The Renin–Angiotensin System Mediates the Effects of Stretch on Conduction Velocity,Connexin43 Expression,and Redistribution in Intact Ventricle

Effect of Stretch on Conduction and Cx43 . Introduction: In disease states such as heart failure, myocardial infarction, and hypertrophy, changes in the expression and location of Connexin43 (Cx43) occur (Cx43 remodeling), and may predispose to arrhythmias. Stretch may be an important stimulus to Cx43 remodeling; however, it has only been investigated in neonatal cell cultures, which have different physiological properties than adult myocytes. We hypothesized that localized stretch in vivo causes Cx43 remodeling, with associated changes in conduction, mediated by the renin–angiotensin system (RAS). Methods and Results: In an open‐chest canine model, a device was used to stretch part of the right ventricle (RV) by 22% for 6 hours. Activation mapping using a 312‐electrode array was performed before and after stretch. Regional stretch did not change longitudinal conduction velocity (post‐stretch vs baseline: 51.5 ± 5.2 vs 55.3 ± 8.1 cm/s, P = 0.24, n = 11), but significantly reduced transverse conduction velocity (28.7 ± 2.5 vs 35.4 ± 5.4 cm/s, P < 0.01). It also reduced total Cx43 expression, by Western blotting, compared with nonstretched RV of the same animal (86.1 ± 32.2 vs 100 ± 19.4%, P < 0.02, n = 11). Cx43 labeling redistributed to the lateral cell borders. Stretch caused a small but significant increase in the proportion of the dephosphorylated form of Cx43 (stretch 9.95 ± 1.4% vs control 8.74 ± 1.2%, P < 0.05). Olmesartan, an angiotensin II blocker, prevented the stretch‐induced changes in Cx43 levels, localization, and conduction. Conclusion: Myocardial stretch in vivo has opposite effects to that in neonatal myocytes in vitro. Stretch in vivo causes conduction changes associated with Cx43 remodeling that are likely caused by local stretch‐induced activation of the RAS. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1276‐1283, November 2010)     

Specific Suppression of Humoral and Delayed Hypersensitivity Responses by Cyclophosphamide in an Experimental Model of Autoimmunity

ABSTRACT: The aim of this report is to investigate the effect of cyclophosphamide (CY) in an experimental model of autoimmunity to rat male accessory glands. The results indicated that 100 mg/kg of this drug suppressed humoral immune response that persisted for at least 45 days when administered 3 days after the first immunization of rats with modified rat male accessory glands (MRAG) in complete Freund's adjuvant (CFA). Administration of the drug 3 days before ID injection of antigen caused a shorter suppression of antibody formation. Delayed type hypersensitivity (DTH) studied 13 days after the first immunization was suppressed only in the animals that were administered CY after the antigen. The specificity of the immunosuppression was studied in rats treated with CY after the first immunization with MRAG using aggregated human γ-globulin (AHGG) as an unrelated antigen. The studies demonstrated significant suppression of DTH (p < 0.005) and humoral immunity only against MRAG. On the contrary, the response to AHGG was not significantly modified.     

Propagation Versus Delayed Activation During Field Stimulation of Cardiac Muscle

This modeling study seeks to explain the experimentally detected delay between the application of an electric field and the recorded response of the transmembrane potential. In this experiment, conditions were deliberately set so that the field should excite all cells at once and so that no delay should be caused by a propagating wave front. The explanation of the observed delay may lie in the intrinsic properties of the membrane. To test this hypothesis, the strength latency curves were determined for three cases: (1) for a membrane patch model, in which the membrane is uniformly polarized and its intrinsic properties can be studied; (2) for the cardiac strand directly excited by the electric field; and (3) for the cardiac strand excited by a propagating wave front. The models of the membrane patch and the directly excited strand yield excitation delays that are comparable to those observed experimentally in magnitude and in the overall shape of the strength latency curves. The delays resulting from propagation are, in general, dependent on the position along the strand, although for some positions the strength latency curves for propagation are similar to those obtained from the directly activated strand and from the patch model. Therefore, the delay in excitation does not necessarily imply the presence of propagating wave fronts and can be attributed to intrinsic membrane kinetics.     

Contact area of bovine somatotropin dimer: involvement of tyrosine 142

The presence of tyrosine residues in the contact area between protomers of bovine somatotropin dimers (Fernandez & Delfino, Biochem. J. 209 , 107-115, 1983) was investigated taking advantage of the impaired self-associating ability of molecules iodinated at such residues. Reaction of bovine somatotropin dissolved in 8 m urea with the NaI-Chloramine T couple (2.1 × 10^?4m ) rendered a preparation with 3.1 iodine atoms per molecule which, by stepwise elimination of the denaturant and gel filtration through Sephadex G-100, originated two distinguishable populations: one able (iododerivatives I), the other unable (iododerivatives II) to self-associate. After frontal analysis, iododerivatives II were found to be unable to interact even with native molecules. Identification of the reacting tyrosine residues indicated that iodination of tyrosine 142 was responsible for the loss of the ability to form dimers in iododerivatives II. Iodohormones retained the ability to bind to somatogenic mouse hepatocyte receptors - the relative potency for iododerivatives I and II being 0.60 (0.34–1.03) and 0.71 (0.41–1.22) respectively.     

