Metabolic and secretory response of parotid cells to cationic amino acids. Uptake and catabolism of L-arginine and L-ornithine.

L-Arginine and L-ornithine, which stimulate amylase release, are taken up by rat parotid cells. L-Arginine is converted, in an NADPH-dependent manner and to a limited extent to L-citrulline in parotid cell homogenates, despite the absence of ornithine transcarbamylase activity. L-Arginine is largely converted to urea and L-ornithine. The generation of putrescine and polyamines from L-ornithine occurs at a very low rate, relative to the cell content in performed amines. The major fate of exogenous or arginine-derived ornithine consists in its conversion to L-glutamate, which is then further metabolized. These findings raise several hypotheses for the secretory response of the parotid cells to cationic amino acids, including their accumulation as positively charged molecules inside the cell and the generation of either NO, amines, substrates for a transglutaminase-catalyzed reaction, or ATP through oxidative catabolism. However, each of these hypotheses meets with objections, the modality for the stimulation of amylase release by cationic amino acids being eventually considered as an unsettled matter.

Stimulus-secretion coupling of arginine-induced insulin release. Metabolism of L-arginine and L-ornithine in pancreatic islets.

Exogenous L-arginine and L-ornithine rapidly accumulate in rat pancreatic islets. L-Arginine is converted to L-ornithine and urea. Endogenous or exogenous L-ornithine generates di- and polyamines, the putrescine turnover being faster than that of spermidine and spermine. However, the major pathway for L-ornithine metabolism consists of its transamination to L-glutamaldehyde and further conversion to L-glutamate. The amines and L-glutamate derived from exogenous L-ornithine are incorporated into islet proteins at the intervention of transglutaminase and cycloheximide-sensitive biosynthetic processes, respectively. These findings suggest the hypothesis that the insulinotropic action of L-arginine and L-ornithine could somehow be related to the metabolism of these cationic amino acids in islet cells.

Stimulus-secretion coupling of arginine-induced insulin release. Uptake of metabolized and nonmetabolized cationic amino acids by pancreatic islets.

In order to assess the possible role of L-arginine accumulation in islet cells as a determinant of its insulinotropic action, the uptake of L-arginine and other cationic amino acids (L-ornithine, L-homoarginine, D,L-alpha-methylornithine, D,L-alpha-difluoromethylornithine) by rat pancreatic islets was compared to the ionic and secretory responses of the islets to the same amino acids. A tight correlation was found between the net uptake of these amino acids and their capacity to stimulate 86Rb efflux, 45Ca uptake and efflux, and insulin release. In the latter respect, there was little difference between metabolized and nonmetabolized amino acids. Thus, although L-homoarginine and 4-amino-1-guanylpiperidine-4-carboxylic acid failed to act as a substrate for either arginase or amino acid aminotransferase in islet homogenates, they both stimulated 86Rb efflux, 45Ca uptake and efflux, and insulin secretion in intact islets. These findings are compatible with the view that the accumulation of these positively charged amino acids in islet cells represents an essential determinant of their secretory action. Hence, the release of insulin evoked by these amino acids could be due to depolarization of the plasma membrane with subsequent gating of voltage-sensitive Ca2+ channels and/or to some other biophysical effect, as suggested by the persistence of a sizeable secretory response to L-arginine or L-ornithine in islets perifused at a high concentrations of extracellular K+ (50 mM).

Stimulus-secretion coupling of arginine-induced insulin release: comparison with lysine-induced insulin secretion.

L-Lysine, like-L-arginine, L-ornithine, or L-homoarginine, accumulated in rat pancreatic islets and stimulated 86Rb efflux, 45Ca uptake and efflux, and insulin release in islets exposed to D-glucose (7.0 mM). The effect of L-lysine differed from that of the other cationic amino acids by such features as the absence of a threshold concentration for stimulation of insulin release, a much lesser sensitivity of the secretory response to intracellular acidification, and the stimulation of 86Rb net uptake over 60 min of incubation. This coincided with the fact that even in the absence of another exogenous nutrient, L-lysine was well oxidized, augmented NH4+ production, increased both the ATP content and ATP/ADP ratio, caused a time-related decrease in 86Rb fractional outflow, and provoked either a transient (10 mM L-lysine) or sustained (20 mM L-lysine) stimulation of insulin secretion. It is proposed, therefore, that the functional response of the pancreatic B-cell to L-lysine involves not only a biophysical mechanism similar to that responsible for the insulinotropic action of L-homoarginine, but also a significant, albeit modest, metabolic component, which reflects the capacity of L-lysine to act as a fuel in islet cells.

