[GABA--the basic mediator of excitation in the early stages of hippocampal development]. / GAMK--osnovnoi mediator vozbuzhdeniia na rannikh étapakh razvitiia gippokampa.

GABA is the principal neurotransmitter of inhibition in the adult mammalian brain. However, at early stages of development, including embryonic period and first week of postnatal life, GABA plays the role of main neurotransmitter of excitation. The paradoxical excitatory effect of GABA is due to an inversed chloride gradient and therefore a depolarizing direction of GABA-A receptor mediated responses. In addition, another type of GABAergic inhibition mediated by postsynaptic GABA-B receptors is not functional at early stage of life. In the neonatal rat hippocampus, GABA, acting via GABA-A receptors, activates voltage gated sodium and calcium channels and potentiates the activity of NMDA receptors by reducing their voltage dependent Mg2+ block. The temporal window when GABA exerts excitatory actions coincides with a particular pattern of activity of hippocampal neuronal network that is characterized by periodical giant depolarizing potentials (GDPs) reminiscent of interictal-like epileptiform discharges. Recent studies have shown that GDPs result from the synchronous discharge of GABAergic interneurons and principal glutamatergic pyramidal cells and are mediated by the synergistic excitatory actions of GABA-A and glutamate receptors. GDPs provide synchronous intracellular Ca2+ oscillations and may therefore be implicated in hebbian modulation of developing synapses and activity-dependent formation of the hippocampal network.

c-jun and multistage carcinogenesis: association of overexpression of introduced c-jun with progression toward a neoplastic endpoint in mouse JB6 cells sensitive to tumor promoter-induced transformation.

Tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF) induce neoplastic transformation, elevated c-jun protein expression, and activator protein-1 (AP-1)-dependent gene expression in JB6 mouse epidermal cells sensitive to tumor promoters (clone 415a P+ cells). In contrast, JB6 cells resistant to tumor promoter-induced transformation (clone 307b P- cells) exhibit a greatly reduced TPA or EGF inducible c-jun expression and AP-1 activity. We have recently shown that induced AP-1 is necessary for tumor promoter-induced transformation of P+ cells because introduction of a dominant negative c-jun mutant into P+ cells inhibits both AP-1 dependent transactivation and the transformation response to tumor promoter. The intent of the investigation presented here was to test the hypothesis that elevation of AP-1 activity is sufficient to cause progression to the P+ phenotype in P- cells or to the transformed phenotype in P+ cells. Clonally derived P+ and P- recipient cells transfected with a human c-jun expression construct and overexpressing c-jun protein were tested for progression by assaying for constitutive or inducible anchorage independent phenotype and nude-mouse tumorigenicity. Overexpression of c-jun did not produce progression in P- cells but did increase the probability of progression in P+ cells (two of five transfectant cell lines progressed to the tumor phenotype). In addition, c-jun overexpression did not increase AP-1 activity in any of the P-/c-jun transfectants or in the two of five P+/c-jun transfectants that acquired the transformed phenotype. The P+/c-jun transfectants that showed elevated AP-1 activity did not progress to the tumor phenotype, demonstrating that an increase in AP-1 activity is insufficient for this progression. Since P(+)-to-tumor phenotype progression occurred in cells overexpressing c-jun but not AP-1, we propose that P(+)-to-transformed phenotype progression is c-jun dependent and AP-1 independent.

Left ventricular dynamics during strenuous isometric exercise in marathon runners, weight lifters and healthy sedentary men: comparative echocardiographic study.

Global and segmental left ventricular dynamics during strenuous large-muscle isometric exercise were compared between endurance and static type professional athletes and sedentary men. Using a trunk dynamometer and supine echocardiography, only the weight lifters manifested increased (p < 0.01) wall thickness during both diastole and systole, resulting in decreased left ventricular volume at end systole. These group-related differences would suggest a causal relationship between chronic intensive weight-lifting training and efficient myocardial dynamics at the time of strenuous isometric exercise.

Usefulness of heavy isometric exercise echocardiography for assessing left ventricular wall motion patterns late (> or = 6 months) after acute myocardial infarction.

