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Molecular and pharmacological approaches to inhibiting nitric oxide after burn trauma
Jean White1, Deborah L Carlson, Marita Thompson
1Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9160, USA.
Abstract:
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 x 2 x 0.3 cm) heated to 100 degrees 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/dtmax, 1,620 +/- 94 vs. 2,240 +/- 58 mmHg/s, P < 0.001), and a lower rate of LVP fall (-dP/dtmax, 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/dt: 1,889 +/- 160 mmHg/s; -dP/dt: 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.
Insights
Burn trauma causes cardiac contractile dysfunction, partly due to inducible nitric oxide synthase (iNOS). Inhibiting iNOS in mice significantly reduced this burn-related heart dysfunction, indicating a role for NO in trauma-induced cardiac issues.
Area of Science:
- Physiology
- Cardiovascular Biology
- Trauma Research
Background:
- Nitric oxide (NO) is implicated in cardiac contractility changes through various pathways.
- The specific role of inducible nitric oxide synthase (iNOS) in burn-induced cardiac dysfunction remains unclear.
Purpose of the Study:
- To investigate whether burn-related upregulation of myocardial iNOS and subsequent NO generation contributes to cardiac contractile dysfunction following major trauma.
- To elucidate the role of iNOS in the pathophysiology of burn-mediated cardiac dysfunction.
Main Methods:
- Utilized iNOS knockout (KO) mice and wild-type (WT) mice subjected to a standardized burn injury (40% total body surface area).
- Assessed cardiac function 24 hours post-burn using isolated perfused hearts, measuring left ventricular pressure (LVP) and its first derivatives (+dP/dtmax, -dP/dtmax).
- Confirmed findings using a pharmacological iNOS inhibitor (aminoguanidine) in WT mice.
Main Results:
- Wild-type mice subjected to burn trauma exhibited significant cardiac contractile dysfunction compared to sham controls (reduced LVP, +dP/dtmax, -dP/dtmax).
- iNOS knockout mice showed significantly attenuated cardiac dysfunction after burn trauma compared to WT burns.
- Pharmacological inhibition of iNOS in WT mice corroborated the protective effects observed in iNOS KO mice.
Conclusions:
- Burn-related upregulation of iNOS and subsequent NO generation contributes significantly to cardiac contractile dysfunction after major trauma.
- Targeting iNOS may represent a therapeutic strategy to mitigate cardiac dysfunction following severe burns.
- While iNOS plays a role, the precise source of NO (cardiac vs. immune cells) requires further investigation.