Metabolic and secretory responses of parotid cells to cationic amino acids. Oxidation of the amino acids and interference with the oxidation of D-glucose or endogenous nutrients.

Cationic amino acids were recently found to stimulate amylase release from rat parotid cells. The possible relevance of their oxidative catabolism to such a secretory stimulation was investigated. D-Glucose, which was efficiently metabolized in parotid cells and which augmented O2 uptake above basal value, failed to affect basal or stimulated amylase release. L-Arginine, L-lysine and L-histidine failed to stimulate the oxidation of either exogenous D-[6-14C]glucose or endogenous nutrients in cells pre-labelled with [U-14C]palmitate or L-[U-14C]glutamine. The oxidation of L-[U-14C]arginine, L-[U-14C]ornithine, L-[U-14C]lysine and L-[U-14C]histidine, all tested at a 10 mM concentration, was much lower than that of D-[U-14C]glucose (5.6 mM). These findings argue against the view that the stimulation of amylase release by cationic amino acids would be related to their role as a source of energy in the parotid cells.

Stimulus-secretion coupling of arginine-induced insulin release: metabolism of L-arginine and L-ornithine in tumoral islet cells.

The metabolism of L-arginine and L-ornithine was examined in tumoral islet cells of the RINm5F line and compared to the situation previously characterized in normal rat islets. The maximal velocity of arginase in cell homogenates, as well as either the production of 14C-urea or the steady-state content of 14C-labelled ornithine in intact cells exposed to L-[U-14C]arginine were about one order of magnitude lower in tumoral than normal islet cells. The activity of ornithine-glutamate transaminase was similar in both cell types, and this coincided with a comparable rate of 14C-labelled L-glutamate generation by intact cells exposed to L-[1-14C]ornithine. Despite a comparable cell content in 14C-labelled ornithine of normal and tumoral cells exposed to exogenous ornithine, the rate of di- and polyamine generation was about one order of magnitude higher in tumoral than normal islet cells, this coinciding with a much higher activity of ornithine decarboxylase in RINm5F cell than islet homogenates.

Orthotopic cardiac transplantation with direct caval anastomosis: is it the optimal procedure?

Total excision of the right atrium with a minimal cuff of left atrium remaining around the four pulmonary veins, followed by direct anastomoses on venae cavae, has been proposed as an alternative to the standard procedure described by Shumway and Lower for orthotopic cardiac transplantation. To investigate whether this "anatomic" transplantation should be proposed as the optimal procedure, we prospectively randomized 78 patients having 81 procedures since 1991 into two groups: group I, standard transplantation (n = 40), and group II, "anatomic" transplantation (n = 41). The two groups were statistically similar in recipient age, sex, weight, disease, and status at the time of transplantation. Also similar were donor age, sex, weight, and drug dependency at the time of harvesting. All patients could be weaned from cardiopulmonary bypass with comparable graft ischemic times (group I, 136 +/- 46 minutes; group II, 138 +/- 51 minutes). Immediate recovery of sinus rhythm occurred in 20 cases of group I and 36 cases of group II. Delayed recovery of sinus rhythm in the first postoperative week occurred in 15 cases of group I and 5 cases of group II. Persistence of atrial arrhythmia occurred in 5 cases of group I and never in group II. These differences were highly significant (p < 0.001). Postoperative hemodynamics showed a higher cardiac index at day 1 in group II (4.12 +/- 0.85 L/min per square meter) than in group I (3.77 +/- 0.65 L/min per square meter) (p = 0.04). There were 13 early deaths in group I and 8 early deaths in group II. One death in group I was related to an acute atrioventricular block at 3 weeks with no evidence of cardiac rejection at histologic examination. Two patients in group I (5%) required definitive pacemaker implantation for prolonged sinus node dysfunction. Echocardiographic and Doppler studies of survivors have been performed 2 to 3 months after transplantation. Right atrial area was significantly reduced (p < 0.01) in group II (18 +/- 4.7 cm2) versus group I (24 +/- 7 cm2), as was left atrial area (group I, 24 +/- 4.5 cm2; group II, 20 +/- 5 cm2) (p = 0.01). Mild tricuspid regurgitation was observed in 82% of group I patients versus 57% of group II patients (p < 0.05), inasmuch as mitral regurgitation was comparable (71% in group I, 67% in group II).(ABSTRACT TRUNCATED AT 400 WORDS)

