The Role of Nitric Oxide in the Efficacy of Adenosine, Lidocaine, and Magnesium Treatment for Experimental Hemorrhagic Shock in Rats

BACKGROUND: Nitric oxide (NO) plays multiple roles regulating the central nervous, cardiovascular, and immune systems. OBJECTIVE: Our aim was to investigate the role of NO in the efficacy of hypertonic saline (7.5% sodium chloride [NaCl]) adenosine, lidocaine, and magnesium (ALM) to improve mean arterial pressure (MAP) and heart rate following hemorrhagic shock. METHODS: One hundred one male Sprague-Dawley rats (mean [SD] weight = 425 [6] g) were randomly assigned to 20 groups (groups of 4–8 rats each). Hemorrhagic shock (MAP < 40 mm Hg) was induced by 20-minute pressure-controlled bleeding (∼40% blood volume), and the animal was left in shock (MAP = 35-40 mm Hg) for 60 minutes. The NO synthase (NOS) inhibitor L-NAME was administered with a 0.3-mL bolus of different combinations of 7.5% NaCl ALM active ingredients and hemodynamic parameters were monitored for 60 minutes. A number of specific NOS and NO inhibitors were tested. RESULTS: We found that 7.5% NaCl ALM corrected MAP after hemorrhagic shock. 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 N(G)-nitro-l-arginine methyl ester (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 NOS inhibitor 1400W to 7.5% NaCl ALM failed to resuscitate, whereas the NO scavenger PTIO and the PI3K inhibitor wortmannin reduced MAP recovery during 60-minute resuscitation. CONCLUSIONS: The ability of 7.5% NaCl ALM to resuscitate appears to be linked to 1 or more NO-producing pathways. Nonspecific 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. (Curr Ther Res Clin Exp. 2022; 82:XXX–XXX)