Nicotinamide restores tissue NAD+ and improves survival in rodent models of cardiac arrest

Abstract

Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD+ and ATP. Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 μM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest.

The role of nicotinamide adenine dinucleotide salvage enzymes in cardioprotection

“…Oxidative phosphorylation at the mitochondrial membrane again converts NADH molecules into NAD + , leading to electron production and a change of cellular barrier potentials which especially plays a vital role in cardiac action potential generation in depolarization and repolarization phases. Recent research findings demonstrated that treatment with NAM can restore cardiac NAD + by increasing the production of lactate, glycolysis, and ATP following cardiac ischemia, which helps in contractile recovery with an increasing rate of survival in a mouse model of cardiac arrest [ 16 ]. There have been several published studies on the relationship between heart diseases and the role of NAD + in this action.…”

Survival and Neurologic Outcomes From Pharmacologic Peptide Administration During Cardiopulmonary Resuscitation of Pulseless Electrical Activity

“… 31 , 32 We have shown that NAD + and ATP are markedly depleted during ischemia in cardiomyocytes and post‐SCA. 33 Treatment with intra‐CPR cooling and nicotinamide to supplement tissue NAD + significantly improves heart cell contractility and survival after SCA. 17 , 33 Akt plays a key role in NAD + and ATP production after SCA.…”

“… 33 Treatment with intra‐CPR cooling and nicotinamide to supplement tissue NAD + significantly improves heart cell contractility and survival after SCA. 17 , 33 Akt plays a key role in NAD + and ATP production after SCA. 17 …”