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Raúl J Gazmuri

Publications and source records attributed to Raúl J Gazmuri.

14 recordsLinked to original sources
PubMed2006

Circulating levels of cytochrome c after resuscitation from cardiac arrest: a marker of mitochondrial injury and predictor of survival.

Ca(2+) overload and reactive oxygen species can injure mitochondria during ischemia and reperfusion. We hypothesized that mitochondrial injury occurs during cardiac resuscitation, causing release of cytochrome c to the cytosol and bloodstream while activating apoptotic pathways. Plasma cytochrome c was measured using reverse-phase HPLC and Western immunoblotting in rats subjected to 4 or 8 min of untreated ventricular fibrillation and 8 min of closed-chest resuscitation followed by 240 min of postresuscitation hemodynamic observation. A sham group served as control. Plasma cytochrome c rose progressively to levels 10-fold higher than in sham rats 240 min after resuscitation (P < 0.01), despite reversal of whole body ischemia (decreases in arterial lactate). Cytochrome c levels were inversely correlated with left ventricular stroke work (r = -0.40, P = 0.02). Western immunoblotting of left ventricular tissue demonstrated increased levels of 17-kDa cleaved caspase-3 fragments in the cytosol. Plasma cytochrome c was then serially measured in 12 resuscitated rats until the rat died or cytochrome c returned to baseline. In three survivors, cytochrome c rose slightly to <or=2 microg/ml and returned to baseline within 96 h. In nine nonsurvivors, cytochrome c rose progressively to significantly higher maximal levels [4.6 (SD 2.0) vs. 1.6 (SD 0.3) microg/ml, P = 0.029] and at faster rates [0.7 (SD 0.5) vs. 0.1 (SD 0.1) microg.ml(-1).h(-1), P = 0.046] than in survivors. Plasma cytochrome c may represent a novel in vivo marker of mitochondrial injury after resuscitation from cardiac arrest that relates inversely with survival outcome.

Animals↗
PubMed2005

Cariporide enables hemodynamically more effective chest compression by leftward shift of its flow-depth relationship.

When given during closed-chest resuscitation, cariporide (4-isopropyl-methylsulfonylbenzoyl-guanidine methanesulfonate; a selective inhibitor of the Na(+)/H(+) exchanger isoform-1) enables generation of viable perfusion pressures with less depth of compression. We hypothesized that this effect results from greater blood flows generated for a given depth of compression. Two series of 14 rats each underwent 10 min of untreated ventricular fibrillation followed by 8 min of chest compression before defibrillation was attempted. Compression depth was adjusted to maintain an aortic diastolic pressure (ADP) between 26 and 28 mmHg in the first series and between 36 and 38 mmHg in the second series. Within each series, rats were randomized to receive cariporide (3 mg/kg) or NaCl (0.9%; control) before chest compression was started. Blood flow was measured using 15-mum fluorescent microspheres. Less depth of compression was required to maintain the target ADP when cariporide was present in both series 1 (13.6 +/- 1.2 vs. 16.6 +/- 1.2 mm; P < 0.001) and series 2 (15.3 +/- 1.0 vs. 18.9 +/- 1.5 mm; P < 0.001). Despite less compression depth, the cardiac index in cariporide-treated rats was comparable to control rats in series 1 (11.1 +/- 0.7 vs. 11.3 +/- 1.4 ml.min(-1).kg(-1); P = not significant) but higher in series 2 (15.5 +/- 2.3 vs. 9.9 +/- 1.4 ml.min(-1).kg(-1); P < 0.05). Increases in compression depth (from series 1 to series 2) increased myocardial, cerebral, and adrenal blood flow in cariporide-treated rats. We conclude that cariporide enhances the efficacy of closed-chest resuscitation by leftward shift of the flow-depth relationship.

Animals↗
PubMed2005

Cariporide minimizes adverse myocardial effects of epinephrine during resuscitation from ventricular fibrillation.

OBJECTIVE: Epinephrine given during closed-chest resuscitation increases blood flow across the coronary and cerebral circuits. However, epinephrine worsens reperfusion arrhythmias and intensifies postresuscitation myocardial dysfunction. We investigated whether cariporide-a selective sodium-hydrogen exchanger isoform-1 inhibitor-could ameliorate such adverse effects without diminishing its vasopressor actions. DESIGN: Randomized animal study. SETTING: University-based animal laboratory. SUBJECTS: Twenty-four anesthetized male domestic pigs (29-43 kg). INTERVENTIONS: Ventricular fibrillation was electrically induced and left untreated for 8 mins. Pigs were randomized to receive after 2 mins of chest compression a 3 mg/kg bolus of cariporide (n = 8), a 0.02 mg/kg bolus of epinephrine (n = 8), or a combination of cariporide and epinephrine (n = 8). Additional doses of epinephrine were given if the coronary perfusion pressure decreased below 15 mm Hg. Successfully resuscitated pigs were observed for 72 hrs. MEASUREMENTS AND MAIN RESULTS: The averaged coronary perfusion pressure was higher in the epinephrine (34 +/- 11 mm Hg, p = .001) and cariporide/epinephrine (35 +/- 10 mm Hg, p < .001) groups compared with the cariporide group (15 +/- 6 mm Hg). All pigs in the epinephrine and cariporide/epinephrine groups but only six in the cariporide group were successfully resuscitated and survived 72 hrs. During the immediate postresuscitation period, four of eight pigs in the epinephrine group had episodes of recurrent ventricular fibrillation or pulseless ventricular tachycardia requiring additional electrical shocks (7.0 +/- 6.4) but none in the cariporide and cariporide/epinephrine groups (chi-square, p = .008). Myocardial dysfunction occurred early after return of spontaneous circulation but only in the epinephrine group. CONCLUSIONS: The combined administration of cariporide and epinephrine prompted adequate pressor effects during chest compression and facilitated reestablishment of cardiac activity without episodes of recurrent ventricular fibrillation or transient myocardial dysfunction as with epinephrine alone.