VARIABLE EFFECTS OF RU 486 ON ENDOMETRIAL MAINTENANCE IN THE LUTEAL PHASE EXTENDED BY EXOGENOUS hCG

This study was designed to assess the features and conditions for endometrial bleeding induction with the synthetic antiprogestin and antiglucocorticoid RU 486 during hCG-induced prolongation of the luteal phase. Eighteen healthy, surgically sterilized women and another five women with an intrauterine contraceptive device (IUD) participated. All subjects received hCG which was injected daily in increasing doses (500 to 15,000 IU) from day 9 to day 15 of the luteal phase. Ten subjects received hCG alone, and groups of three to 16 subjects received hCG combined with RU 486 (25, 50, 100, 200 or 400 mg/day). RU 486 administration was commenced on day 12 following the LH surge and given either for 1, 4 or 7 consecutive days. In certain cycles, tamoxifen (20 mg/day) was given for 4 consecutive days with hCG, or with hCG and RU 486. All treatment cycles were separated by one or two resting cycles. Frequent blood samples were taken to monitor the endocrine response. Treatment with hCG alone or with the various combinations of RU 486 produced similar serum levels of oestradiol and progesterone which were equivalent to those observed during early pregnancy. With hCG alone, the onset of bleeding was on day 21-24 after the LH surge, coinciding with the drop in oestradiol and progesterone. With RU 486 doses of 50 mg/day or more, an early bleeding episode almost invariably occurred on day 14-17 after the LH surge in the presence of high circulating steroid levels. In contrast, 25 mg/day RU 486 for 4 days failed to induce this early onset of bleeding in three out of six cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of accessory cells in the Trypanosoma cruzi-induced inhibition of the polyclonal response of T lymphocytes

Infection with Trypanosoma cruzi is characterized by hyporesponsiveness of the immune system during the acute phase of infection. To better understand the immunological mechanisms affected by T. cruzi , we studied if a reduced T cell proliferative response could originate from an inability of T cells to proliferate or a functional deficiency at the level of accessory cells (AC). The inhibitory effect exerted by T. cruzi was during the induction phase of the lymphoproliferative response, suggesting the participation of AC in the hyporesponse. Then we further investigated the potential of the parasite to interfere with accessory cell-dependent and -independent pathways of human T cell proliferation. Peripheral blood mononuclear cells and peripheral blood lymphocytes from healthy individuals, enriched for T cells, were analysed with regard to their proliferative capacity using: phytohaemagglutinin, immobilized anti-CD3 monoclonal antibody (MoAb) and MoAb to the CD28 antigen, anti-CD3 MoAb and recombinant IL-2 and anti-CD3 MoAb plus phorbol myristate acetate in the presence of parasites. Significant suppression of the proliferative response was caused by the parasite only when AC were present. The parasite markedly reduced the surface expression of HLA-DR and CD11b antigens, key molecules in PHA-induced proliferation. Addition of indomethacin to the culture failed to reverse the inhibitory effect of the parasites, suggesting that prostaglandin E₂ was not involved. These data suggest that AC in contact with T. cruzi become incompetent as antigen presenting cell because they are unable to induce a normal proliferative response in T lymphocytes.     

Clinical Experience with Dynamic Cardiomyoplasty

Dynamic cardiomyoplasty using the latissimus dorsi muscle graft (LDMG) was applied to 11 patients with dilated cardiomyopathy of different etiologies. Our first case was operated on July 1987. All patients were in Functional Class (FC) IV New York Heart Association (NYHA) and had multiple previous admissions in intensive care units for intractable cardiac insufficiency. Two patients died during the procedure, the perioperative mortality was 18%. One patient died of recurrent acute myocarditis at the fourth postoperative month and a second patient died in the sixteenth postoperative month. Both patients were asymptomatic, in FC I-II, and the cause of death was sudden arrhythmia (ventricular fibrillation). The remaining seven patients (63.6%) were in FC I-II and the longest follow-up was 30 months. In all patients, the ejection fraction (EF) by radioisotopic ventriculography improved an average of 50% as well as their ergometric test. Dynamic cardiomyoplasty appears to be a satisfactory alternative for the treatment of patients with severe cardiac insufficiency secondary to dilated cardiomyopathy. Its main advantage seems to be a significant improvement in the quality of life for these patients.     

QT Prolongation and Torsade de Pointes Ventricular Tachycardia Produced by Ketanserin

A 65-year-old man with arterial hypertension received oral treatment with Ketanserin, a new drug, during a period of five months. He developed marked QT interval prolongation and have several Stokes-Adams attacks. A Holter recording obtained during one of these episodes showed torsade de pointes ventricular tachycardia. The arrhythmias occurred during maximum QT interval prolongation, The correlation between Ketanserin and QT interval prolongation was evaluated by using several Holter studies during administration and withdrawal of the drug. The effect of Ketanserin on the QTc interval was analyzed retrospectively in six patients who had been taking the drug orally. Following a period of four to eight months, the QTc interval was prolonged by the drug (5 to 31%, mean 17%) in five patients. We conclude that torsade de pointes is a potential hazard of long-term treatment with Ketanserin.