Characterization of pulmonary function in Duchenne Muscular Dystrophy.

Decline in pulmonary function in Duchenne Muscular Dystrophy (DMD) contributes to significant morbidity and reduced longevity. Spirometry is a widely used and fairly easily performed technique to assess lung function, and in particular lung volume; however, the acceptability criteria from the American Thoracic Society (ATS) may be overly restrictive and inappropriate for patients with neuromuscular disease. We examined prospective spirometry data (Forced Vital Capacity [FVC] and peak expiratory flow [PEF]) from 60 DMD patients enrolled in a natural history cohort study (median age 10.3 years, range 5-24 years). Expiratory flow-volume curves were examined by a pulmonologist and the data were evaluated for acceptability using ATS criteria modified based on the capabilities of patients with neuromuscular disease. Data were then analyzed for change with age, ambulation status, and glucocorticoid use. At least one acceptable study was obtained in 44 subjects (73%), and 81 of the 131 studies (62%) were acceptable. The FVC and PEF showed similar relative changes in absolute values with increasing age, i.e., an increase through 10 years, relative stabilization from 10-18 years, and then a decrease at an older age. The percent predicted, FVC and PEF showed a near linear decline of approximately 5% points/year from ages 5 to 24. Surprisingly, no difference was observed in FVC or PEF by ambulation or steroid treatment. Acceptable spirometry can be performed on DMD patients over a broad range of ages. Using modified ATS criteria, curated spirometry data, excluding technically unacceptable data, may provide a more reliable means of determining change in lung function over time.

Inotropic, chronotropic, and radioligand binding characteristics of leukotriene B4 in cardiac myocyte, papillary muscle, and membrane preparations.

Cardioprotective effects of dietary fish oil consumption have been attributed to the substitution of eicosapentaenoic acid (EPA) for arachidonic acid (AA) in cellular membranes. This substitution blocks the formation of leukotriene B(4) (LTB(4)) which is elaborated locally in the area of ischemic myocardium. We studied the in vitro inotropic, chronotropic, and radioligand binding characteristics of LTB(4) to gain potentially important insights into the mechanisms involved in the cardioprotective effect of EPA. LTB(4) was a concentration-dependent and reversible negative inotrope in isolated papillary muscle preparations. LTB(4) significantly blocked the positive inotropic effect of Bay K 8644 (BK) (calcium channel regulator) on papillary muscles and the positive chronotropic effect of BK on spontaneously beating neonatal cardiac myocytes. LTB(4) had no direct effect on [(3)H]PN200-110 binding to cardiac sarcolemmal L-type calcium channels or [3H]ryanodine binding to cardiac SR calcium release channels. These studies support a potentially important indirect effect of LTB(4) on myocardial E-C coupling.

Nitric oxide synthase inhibitor alters papillary muscle force-frequency relationship.

We provide evidence for an immediate effect of NG-monomethyl-L-arginine (L-NMMA) on the force-frequency relationship in isolated hamster papillary muscles. L-NMMA (competitive inhibitor of nitric oxide synthase) reversed the force-frequency relationship (staircase effect) in isolated hamster papillary muscles from negative to positive (P < .01; ANOVA; n = 6). The addition of L-arginine (substrate for nitric oxide synthase) blocked the L-NMMA effect (P < .01; ANOVA; n = 6). The addition of the nitric oxide (NO) donor, sodium nitroprusside (NTP), significantly increased the level of cGMP in the tissue bath (P < .01; test; n = 6) and reversed the positive inotropic effect of L-NMMA on staircase (P < .01; ANOVA; n = 6). The addition of 8-Br-cGMP to the bath resulted in a concentration-dependent decrease in tension generated by the papillary muscles (n = 6). Methylene blue (known inhibitor of cGMP) mimicked the effect of L-NMMA on staircase (P < .01; ANOVA; n = 6). L-NMMA also significantly blunted the negative inotropic effect of ryanodine (SR calcium release channel regulator) (P < .01; ANOVA; n = 6). The positive inotropic effect of Bay K 8644 (sarcolemmal, L-type calcium channel regulator) was not affected by L-NMMA (P = NS; ANOVA; n = 6). L-NMMA had no effect on either [3H]ryanodine or [3H]PN200-110 (sarcolemmal, L-type calcium channel regulator) binding to cardiac membranes. These findings support a cGMP-dependent role for endogenous NO in myocardial E-C coupling.