Abstract 2842: Protective Role Of Soluble Guanylate Cyclase On The Outcome Of Cardiac Arrest And Resuscitation In Mice
Introduction: Previously we reported that NOS3 deficiency worsened outcome of cardiac arrest (CA) and CPR in mice. To elucidate the mechanism responsible for the protective role of NOS3 in the recovery from CA/CPR, we examined the impact of soluble guanylate cyclase (sGC) on neurological and myocardial function after CA/CPR.
Methods: Wild-type C57BL/6 mice (WT, n=13), NOS3-deficient mice (NOS3-/-, n=15), and mice deficient for α1 subunit of sGC (sGCα1-/-, n=7) were subjected to potassium-induced CA for 9 min with mild hypothermia (~30°C) whereupon CPR was attempted with chest compression and mechanical ventilation. To examine effects of activation of sGC, subgroup of mice of each genotype (n=4 – 6) received NO-independent sGC activator BAY42–2271 just before the induction of CA. Cardiac function was examined with a pressure-volume catheter in the first 60 min and 24 h after CPR in anesthetized mice and compared with mice that were not subjected to CA (n=4 for each genotype). Neurological function was assessed 24h after CPR by a neurological function scoring system.
Results: Pre-arrest myocardial function was similar between genotypes except that LV end-systolic pressure was higher in NOS3-/- and sGCα1-/- than in WT. During the first hour after CA/CPR, deficiency of NOS3 or sGCα1 was associated with impaired ventricular relaxation as demonstrated by a prolonged time constant of isovolumic relaxation (τ, 19±2, 18±1, and 11±2 in NOS3-/-, sGCα1-/-, and WT respectively, P<0.05 for both vs WT) and with depressed cardiac contractility as shown by an decreased maximal rate of pressure rise divided by instantaneous pressure (dP/dtmax/IP, 108±9, 84±5, and 140±11 in NOS3-/-, sGCα1-/-, and WT respectively, P<0.05 for both vs WT). Cardiac and neurological dysfunction at 24h after CPR was more marked and 24h mortality rate was higher in NOS3-/- and sGCα1-/- than in WT. CA/CPR induced more marked increase of CD45+ cells in cardiac sections of NOS3-/- and sGCa1-/- compared to WT. Administration of BAY42–2271 improved myocardial function in NOS3-/- but not in sGCα1-/- and WT during the first hour after CA/CPR.
Conclusion: These results demonstrate that sGC activation confers salutary impact on cardiac and neurological function during recovery from CA/CPR in mice.