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)

Localization of preangiotensinogen messenger RNA sequences in the rat brain.

Angiotensinogen (renin substrate) and its messenger RNA are known to accumulate in the rat brain. We have cloned rat preangiotensinogen cDNAs and used them as probes to measure the accumulation of preangiotensinogen messenger RNA sequences in eight regions of rat brain, as well as in liver and kidney. The brain regions examined were the cerebral cortex, hippocampus, striatum, cerebellum, diencephalon (including basal forebrain structures), midbrain, brainstem, and pituitary. On a tissue weight basis, the accumulation of preangiotensinogen RNA sequences was greatest in the liver, midbrain, and brainstem. The relative concentrations of messenger RNA were ranked as follows: liver, brainstem, midbrain greater than cerebellum, diencephalon greater than hippocampus greater than cortex, striatum, kidney greater than pituitary. Relative RNA concentrations from liver to kidney varied over a 16-fold range. Liver and brain preangiotensinogen RNA sequences were indistinguishable in size as measured by gel electrophoresis; however, the kidney sequences appeared some 100 nucleotides larger. Our data agree with previous measurements of angiotensinogen in the rat brain as assayed by renin-catalyzed angiotensin I release.

Echocardiographic evaluation of the effects of gallopamil on left ventricular function.

Two-dimensional echocardiography was used to determine global and regional left ventricular function in 32 patients treated with gallopamil (methoxyverapamil) for angina pectoris. Ejection fraction (EF), pressure/volume ratio (PVR), and segmental wall motion were assessed. Evaluations were made before therapy (T1) and repeated 3 weeks later; this assessment included examination 2 and 8 hours after the morning dose (T2 and T3, respectively). Patients were randomized to either a placebo group or three study groups (25, 37.5, and 50 mg t.i.d.). In the 37.5 and 50 mg groups there was an increase in EF (T1 = 53.8% and 54.5%, T2 = 57.9% and 60.1%, and T3 = 57.6% and 60%) and PVR values (T1 = 5.2 and 7.2 mm Hg/ml/m2, T2 = 5.8 and 7.7 mm Hg/ml/m2, and T3 = 5.9 and 7.6 mm Hg/ml/m2, respectively). Wall motion remained the same or improved in 92.3% of the patients. In conclusion, gallopamil had no cardiodepressant effects in most patients. On the contrary, EF, PVR, and segmental contractility tended to improve with the higher doses.

Effects of prolonged intensive versus moderate leg training on the untrained arm exercise response in angina pectoris.

To compare the effects of 2 different leg training intensities on the cardiocirculatory exercise response of the untrained arm, 58 patients with angina pectoris were randomized to either an intensive (at least 85% of symptom-limited exercise, n = 28) or a moderate (70 to 85% of symptom-limited exercise, n = 30) training group. Patients trained for 6 months, 2 times per week for 30 minutes each. Results of the 2 groups after training showed similar significant (p less than or equal to 0.001) decreases in heart rate (HR), systolic blood pressure (BP) and HR X BP product for trained legs and untrained arms at matched subanginal workloads and significant (p less than 0.01 to 0.001) increase in anginal threshold HR and HR X BP for the onset of 1 mm or more ST horizontal depression during testing of trained legs as well as of untrained arms. The improvement in exercise capacity at subanginal workloads results from decreased HR X BP product. In contrast, the significant increase in HR X BP product for the onset of ST-segment displacement and precipitation of anginal pain for both the trained and untrained limbs may imply an increase in myocardial blood flow. Thus, prolonged intensive or moderate training may significantly improve coronary blood flow in selected patients with angina pectoris. Patients with the highest anginal threshold HR and HR X BP product before training showed the most improvement at 6 months after training.

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.

Left ventricular exercise echocardiographic abnormalities in apparently healthy men with exertional hypotension.