Mechanical bridge to transplantation: when is too early? When is too late?

BACKGROUND: Optimal timing of implantation of a mechanical circulatory support system in the treatment of acute cardiogenic shock is still unsettled. The issue has been addressed in a retrospective analysis of a group of 98 patients in cardiogenic shock refractory to medical therapy who were candidates for cardiac transplantation, admitted from 1987 to 1994. METHODS: The treatment included reinforced inotropic support by addition of phosphodiesterase inhibitors to sympathomimetic agents. The patients who did not improve were immediately brought to the operating room for mechanical circulatory support system implantation. RESULTS: The overall survival in the group of 28 patients selected for mechanical bridge is 50%. No predictive factors of death or multiorgan failure while on the device could be identified, suggesting a lack of contraindications to mechanical circulatory support system implantation. CONCLUSIONS: The high death rate in patients maintained on medical therapy because of initial improvement as they are awaiting transplantation suggests the benefit of a rapid semielective implantation of an intracorporeal device.

Use of the Nippon-Zeon pneumatic ventricular assist device as a bridge to cardiac transplantation.

The Nippon-Zeon (NZ) ventricular assist device is a sac type, air driven, heterotopic, external pump. Its performance has been evaluated in Japan as a bridge to myocardial recovery. Few data are available on the device as a bridge to heart transplantation. Since 1991, 10 patients (9 men) were bridged to heart transplantation with NZ, all in biventricular support. The mean age was 39 +/- 13 years (range, 21-60 years), mean body weight was 75 +/- 13 kg (range, 51-95 kg). Five patients had a dilated cardiopathy, and five were ischemic (three acute myocardial infarctions). Despite maximal inotropic support, including enoximone in seven, epinephrine in three, and intraaortic balloon pumping in one, eight patients were anuric, three were in acute hepatic failure, and three were intubated. Preoperative hemodynamic and biologic values were: cardiac index, 1.57 +/- 0.4 l/min/m2; pulmonary capillary wedge pressure, 34 +/- 5 mmHg; creatinine, 200 +/- 80 mumol/l; blood urea nitrogen, 17.5 +/- 8 mmol/l; total bilirubin 36 +/- 6 mumol/l; aspartate aminotransferase, 1,000 +/- 2,000 IU/l. In all patients, a biventricular assist device was implanted without the use of cardiopulmonary bypass. Improvement occurred immediately in all but one. Mean left ventricular flow was 4.5 +/- 0.8 l/min. Anticoagulation was maintained with intravenous heparin. Recently for bleeding was required in one case (10%), and two patients had positive blood cultures that were successfully treated. There was no mechanical failure. Hemolysis was not significant (lactate dehydrogenase, 378 +/- 50 IU/l; plasma-free hemoglobin below 10 mg/dl). Each device was free of thrombi and deposits at time of explantation. One patient died while on assist. Nine patients (90%) were transplanted after 11 +/- 8 days (range, 1-32 days). Three died early after transplantation, one of graft failure, two of sepsis. Six patients (66%) could be discharged. The follow-up ranges from 7 to 28 months. NZ is a simple, reliable, pneumatic device driven by a light, silent console; it can be rapidly implanted without cardiopulmonary bypass in patients in desperate condition who are awaiting cardiac transplantation. The difficulty of patient rehabilitation while using this device should limit the duration of support to weeks to allow the patient to be in optimal condition for heart transplantation.

