Role of cysteinyl leukotrienes in adenosine 5'-monophosphate induced bronchoconstriction in asthma

BACKGROUND: Adenosine induced bronchoconstriction in patients with asthma is thought to be mediated by the synthesis and release of autacoids from airway mast cells. In vitro, adenosine induced constriction of asthmatic bronchi is blocked by a combination of specific histamine and cysteinyl leukotriene receptor antagonists, but the relative contribution of these mediators in vivo is unclear. We hypothesised that adenosine induced bronchoconstriction in asthmatic patients may be blocked by pretreatment with the orally active selective cysteinyl leukotriene-1 (CysLT(1)) receptor antagonist, montelukast. METHODS: In a randomised, double blind, crossover study, oral montelukast (10 mg) or placebo was administered once daily on two consecutive days to 18 patients with mild to moderate persistent atopic asthma. Incremental doses of adenosine 5'-monophosphate (AMP) from 0.39 to 400 mg/ml were inhaled by dosimeter and the dose producing a 20% fall in FEV(1) (PC(20)AMP) after AMP inhalation was recorded. Leukotriene E(4) (LTE(4)) urinary concentrations were measured by enzyme immunoassay 4 hours after AMP challenge. RESULTS: Montelukast pretreatment provided highly significant protection against adenosine induced bronchoconstriction, with geometric mean PC(20)AMP values of 52.6 mg/ml (95% CI 35.2 to 78.7) after placebo and 123.9 mg/ml (95% CI 83.0 to 185.0) after montelukast (p=0.006). The geometric mean of the montelukast/placebo PC(20)AMP ratio was 2.4 (95% CI 1.3 to 4.2). Montelukast had no significant effect on 4 hour urinary excretion of LTE(4) compared with placebo. CONCLUSIONS: Selective CysLT(1) receptor antagonism with montelukast provides highly significant protection against AMP induced bronchoconstriction in patients with atopic asthma, implying that cysteinyl leukotrienes are generated from airway mast cells through preferential activation of their A(2B) receptors.     

Sexual activity as a trigger for ventricular tachycardia in a patient with implantable cardioverter defibrillator

Occurrence of life threatening arrhythmias and sudden death during or following sexual activity is infrequent. We describe a patient with an implantable cardioverter defibrillator who developed increased ventricular ectopic activity followed by sustained ventricular tachycardia during extramarital coitus. A review of literature and management is discussed.     

Pluchea lanceolata attenuates cadmium chloride induced oxidative stress and genotoxicity in Swiss albino mice

Cadmium intoxication induces lipid peroxidation and causes oxidative damage to various tissues by altering antioxidant defence system enzymes. At 24 h after treatment with a single intraperitoneal dose of cadmium chloride (5 mg kg-1), Swiss albino mice showed a significant increase in the levels of malanodialdehyde and xanthine oxidase (P<0.001), and a concomitant depletion of renal glutathione, catalase (P<0.001) and other antioxidant enzymes. CdCl2 also led to a simultaneous increase in micronuclei formation (P<0.001) and chromosomal aberrations (P<0.05) in mouse bone marrow cells. Oral pre-treatment with Pluchea lanceolata extract at doses of 100 and 200 mg kg-1 for 7 consecutive days before CdCl2 intoxication caused a significant reduction in malanodialdehyde formation and xanthine oxidase activity (P<0.001). A significant restoration of the activity of antioxidant defence system enzymes such as catalase, glutathione peroxidase (P<0.05), glutathione-S-transferase and glutathione reductase (P<0.001) was observed. A significant dose-dependent decrease in chromosomal aberrations and micronuclei formation was also observed (P<0.05). The results indicate that pre-treatment with P. lanceolata attenuates cadmium chloride induced oxidative stress and genotoxicity by altering antioxidant enzymes and reducing chromatid breaks and micronuclei formation.     

Direct microvascular repair of an infant's transected coronary artery: case report

The authors report the direct, microvascular repair of a right coronary artery transected during reoperation fOr complications of arterial switch operation (ASO) in a 3 month-old child. This is the first documented use of direct microsurgical anastamosis in the repair of an infant's transected coronary artery. Deviation from standard coronary bypass graft repair was permitted by vessel characteristics, as well as close collaboration between plastic surgery and cardiac surgery services. Patency of repair was confirmed intraoperatively with Doppler ultrasound and through postoperative echocardiograms documenting stable right ventricular function. This case highlights the benefit of a multidisciplinary approach to an emergent clinical problem using microsurgical techniques.     

Decreased septal wall thickening in patients with left bundle branch block

OBJECTIVES: Septal wall motion abnormalities are frequently observed in patients with left bundle branch block (LBBB). However, septal wall thickening in LBBB patients has not been thoroughly evaluated. METHODS AND RESULTS: To investigate the relationship between septal wall motion and wall thickening, we studied 31 normal control subjects, 24 LBBB patients with normal wall motion (LBBB-NWM), and 24 LBBB patients with septal dyssynchrony (LBBB-SDS), all with a low likelihood (<15%) of coronary artery disease. The septal and lateral quadrants of the left ventricle were analyzed in stress 8-frame gated technetium 99m sestamibi tomograms. The percent wall thickening was calculated by use of a 25-segment polar map with the p-FAST software program by two independent methods: the regional count density increase from end diastole to end systole (CD method) and the geometric increase in the distance between the 50% thresholded endocardial and epicardial borders from end diastole to end systole (GD method). In addition, the ratio of septal/lateral percent wall thickening was calculated. The relative septal wall thickening in the entire LBBB population was decreased as compared with the normal control subjects (0.35 +/- 0.37 vs 0.81 +/- 0.17, P <.001). Decreased wall thickening was observed in not only LBBB-SDS patients but also to a lesser degree in LBBB-NWM patients (0.12 +/- 0.35, P <.001; 0.57 +/- 0.24, P =.005, respectively). This abnormality was most apparent when the CD method was used. CONCLUSIONS: Septal wall thickening is decreased in patients with LBBB even with normal wall motion. LBBB per se may compromise septal wall thickening, and dyssynchronous wall motion results in further deterioration of wall thickening.     

Genetic disruption of Kir6.2, the pore-forming subunit of ATP-sensitive K+ channel, predisposes to catecholamine-induced ventricular dysrhythmia

Metabolic-sensing ATP-sensitive K+ channels (KATP channels) adjust membrane excitability to match cellular energetic demand. In the heart, KATP channel activity has been linked to homeostatic shortening of the action potential under stress, yet the requirement of channel function in securing cardiac electrical stability is only partially understood. Here, upon catecholamine challenge, disruption of KATP channels, by genetic deletion of the pore-forming Kir6.2 subunit, produced defective cardiac action potential shortening, predisposing the myocardium to early afterdepolarizations. This deficit in repolarization reserve, demonstrated in Kir6.2-knockout hearts, translated into a high risk for induction of triggered activity and ventricular dysrhythmia. Thus, intact KATP channel function is mandatory for adequate repolarization under sympathetic stress providing electrical tolerance against triggered arrhythmia.