Of a total of 1,435 healthy untrained asymptomatic individuals referred for a routine periodic checkup, 23 subjects with exertional hypotension on upright bicycle stress testing were identified. All were male. This study assesses by means of echocardiography the responses to exercise of left ventricular (LV) volumes, ejection fraction and segmental LV contractility in these subjects. Exertional hypotension was defined as a decrease in systolic blood pressure to below the resting value at the end of stress test. Supine systolic blood pressure after exercise was significantly greater in the control group than in the study group (179 vs 121 mm Hg, respectively; p less than 0.001); there was no significant intra- or intergroup difference in the resting values. In the study group end-systolic volume was 37 ml at rest and 35 ml after exercise; ejection fraction varied from 65% at rest to 63% after exercise. The sex- and age-matched control group with a normal systolic blood pressure response to exercise showed a shift from 35 to 23 ml and 65 to 77%, respectively (p less than 0.01 and 0.001). Ejection fraction correlated well with radionuclide angiography values. Exertional hypotension was noted after both upright and supine exercise. The pattern of regional wall motion remained unchanged or was hypokinetic in 87% of the subjects; only 13% presented the normally expected hyperkinesia after exercise. This study demonstrates that exertional hypotension is accompanied by an abnormal LV performance.

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.

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.

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.

Usefulness of immediate postexercise two-dimensional echocardiography in post-myocardial infarction patients without ischemic ECG changes in stress testing: comparison with radionuclide angiography.

Of 38 post-myocardial infarction (MI) applicants for a cardiac rehabilitation program, 17 (45%) did not have ischemic ECG changes in exercise testing. Ten (59%) of these 17 patients had echocardiographic wall motion abnormalities at rest. Immediate postexercise two-dimensional echocardiography demonstrated exercise-induced changes in 8 (47%) patients (2 with normal and 6 with abnormal results from rest studies). The comparative radionuclide (RNA) examinations showed that there were 6 patients with abnormal findings from rest RNA; exercise-induced changes were detected in 7 (44%) of 16 patients (3 with normal and 4 with abnormal results from rest RNA tests). Statistical analyses, using RNA as reference point, revealed that the total correctly diagnosed cases for the echocardiographic rest studies was 13/17 (77%) and for the exercise studies, 13/16 (81%). The negative predictive values were 7/7 (100%) and 7/8 (88%), respectively. The corresponding positive predictive values were 6/10 (60%) and 6/8 (75%). The same pattern was observed when each segment (septal, apical, and posterolateral) was evaluated separately. The authors conclude that in post-MI patients with a negative stress test, the efficacy of postexercise echocardiography equals that of RNA in the identification of additional patients with ischemia.

[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.

Contraindications to physical training in patients with impaired ventricular function.

Exercise performance in patients with impaired ventricular function does not correlate well with the severity of dysfunction. Patients with ventricular dysfunction can achieve a fairly high work capacity, and the physiological variables respond in a similar way, regardless of whether or not the patients do or do not have impaired function. Furthermore, patients with pump dysfunction can benefit from a supervised physical training programme by improving their functional capacity and thus, their quality of life. The absolute contraindications for exercise therapy in this group of patients with coronary artery disease should therefore be identical to those who have normal ventricular function. In our opinion, special attention should be exercised in patients who have chronotropic incompetence, lack of an elevation or decrease in blood pressure during exercise performance and in those whose stroke volume is not elevated during even low to moderate work-loads. Recommendations as to the implication of exercise therapy as a therapeutic modality in patients with ventricular impairment must be accepted with caution. The reason for this is that our observations are based on historical, anecdotal trials, most of which included only a modest number of patients. Future research and a prolonged follow-up is needed in order to obtain both a more exact analysis and eventually scientifically based evidence on the benefits and hazards involved.

Regulation of angiotensinogen mRNA accumulation in rat hepatocytes.

Experiments were undertaken using isolated rat liver cells to determine whether the stimulation of angiotensinogen synthesis by glucocorticoids, estrogens, and angiotensin II is due to a direct action on the liver and whether these effects involve an increase in angiotensinogen mRNA levels. Dexamethasone and other corticosteroids stimulated angiotensinogen mRNA accumulation in hepatocytes up to 3.5-fold after 2.5-3 h of incubation. The effect of dexamethasone was inhibited competitively by the glucocorticoid antagonist RU486. These results indicate that the stimulation of hepatic angiotensinogen production by glucocorticoids is a direct, receptor-mediated effect and occurs via an increase in angiotensinogen mRNA accumulation. The stimulatory diastereomer of adenosine 3',5'-cyclic phosphorothioate, an active adenosine 3',5'-cyclic monophosphate analogue, caused a 1.8-fold increase in angiotensinogen mRNA accumulation, and this effect was additive with that of dexamethasone, suggesting a distinct mechanism of action. Angiotensin II increased angiotensinogen mRNA levels by only 1.2-fold after 2.5 h, whereas ethinyl estradiol had no effect.