[Cardiac surgery in chronic hemodialysed patients: immediate and long-term results]. / Chirurgie cardiaque chez l'hémodialysé chronique: résultats immédiats et à long terme.

Between 1979 and 1993, 50 patients (33 men and 17 women) receiving chronic haemodialysis, underwent 53 cardiac surgical procedures in the department. The mean age was 56 +/- 13 years. The average duration of preoperative dialysis was 82 +/- 63 months. The average duration of cardiac symptoms before surgery was 35 +/- 52 months. Twenty-seven patients (54%) were in NYHA functional classes III or IV before surgery. Sixteen patients (32%) had preoperative left ventricular ejection fractions of less than 0.40. Twelve patients (24%) were emergency referrals. Twenty-nine patients underwent isolated coronary bypass surgery, 13 patients underwent isolated aortic valvular replacement which had to be repeated in one case, 3 patients underwent mitral valve replacement, which had to be repeated in 2 cases, and 5 patients underwent combined surgery. The average aortic clamping time was 75 +/- 32 minutes, the average cardio-pulmonary bypass time was 125 +/- 50 minutes. The surgical revascularisation of the coronary patients was incomplete in 37% of cases because of the severity of the underlying coronary artery disease. The average postoperative bleeding was 800 +/- 650 ml; 29 patients (58%) were transfused with an average of 4.3 +/- 3 units of blood. The global early mortality was 9 patients (18%); 10% in coronary bypass, 7% in aortic valve replacement and 50% in patients with more complex procedures. The causes of death were cardiac (n = 4), sepsis (n = 2) and multiple organ failure (n = 3). The morbidity was 39%, mainly due to low cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cardiac transplantation; results after 5 years]. / La transplantation cardiaque; résultats après 5 ans.

After cardiac transplantation, long-term results were assessed in a group of 46 patients who survived more than 5 years after surgery. They were the survivors (50%) of a group of 92 patients who underwent transplantation before January 1990. On January 1995, mean follow-up was 82 +/- 14 months. Quality of life was estimated satisfactory (mean score 8.4 +/- 2); 60% of the patients were active; 89% were class NYHA I or II. Nevertheless, several problems have been identified: rise in body weight for all, over 10 kg in 31%; hypertension, renal failure, considered to be severe (serum creatinine > 250 micrograms/l) in 26%, diabetes in 13%, osteoarthropathy in 33%, cancer in 6%, and, above all, chronic alteration of the coronary arterial bed in 53% of the patients. These problems reflect the immunological conflict and complications of immuno-suppression.

[Orthotopic cardiac transplantation with caval anastomosis: a comparative randomized study with standard procedure in 81 cases]. / Transplantation cardiaque orthotopique avec anastomoses caves: étude randomisée comparative avec la technique standard sur 81 procédures.

Complete resection of the right atrium with conservation of a strip of left atrium around the 4 pulmonary veins followed by direct anastomosis on the vena cava has recently been proposed as an alternative to the standard orthotopic cardiac transplantation described by Shumway and Lower. In order to determine whether this "anatomical" transplantation should now be considered to be the procedure of choice, a prospective randomised study was undertaken in 1991 including 78 patients undergoing 81 cardiac transplantations by one of the two techniques: gr. I: classical transplantation (n = 40), gr. II: "anatomical" transplantation (n = 41). The groups were comparable in age, sex, weight, nature of the underlying cardiac disease and clinical status at the time of transplantation. Similarly, the parameters of the donors were comparable with respect to age, sex, weight and dosage of inotropic drugs at the time of explantation. All patients came of cardiopulmonary bypass with comparable ischaemia time of the graft (gr. I: 136 +/- 46 min; gr. II: 138 +/- 51 min). Immediate return to sinus rhythm occurred in 20 cases in gr. I and 36 cases in gr. II. Atrial arrhythmia persisted in 5 cases in gr. I but in no cases of gr. II. These differences were very significant (p < 0.001). There were 13 early deaths in gr. I and 8 in gr. II. Doppler echocardiography was performed two to three months after transplantation. The right atrial surface was significantly decreased in gr. II (18 +/- 4.7 cm2) compared with gr. I (24 +/- 7 cm2): the same difference was observed for the left atrium (gr. I: 24 +/- 4.5 cm2; gr. II: 20 +/- 5 cm2), p = 0.001. Tricuspid regurgitation was observed in 82% of patients in gr. I compared with 57% in gr. II (p < 0.005). Exercise stress tests during the same period showed no difference in peak oxygen consumption between the groups. Holter ECG monitoring led to permanent pacing in 2 patients of gr. I (5%). The technical simplicity and reduction of postoperative morbidity, especially with respect to arrhythmias, suggest an advantage with the "anatomical" technique considering the lack of surgical complications.

