Utrophin deficiency worsens cardiac contractile dysfunction present in dystrophin-deficient mdx mice

The loss of dystrophin in patients with Duchenne muscular dystrophy (DMD) causes devastating skeletal muscle degeneration and cardiomyopathy. Dystrophin-deficient ( mdx) mice have a much milder phenotype, whereas double knockout (DKO) mice lacking both dystrophin and its homolog, utrophin, exhibit the clinical signs observed in DMD patients. We have previously shown that DKO and mdx mice have similar severities of histological features of cardiomyopathy, but no contractile functional measurements of DKO heart have ever been carried out. To investigate whether DKO mice display cardiac dysfunction at the tissue level, contractile response of the myocardium was tested in small, unbranched, ultrathin, right ventricular muscles. Under near physiological conditions, peak isometric active developed tension (Fdev, in mN/mm2) at a stimulation frequency of 4 Hz was depressed in DKO mice (15.3 ± 3.7, n = 8) compared with mdx mice (24.2 ± 5.4, n = 7), which in turn were depressed compared with wild-type (WT) control mice (33.2 ± 4.5, n = 7). This reduced Fdev was also observed at frequencies within the murine physiological range; at 12 Hz, Fdev was (in mN/mm2) 11.4 ± 1.8 in DKO, 14.5 ± 4.2 in mdx, and 28.8 ± 5.4 in WT mice. The depression of Fdev was observed over the entire frequency range of 4–14 Hz and was significant between DKO versus mdx mice, as well as between DKO or mdx mice versus WT mice. Under β-adrenergic stimulation (1 μmol/l isoproterenol), Fdev in DKO preparations was only (in mN/mm2) 14.7 ± 5.1 compared with 30.9 ± 8.9 in mdx and 41.0 ± 4.9 in WT mice. These data show that cardiac contractile dysfunction of mdx mice is generally worsened in mice also lacking utrophin.

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Molecular and pharmacological approaches to inhibiting nitric oxide after burn trauma

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00061.2002 ◽

2003 ◽

Vol 285 (4) ◽

pp. H1616-H1625 ◽

Cited By ~ 7

Author(s):

Jean White ◽

Deborah L. Carlson ◽

Marita Thompson ◽

David L. Maass ◽

Billy Sanders ◽

...

Keyword(s):

Nitric Oxide ◽

Cardiac Function ◽

Total Body Surface Area ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Contractile Dysfunction ◽

Wild Type ◽

Burn Trauma ◽

Cardiac Contractile ◽

Cardiac Contractile Dysfunction

Whereas controversial, several studies have suggested that nitric oxide (NO) alters cardiac contractility via cGMP, peroxynitrite, or poly(ADP ribose) synthetase (PARS) activation. This study determined whether burn-related upregulation of myocardial inducible NO synthase (iNOS) and NO generation contributes to burn-mediated cardiac contractile dysfunction. Mice homozygous null for the iNOS gene (iNOS knockouts) were obtained from Jackson Laboratory. iNOS knockouts (KO) as well as wild-type mice were given a cutaneous burn over 40% of the total body surface area by the application of brass probes (1 × 2 × 0.3 cm) heated to 100°C to the animals' sides and back for 5 s (iNOS/KO burn and wild-type burn). Additional groups of iNOS KO and wild-type mice served as appropriate sham burn groups (iNOS/KO sham and wild-type sham). Cardiac function was assessed 24 h postburn by perfusing hearts ( n = 7–10 mice/group). Burn trauma in wild-type mice impaired cardiac function as indicated by the lower left ventricular pressure (LVP, 67 ± 2 mmHg) compared with that measured in wild-type shams (94 ± 2 mmHg, P < 0.001), a lower rate of LVP rise (+dP/d tmax, 1,620 ± 94 vs. 2,240 ± 58 mmHg/s, P < 0.001), and a lower rate of LVP fall (–dP/d tmax, 1,200 ± 84 vs. 1,800 ± 42 mmHg/s, P < 0.001). Ventricular function curves confirmed significant contractile dysfunction after burn trauma in wild-type mice. Burn trauma in iNOS KO mice produced fewer cardiac derangements compared with those observed in wild-type burns (LVP: 78 ± 5 mmHg; +dP/d t: 1,889 ± 160 mmHg/s; –dP/d t: 1,480 ± 154 mmHg/s). The use of a pharmacological approach to inhibit iNOS (aminoguanidine, given ip) in additional wild-type shams and burns confirmed the iNOS KO data. Whereas the absence of iNOS attenuated burn-mediated cardiac contractile dysfunction, these experiments did not determine the contribution of cardiac-derived NO versus NO generated by immune cells. However, our data indicate a role for NO in cardiac dysfunction after major trauma.

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