The aim of this prospective study was to determine the effects of heavy isometric exercise on left ventricular (LV) wall motion patterns in patients who have had myocardial infarction, and to compare heavy isometric exercise with dynamic exercise for competence in eliciting LV wall motion abnormalities at equivalent rate-pressure products. Echocardiography was performed in 42 patients during supine bicycle ergometry and during heavy dynamometer stretching at 50% of maximal voluntary contraction. Systemic vascular resistance increased from 1,484 to 1,649 dynes s cm-5 (p < 0.05) during isometric exercise, and decreased significantly during dynamic exercise. Wall motion abnormalities or new asynergy were induced by isometric exercise in 120 segments, 107 of which (89%) showed significant stenosis of the perfusing coronary artery. Hypokinesia was the dominant pattern in the range of 76 to 90% narrowing; akinesia was dominant at 91 to 100% narrowing. Wall motion abnormalities were also documented in 13 segments (11%) assumed to be supplied by vessels with nonsignificant stenosis. Dyskinesia, seen in 7% of the segments, was equally distributed between both groups with significant stenosis. Sensitivity and positive predictive value in identifying specific coronary vessel disease was similar for both isometric and dynamic exercise. In conclusion, heavy isometric exercise in patients who have had myocardial infarction induces wall motion abnormalities of a severity proportional to the degree of coronary narrowing. This exercise method is similar to dynamic exercise for ability in identifying obstructions in a specific vessel. Furthermore, when compared at near-equal rate-pressure products, heavy isometric exercise is far superior in sensitivity to dynamic exercise.

Doppler-derived aortic flow measurements during and after heavy isometric exercise in healthy men versus men with myocardial infarction.

Doppler echocardiography is a useful noninvasive determination of left ventricular function during dynamic exercise. Scarce data are available for the use of this technique during heavy isometric exercise. Therefore, Doppler-derived aortic flow indexes were assessed during and after 50% maximal upper-body isometric exercise in 25 healthy men (aged 47 +/- 6 years) and compared with those of 22 men (aged 48 +/- 9 years) who had suffered myocardial infarction. The heart rate increased (p = 0.01) in each of the groups from a mean of 68 +/- 12 at rest to 84 +/- 11 during isometric exercise. At rest, systolic blood pressure was higher (p = 0.05) in the patients with coronary artery disease. During exercise, the patients with cardiac disease, compared with the healthy volunteers, demonstrated a lesser reduction in flow velocity integral, stroke volume, and cardiac indexes (p = 0.001). Immediately on recovery, the patients with cardiac disease, compared with the healthy group, showed significantly greater (p = 0.001) increase in stroke volume and cardiac indexes. At 3 minute's recovery, the stroke volume index continued to increase in the patients with cardiac disease, while the healthy group showed a decrease to below its resting value. Although 50% of maximal upper-body isometric exercise caused similar heart rate and systolic blood pressure responses in healthy patients and patients with cardiac disease, there were significant group differences in Doppler-derived left ventricular systolic function indexes, which were greatest on immediate and 3 minute's recovery. The results suggest that this novel isometric test may be useful in clinical testing.

Influence of ocular tropicamide on exercise testing.

This study was aimed to evaluate the effects of tropicamide 0.5% eye drops on cardiovascular parameters during exercise testing. The study group included 154 healthy subjects (mean age: 44.7 +/- 8 years). The subjects were divided into three groups according to the size of the pupils at the onset of exercise: A: pupils not dilated (n = 27), B: pupils partially dilated (n = 90) and C: pupils widely dilated (n = 37). They were compared to 66 healthy controls (age 43.8 +/- 8) who did not receive the drops. Rest and exercise parameters were affected in groups A and B, while the results of group C resembled those of the controls: (a) resting heart rate -66.7, 66.6, 70.9 and 69.3, respectively (p = 0.03); (b) heart rate at 50 and 100 W - 104, 107, 110 and 111 (p = 0.01) and 131, 131, 137, 139, respectively (p = 0.01); and (c) peak systolic blood pressure - 192, 186, 183, 175; respectively (p = 0.004). Reanalyzing the data by scoring of visual impairment gave identical results. As a whole, the study group achieved higher work loads than the controls (126 vs. 119 W; p = 0.03). We conclude that the instillation of ocular tropicamide has definite effects on cardiovascular parameters, both at rest and during exercise. Mainly, patients showed a lower heart rate at the initial levels of exercise. However, at symptom-limited level, tropicamide does not influence a patient's ability to achieve the target heart rate, and stress testing results are not altered by the drug.