[Myocardial mass index in the diagnosis of acute rejection of allogeneic heart transplants]. / Intérêt de déterminer la variation d'un indice de masse myocardique dans le diagnostic du rejet aigu d'une greffe cardiaque allogénique.

Changes in an index of left ventricular mass were evaluated in the diagnosis of acute cardiac transplant rejection in a prospective study involving 28 transplant patients by comparison with the histology of endomyocardial biopsy. The surface of a ring of left ventricular myocardium obtained from a 2D echocardiographic examination was used as an index of mass. Eighty-three pairs of results--biopsy and index of mass--recorded within a 12 hour interval were obtained between the first day and 10th month of transplantation over a period of 12 consecutive months. Echocardiographic diagnosis of acute rejection was made when the index of myocardial mass increased by over 7 per cent compared with baseline values recorded during the first 3 days of transplantation or during a new period of equilibrium after an episode of rejection. Two groups of patients were identified from the results of biopsy, taken as the reference: in 16 patients with mild or moderate histological signs of rejection the variation of the index of mass was 18.3 +/- 9.1%; endomyocardial biopsy was negative in the 12 other patients and the change in index of mass was -1.5 +/- 5.2% (p less than 0.001). The overall concordance in the 83 successive results was good with a Kappa coefficient of 0.71. The other parameters which have been reported to be useful in diagnosing rejection (relaxation, antegrade diastolic mitral flow, acoustic density of myocardium) present a number of problems in routine practice related either to difficulties with the recording of the data or to its interpretation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Carbamazepine and vigabatrin in epileptic pregnant woman and side effects in the newborn infant]. / Carbamazépine et vigabatrin chez la femme enceinte épileptique et effets secondaires chez le nouveau-né.

BACKGROUND: Carbamazepine (Tegretol) is frequently prescribed to pregnant epileptic women. Various congenital malformations constitute the most described side-effects in their newborns. CASE REPORTS: Case 1. Esteban was born by caesarean section at 39 weeks of gestation, weighing 3,860 g. His Apgar score was 8, 9, 10 at 1, 3 and 5 minutes. His mother was given phenobarbital until 1.5 months of pregnancy then carbamazepine 400 mg LP x 2/day, raised to 600 mg LP x 2/day at the 25th week of gestation because of epileptic crisis. The newborn was transferred at day 4 for drowsiness, mild jaundice, persistent vomiting and bouts of hypotonia/hypertonia, tremors and hyperexcitability. His plasma Tegretol level was 5.9 micrograms/mL and severe hypocalcemia (1.35 mmol/L) was noted. Hypocalcemia disappeared within 48 hours and gastric and neurologic troubles by day 6. The patient left the hospital at day 14. Case 2. Matheo, Esteban's brother, was born by caesarean section after 39 weeks of gestation, weighing 3,210 g. His Apgar score was 9, 10, 10 at first, third and fifth minutes. The mother's anti-epieptic treatment associated carbamazepine LP 400 mg x 3/day and vigabatrin four tablets of 500 mg/d until the 6th month of pregnancy and five tablets by day thereafter. The newborn presented vomiting from the first feeding; tremors were noted on day 2. His plasma Tegretol level was 5.7 micrograms/mL (N = 4-8 micrograms/mL) and the baby was transferred. Upon arrival, persistent vomiting and succession of hypotonia/hypertonia with intermittent opisthotonos were noted. Blood and urine tests showed: low calcemia (2.19 mmol/L), negative Brand reaction and DNPH test, normal urinary and blood amino acid chromatography. The course was spontaneously favourable and the child went home at day 11. CONCLUSION: Newborns of epileptic mothers treated with carbamazepine and/or vigabatrin during pregnancy should be placed under clinical observation during their first postnatal week. Calcemia monitoring is suggested for infants whose mothers were not supplemented with vitamin D during pregnancy. With a follow up of respectively 26 and 7 months, both brothers have normal milestones, confirming the transitory and benign character of reported side-effects.

