The role of nitric oxide in the efficacy of adenosine, lidocaine and magnesium (ALM) treatment of experimental hemorrhagic shock in rats

Letson, Hayley L.;Dobson, Geoffrey P.

Abstract

Background: Since nitric oxide (NO) plays multiple roles regulating the central nervous, cardiovascular and immune systems, our aim was to investigate the role of NO in the efficacy of 7.5% NaCl adenosine, lidocaine and magnesium (ALM) to improve mean arterial pressure (MAP) and heart rate (HR) following hemorrhagic shock (HS). Methods: Male Sprague-Dawley rats (101; 425±6g) were randomly assigned to 20 groups (n=4-n=8). HS (MAP<40mmHg) was induced by 20min pressure-controlled bleeding (∼40% blood volume), and the animal was left in shock (MAP 35-40mmHg) for 60min. NO synthase (NOS) inhibitor L-NAME was administered with a 0.3ml bolus of different combinations of 7.5% NaCl ALM active ingredients and hemodynamics were monitored for 60min. A number of specific NOS and NO inhibitors were tested. Results: 7.5% NaCl ALM corrected MAP after HS. In contrast, the addition of L-NAME to 7.5% NaCl ALM led to a rapid fall in MAP, sustained ventricular arrhythmias, and 100% mortality. Saline controls receiving 7.5% NaCl with L-NAME showed improved MAP with no deaths. None of the specific NOS and NO inhibitors mimicked L-NAME's effect on ALM. The addition of inducible (iNOS) inhibitor 1400W to 7.5% NaCl ALM failed to resuscitate, while NO scavenger PTIO and PI3K inhibitor Wortmannin reduced MAP recovery during 60min resuscitation. Conclusions: The ability of 7.5% NaCl ALM to resuscitate appears to be linked to one or more NO-producing pathways. Non-specific NOS inhibition with L-NAME blocked ALM resuscitation and led to cardiovascular collapse. More studies are required to examine NO site-specific contributions to ALM resuscitation.

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Current Therapeutic Research

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1879-0313

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Elsevier

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DOI

10.1016/j.curtheres.2021.100655