Differential c-jun expression in response to tumor promoters in JB6 cells sensitive or resistant to neoplastic transformation.

The activity of AP-1, a trans-acting transcription factor, is stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF) in promotion-sensitive (P+) but not in promotion-resistant (P-) JB6 mouse epidermal cell lines. TPA and EGF also promote neoplastic transformation only in P+ cells. Thus, it has been proposed that AP-1-dependent gene expression is involved in determining sensitivity to tumor promotion. This paper explores the possible basis for the differential inducibility of AP-1 activity in P+ and P- JB6 cells, focusing in particular on the regulation of expression of the components of the AP-1 complex at the mRNA level. The expression of jun and fos gene family members, which make up the AP-1 complex, can be stimulated by serum and a number of growth factors, including EGF, and by TPA. Therefore, the possibility that differential expression of one or more forms of jun or fos contributes to the differential AP-1 activity was considered. The data presented here demonstrate both similarities and differences in the basal and TPA- or EGF-induced levels of fos and jun family members between P+ and P- cells. The most striking observation was that the overall TPA- and EGF-induced levels of jun but not fos expression were higher in P+ cells. This suggests that tumor promoter-regulated c-jun expression may contribute to the differential AP-1 activation observed in these cells and may be important in determining sensitivity to promotion of neoplastic transformation.

Pronounced reduction of aortic flow velocity and acceleration during heavy isometric exercise in coronary artery disease.

Doppler-derived parameters of aortic flow were examined during heavy isometric exercise in 48 men with coronary artery disease (CAD) and in 48 gender- and age-matched healthy controls. The aim was to determine which parameters best separated the groups and to look for a possible relation between exercise-induced Doppler patterns and the extent of CAD. Isometric exercise was performed with a 2-hand bar dynamometer, and the subjects were required to perform 50% of maximal voluntary contraction for 2 minutes. Examination was performed with a pulsed Doppler transducer positioned at the suprasternal notch. Resting peak flow velocity, acceleration time, stroke volume index and cardiac index did not show significant differences between the groups. However, mean acceleration and stroke work were significantly lower in patients with CAD. In this group, exercise peak flow velocity decreased from 98 +/- 13 to 55 +/- 12 cm/s, flow velocity integral from 14 +/- 3 to 7 +/- 3 cm, mean acceleration from 11 +/- 0.9 to 4.7 +/- 1 m/s/s, and stroke volume index from 41 +/- 6 to 23 +/- 4 ml/m2 (p less than 0.001 for all). Cardiac index decreased from 2.7 +/- 0.4 to 2 +/- 0.2 liters/min/m2 (p less than 0.05). Acceleration time increased from 82 +/- 6 to 116 +/- 7 ms. In most of the indexes, the directional changes induced by isometric exercise were similar in patients with CAD and in normal control subjects. The differences compared with the rest values were significantly greater in the CAD group, and especially in patients presenting with 3-vessel disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Gene regulation and genetic susceptibility to neoplastic transformation: AP-1 and p80 expression in JB6 cells.

The mouse epidermal JB6 cell system consists of clonal genetic variants that are sensitive (P+) or resistant (P-) to the promotion of neoplastic transformation by phorbol esters and other tumor-promoting agents. P+ cells display AP-1-dependent phorbol-ester-inducible transactivation of gene expression, whereas P- cells have a defect in transactivation. Transfection of promotion sensitivity gene pro-1 into P- cells reconstituted both P+ phenotype and AP-1-dependent phorbol-ester-inducible transactivation. P- and P+ cells exhibited induction of c-jun and c-fos messenger RNA levels by phorbol ester, but P- cells had significantly lower basal and induced levels of jun mRNA than P+ cells. Basal and induced levels of c-jun protein were significantly lower in P- cells as well. Differences in levels the 80-kDa pI 4.5 protein p80 were also observed in JB6 cells as a function of preneoplastic progression; high levels of p80 protein and mRNA were observed in P- cells, intermediate levels in P+ cells, and negligible levels were observed in transformed derivatives of JB6 cells. Phorbol ester treatment induced phosphorylation but not synthesis of p80. These data are consistent with the hypotheses that AP-1 is required in the signal transduction pathway for promotion of neoplastic transformation by tumor promoter, that pro genes may control AP-1 activity, that threshold levels of Jun mRNA and protein may play a role in transactivation and promotion sensitivity, and that the p80 protein in JB6 cells may behave in vivo as a suppressor of cellular transformation.

