Experiments were conducted to determine whether relaxation of the opossum isolated lower esophageal sphincter (LES), induced by electrical field stimulation (EFS) or various pharmacological agents, is associated with changes in cyclic nucleotide content. EFS relaxed the LES in a frequency-dependent manner with 0.7 Hz producing half-maximal relaxation. Control tissues and tissues stimulated at various frequencies were clamp-frozen and assayed for cyclic nucleotide content. EFS had no effect on adenosine 3',5'-cyclic monophosphate (cAMP) content but increased guanosine 3',5'-cyclic monophosphate (cGMP) content in a frequency-dependent manner. Tetrodotoxin eliminated both the relaxation and cGMP accumulation in response to EFS. Vasoactive intestinal polypeptide (VIP) relaxed the LES with an EC50 of 0.1 microM. In contrast to the results with EFS, VIP enhanced cAMP content but had no effect on cGMP content. Relaxation of the LES produced by sodium nitroprusside or atriopeptin II was accompanied by an increase in cGMP accumulation, whereas isoproterenol- and dopamine-induced relaxation was accompanied by an increase in cAMP content. The data indicate that, depending on the stimulus, increases in either cAMP or cGMP content can accompany LES relaxation. These results are consistent with the proposed role of cyclic nucleotides as second messengers mediating LES relaxation.

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Key Points The COX inhibitor indomethacin delays progression of ALL in a human xenograft mouse model. The xenograft-derived ALL cells treated with indomethacin express elevated levels of p53.

Purpose Exercise intolerance is a common complication in survivors of allogeneic hematopoietic stem‐cell transplantation (allo‐HSCT). The aim of this study was to determine if cardiac function measured with echocardiography is associated with exercise capacity measured with cardio‐pulmonary exercise tests in long‐term survivors treated in their youth with allo‐HSCT. Methods The study included 96 patients, of which 54.2% were female, aged 34.9 ± 11.6 years and 17.7 ± 9.3 years after allo‐HSCT. Reduced exercise capacity was defined as <85% of predicted‐peak oxygen uptake (VO2peak). Linear regression was used in the prediction of VO2peak (ml/kg/min). Receiver operating characteristic evaluated the accuracy of predicting reduced exercise capacity. Results VO2peak was 36.2 ± 7.7 ml/kg/min and 43 (44.8%) had reduced exercise capacity. Left ventricular ejection fraction was 55.4 ± 5.9% and global longitudinal strain (GLS) was −17.6% ± 2.0%. Left and right ventricular functions were significantly lower in survivors with reduced exercise capacity. Increased body mass index, lower physical activity score, reduced pulmonary function (by forced expiratory volume in 1‐s) and reduced left ventricular systolic function (by GLS) were significant independent predictors for reduced VO2peak. GLS was superior to other echocardiographical indices for identifying reduced exercise capacity (area under curve = 0.64, p = 0.014). Conclusions Left ventricular systolic dysfunction measured by GLS is associated with reduced exercise capacity in long‐term allo‐HSCT survivors.