[Mechanical assistance of circulation. 42 cases]. / Assistance mécanique de la circulation. 42 observations.

OBJECTIVES: Mechanical circulatory support was proposed in patients in cardiogenic shock, as a bridge to cardiac transplantation or weaning. The aim of the present study is an analysis of the first 42 cases. METHODS: The 42 cases included 31 patients in cardiogenic shock unresponsive to medical therapy, good cardiac transplant candidates, and 11 patients unweanable off ventricular assist, or in shock in the intensive care unit. Results are evaluated in terms of transplantability and hospital survival. RESULTS: Overall success rate is 67%, ranging from 25% in previously transplanted patients to 46% following acute myocardial infarction and 57% in cardiomyopathy. Age and learning curve played a significative role. CONCLUSION: These data suggest that mechanical support improves survival in patients in cardiogenic shock. Earlier implantation should improve the patient outcome.

Echocardiographic assessment of aortic stenosis.

Abnormal thickening and limited or eccentric mobility of the aortic leaflets were used as indicators of the aortic stenosis (AS). The magnitude of ventricular hypertrophy in response to afterloading was determined by wall stress, with wall thickness. Measures of the echocardiographic internal dimensions of the left ventricle, wall thickness and circumferential fiber shortening (Vcf), were able to characterize left ventricular function in 13 patients with AS. In moderate and severe AS with normal left ventricular function, left ventricular end-diastolic dimension (Dd) was normal, posterior wall thickness (Wt) increased and myocardial contraction (Vcf) was normal. In patients with left ventricular failure, Dd was increased and myocardial contraction markedly depressed. Echocardiography is a noninvasive method for estimating the severity of aortic stenosis and it appears to be more sensitive than other currently employed techniques.

Echocardiographic evaluation of left ventricular function before and after cardioversion of atrial fibrillation to normal sinus rhythm.

Echocardiographic measurements were obtained in 20 patients before cardioversion immediately after and two, four and six hours after cardioversion to normal sinus rhythm. At six hours after cardioversion there was no significant change in heart rate, left atrial diameters (LAD), left ventricular end-diastolic diameters (LVEDD) or left ventricular end-systolic diameters (LVESD). On follow-up one month to nine months after cardioversion, 14 of the 20 patients (70%) remained in normal sinus rhythm. Neither LAD, LVEDD, or LVESD, nor the presence or amplitude of the A-wave on the mitral valve echogram correlated with the persistence or normal sinus rhythm.

Stimulation of 45Ca uptake and amylase release by cationic amino acids in parotid cells.

L-arginine, L-ornithine, L-lysine and L-histidine (each 10 mM) stimulated amylase release from rat parotid cells. The secretory response to the cationic amino acids was suppressed in the absence of extracellular Ca2+ and, at physiological Ca2+ concentration, coincided with stimulation of 45Ca net uptake by the parotid cells. All cationic amino acids also accumulated inside the parotid cells. Nevertheless, the concept that the stimulation of amylase release is merely attributable to depolarization of the plasma membrane, secondary to the accumulation of these positively charged amino acids in the parotid cells, is questioned in view of both the inverse correlation found between their secretory effects and degree of ionization and the knowledge that parotid cells are electrically inexcitable.

Evaluation of segmental wall motion disturbances by echocardiography in ischemic heart disease.

Echocardiographic septal and posterior wall motion and thickness were measured in 55 subjects, of whom 20 patients with acute myocardial infarction, 20 with chronic coronary artery disease and 15 control subjects without evidence of cardiac disease. The results of the study that systolic thinning is indicative of an acute event. Abnormal changes in systolic wall thickening and wall motion occur commonly in patients with chronic coronary artery disease. Useful information about segmental wall motion abnormalities can be obtained from the echocardiogram when the areas involved can be visualized, but much of the ventricle is not routinely examined.