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

Abstract

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)

Adenosine, lidocaine and Mg2+ update: teaching old drugs new tricks

“…It is widely known that L-NAME increases MAP following hemorrhagic shock via its cardiac and arteriolar vasoconstrictive effects ( 50 ). We confirmed this MAP-raising effect in our saline controls in a rat hemorrhagic shock model where MAP increased from ~30 to ~60 mmHg following bolus administration of 7.5% NaCl + (L-NAME) [ Figure 3 ; ( 25 )]. The inability of ALM to resuscitate MAP in the presence of L-NAME indicates activation of one or more NO-producing pathways for its normal operation ( 25 ).…”

“…We confirmed this MAP-raising effect in our saline controls in a rat hemorrhagic shock model where MAP increased from ~30 to ~60 mmHg following bolus administration of 7.5% NaCl + (L-NAME) [ Figure 3 ; ( 25 )]. The inability of ALM to resuscitate MAP in the presence of L-NAME indicates activation of one or more NO-producing pathways for its normal operation ( 25 ). Two likely candidates for ALM-NO interactions are possible.…”

“…We will further argue that ALM is emerging as a systems-acting therapy that has wide applications by reducing the progression of secondary injury after trauma, surgery or infection. Lastly, we will discuss possible mechanisms underlying ALM’s short- and long-term benefits which appear to involve NO synthesis pathways ( 25 ).…”

“…Another curious finding was that ALM’s ability to resuscitate MAP is abolished in the presence of the nonselective NO synthase (NOS) inhibitor L-N G -Nitro arginine methyl ester (L-NAME) [ Figure 3 ; ( 25 )]. It is widely known that L-NAME increases MAP following hemorrhagic shock via its cardiac and arteriolar vasoconstrictive effects ( 50 ).…”

A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach

“…A recent study in a severe hemorrhagic shock animal model showed that the efficacy of 7.5% saline and ALM (adenosine, lidocaine, magnesium) for resuscitation was blocked by NOS inhibitors, which produced a rapid fall in mean arterial pressure (MAP), cardiovascular collapse, sustained ventricular arrhythmias and 100% mortality. The study concluded that the ability of 7.5% NaCl ALM to resuscitate appears to be linked to NO-enhancing pathway [74]. In human studies, the administration of NO by inhalation in patients with sepsis has been found safe [63].…”