related decline in the responsiveness of rat thymocytes to Con A does not result from a change in the binding of Con A by the lymphoid cell, but from, at least in part, a decrease in its cellular stimulation of calcium and sugar uptake.

Aging↗
PubMed1986

Adverse reactions to antihypertensive drugs in pregnancy.

In conclusion from a clinical pharmacological point of view it is stressed that side effects from antihypertensive therapy in part is related to dosage. Increased knowledge should make it possible to reduce the rate of side effects. In the individual case the physician always has to compare a number of factors: general condition of the patient, age, adherence to the prescribed therapy, side effects, and other factors in addition to blood pressure values. With all these limitations in mind there is agreement that the benefit of antihypertensive therapy far out-weigh the negative aspects of such treatment.

Antihypertensive Agents↗