The effects of hormone replacement therapy in normal postmenopausal women: measurements of Doppler-derived parameters of aortic flow.

In this study the effects of hormone replacement therapy on cardiac function in healthy postmenopausal women were evaluated by Doppler echocardiography that was performed before (T1) and 2.5 months after the initiation of hormone replacement therapy (T2) in the peak estrogenic phase. The following parameters of aortic flow were measured: peak flow velocity, acceleration time, and ejection time. Additional parameters were calculated: flow velocity integral and mean acceleration. The study group included 24 postmenopausal women aged 43 to 60 years (mean 51.6 years). The control group consisted of 19 postmenopausal women aged 46 to 60 years (mean 53.5 years) who were not receiving hormone replacement therapy and who underwent the same evaluation. There were no changes in all Doppler parameters between T1 and T2 in the control group. However, in the study group there were significant increases in peak flow velocity (108.3 +/- 16.7 cm/sec at T1 vs 123 +/- 20.7 cm/sec at T2; p = 0.002), flow velocity integral (17.7 +/- 3.9 vs 21.5 +/- 4.7 cm; p = 0.0003), mean acceleration (11.5 +/- 1.9 vs 13.1 +/- 2.6 m/sec/sec; p = 0.001), and ejection time (324 +/- 37.6 vs 348.8 +/- 40.7 msec; p = 0.002). There was no change in acceleration time (94.8 +/- 6.6 vs 95 +/- 10.9 msec). These results demonstrate that estrogens increase both stroke volume and flow acceleration. The latter probably reflects a combination of enhanced inotropism and vasodilatation. We assume that the cardioprotective effect of hormone replacement therapy in postmenopausal women may be due not only to changes in lipid profile but also to direct effects of estrogens on central and peripheral hemodynamic parameters.

Altered left ventricular volume and ejection fraction responses to supine dynamic exercise in athletes.

Two-dimensional echocardiography was used to determine the responses of left ventricular volumes, ejection fraction and segmental left ventricular motion to supine dynamic exercise in 22 professional athletes, comparing these responses with those in 22 age- and gender-matched healthy untrained individuals. End-systolic volume was significantly greater at rest and during exercise in the athletes (50 +/- 6 versus 29 +/- 4 ml and 40 +/- 5 versus 17 +/- 4 ml, respectively, p less than 0.001 for both). It decreased during exercise in all the untrained subjects, but did not change or increased in nine athletes (41%). End-diastolic volume was greater in the athletes at rest (143 +/- 12 versus 98 +/- 9 ml) and during exercise (157 +/- 14 versus 121 +/- 13 ml, p less than 0.01 for both). It increased in all the untrained subjects, but decreased or did not change in six athletes (27%). Ejection fraction was significantly lower in the athletes at rest and during exercise (65 +/- 4% versus 70 +/- 5% and 73 +/- 5% versus 86 +/- 5%, p less than 0.01 and 0.001, respectively); the values augmented normally in all the untrained subjects, but increased only by less than 5% units, did not change or decreased in nine athletes (41%). Eight athletes (36.5%) failed to demonstrate the expected symmetric hyperkinetic wall motion changes during exercise, which were seen in all the untrained subjects. No correlation was found between atypical responses to exercise and electrocardiographic patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

Arm exercise training in the rehabilitation of patients with impaired ventricular function and heart failure.

Although exercise training is an accepted part of comprehensive coronary care programs in patients with coronary artery disease, it still remains to be demonstrated whether or not exercise training should also be applied to patients with impaired ventricular function. Circumstantial evidence exists that patients with impaired ventricular function may eventually benefit from an individually adapted exercise training program provided that contraindications for acceptance of cardiac patients to such a program are well observed. Our study is based on 22 patients with impaired ventricular function, of which 18 were at least 6 months after a Q-wave myocardial infarction and the remaining 4 after coronary artery bypass grafting. Eleven patients with impaired left ventricular function performing upper extremity (arm) ergometry were followed up for 36 months. These patients were trained twice weekly with exercise periods of 30 min duration. The reason for choosing arm ergometry training was that the peak heart rate obtained in arm ergometry is higher when compared to leg ergometry. Rate-pressure product and heart rate were higher for given submaximal work tasks in arm ergometry, while maximal work aerobic capacity was found to be lower in comparison to leg work. The assessment of our patients was based on cardiopulmonary testing, continuous electrocardiographic monitoring (48 h), two-dimensional echocardiography and equilibrium multigated radionuclide ventriculography (99mTc). Group 1, consisting of 11 patients with left ventricular ejection fraction (LVEF) 30.1 +/- 9.5%, were trained by arm exercise for 3 years with a significant increase in work capacity and LVEF. Group 2 consisted of 11 patients with LVEF 25.5 +/- 6.8% who underwent a 12 months' calisthenic program. Peak work capacity and LVEF remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoids induce the accumulation of novel angiotensinogen gene transcripts.

Previous work from this laboratory has shown that glucocorticoids and (Sp)-cAMPS, a cyclic AMP analogue, stimulate the accumulation of angiotensinogen mRNA in isolated hepatocytes. The present study demonstrated that glucocorticoids stimulate the accumulation of a novel, 2.25-kilobase transcript of the angiotensinogen gene, both in isolated hepatocytes and in the intact liver. (Sp)-cAMPS was synergistic with dexamethasone in causing the accumulation of the larger species of RNA in hepatocytes, but had no effect by itself. Primer extension analysis and S1 mapping experiments proved that the 2.25-kilobase angiotensinogen RNA consisted of two larger forms of angiotensinogen RNA extended at their 5' ends. The novel transcripts are generated by the use of two new transcription initiation sites in the angiotensinogen gene, located at nucleotide positions -328 and -386 relative to the start site at position +1 used in the absence of hormone. A consensus TATA box is found at the expected position 25-30 nucleotides upstream from the start site at position -328, and another TATA-like sequence is found 25-30 nucleotides upstream from the start site at -386. In addition, two consensus glucocorticoid response elements occur upstream from the initiation sites. The larger angiotensinogen RNAs do not appear to code for a novel form of the angiotensinogen protein. It appears that glucocorticoids can direct transcription from a second promoter in the angiotensinogen gene and that this promoter is absolutely dependent on the hormone. To date, this situation appears to be unique to the angiotensinogen gene.

Painful versus silent myocardial ischemia during leg and arm exercise testing in stable angina pectoris.

When 51 patients with proven coronary heart disease and stable angina pectoris underwent exercise testing, 22 experienced painful myocardial ischemia during both leg and arm exercise testing (group L + A), whereas 29 patients had such episodes only during the leg testing (group L). Upright bicycle exercise was performed with the legs first, followed 2 days later by arm testing. Exercise was stopped when typical anginal pain and greater than 1-mm ST horizontal depression occurred during leg testing, and when greater than 1-mm ST horizontal depression was noted during arm testing. Heart rate, systolic blood pressure and rate-pressure product for leg and arm testing, either at the beginning of anginal pain or at the time when 1-mm ST depression was noted, were similar. Two-dimensional echocardiography showed that the L group had higher (p less than 0.01) end-systolic volume at rest and decreased (p less than 0.05) ejection fraction during exercise. Coronary angiography showed that the L group had a greater (p less than 0.001) number of patients with 3-vessel disease, a decreased (p less than 0.001) ejection fraction and less patients with 1-vessel disease. In these patients, absence of anginal pain during arm exercise suggests defective segmental transmission of pain sensation related to severe coronary artery disease. Thus, arm testing, in addition to leg testing, seems to be a simple and useful tool for the detection of severe coronary disease.