Adrenergic beta-Agonists↗
PubMed2005

Cariporide potentiates the effects of epinephrine and vasopressin by nonvascular mechanisms during closed-chest resuscitation.

BACKGROUND: The efficacy of vasopressor therapy during closed-chest resuscitation is limited and decreases over time. We previously reported that sodium-hydrogen exchanger isoform-1 inhibition during ventricular fibrillation (VF) using cariporide ameliorates ischemic contracture and enhances the efficacy of chest compression. We currently investigated whether cariporide could potentiate pressor responses to epinephrine and vasopressin. METHODS: VF was induced and left untreated for 12 min in two series of 16 rats each. Chest compression was then started and the depth adjusted within the initial 2 min to attain an aortic diastolic pressure between 26 and 28 mm Hg. In one series, rats received boluses of epinephrine (150 microg/kg); in the other series, rats received boluses of vasopressin (0.8 U/kg) to maintain the aortic diastolic pressure > 25 mm Hg. Within each series, rats were randomized to receive a 3 mg/kg bolus of cariporide or 0.9% NaCl immediately before starting chest compression. Defibrillation was attempted at 20 min of VF (8 min of chest compression). RESULTS: Cariporide prompted higher and more sustained coronary perfusion pressures in both the epinephrine group (37 +/- 5 mm Hg vs 29 +/- 7 mm Hg, p < 0.05) and the vasopressin group (36 +/- 5 mm Hg vs 28 +/- 6 mm Hg +/- SD, p < 0.02) even though fewer additional vasopressor doses were required. After resuscitation, cariporide-treated rats had less ventricular ectopic activity, better hemodynamic function, and improved survival scores. In separate experiments, in situ perfusion of the aorta excluded a vascular-mediated effect of cariporide. CONCLUSION: Cariporide enhanced the hemodynamic efficacy of vasopressor agents and improved resuscitation outcomes probably as a result of enhanced forward blood flow without effect on the peripheral vasculature.

Animals↗
PubMed2003

Sodium-hydrogen exchange inhibition during ventricular fibrillation: Beneficial effects on ischemic contracture, action potential duration, reperfusion arrhythmias, myocardial function, and resuscitability.

BACKGROUND: Inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) is emerging as a promising novel strategy for ameliorating myocardial injury associated with ischemia and reperfusion. We investigated whether NHE-1 inhibition (with cariporide) could minimize mechanical and electrical myocardial abnormalities that develop during ventricular fibrillation (VF) and improve outcome using a porcine model of closed-chest resuscitation. METHODS AND RESULTS: Two groups of 8 pigs each were subjected to 8 minutes of untreated VF and randomized to receive either a 3-mg/kg bolus of cariporide or 0.9% NaCl immediately before an 8-minute interval of conventional closed-chest resuscitation. Cariporide prevented progressive increases in left ventricular free-wall thickness (from 1.0+/-0.2 to 1.5+/-0.3 cm with NaCl, P<0.001 versus 0.9+/-0.1 to 1.1+/-0.3 cm with cariporide, P=NS), maintained the coronary perfusion pressure above resuscitability thresholds (10+/-8 versus 19+/-3 mm Hg before attempting defibrillation, P<0.05), and increased resuscitability (2 of 8 versus 8 of 8, P<0.005). In 2 additional groups of 4 pigs each subjected to a briefer interval of untreated VF, cariporide ameliorated postresuscitation shortening of the action potential duration (APD) at 30%, 60%, and 90% repolarization (ie, APD60 at 2 minutes after resuscitation; 75+/-29 versus 226+/-16 ms, P<0.05), minimized postresuscitation ventricular ectopic activity preventing recurrent VF, and lessened postresuscitation myocardial dysfunction. CONCLUSIONS: NHE-1 inhibition may represent a highly potent novel strategy for resuscitation from VF that can ameliorate myocardial manifestations of ischemic injury and improve the effectiveness and outcome of closed-chest resuscitation.

Action Potentials↗
PubMed2003

Myocardial protection during resuscitation from cardiac arrest.

PURPOSE OF REVIEW: Successful treatment of cardiac arrest requires that an electrically stable and mechanically competent cardiac activity be promptly reestablished. However, many interventions used to attempt to reestablish cardiac activity may also inflict additional myocardial injury and, in turn, compromise resuscitability. In this review, we examine mechanisms of such myocardial injury and discuss potential new strategies for myocardial protection during resuscitation from cardiac arrest. RECENT FINDINGS: Efforts are currently directed at understanding underlying mechanisms of myocardial injury associated with current resuscitation methods, with the purpose of developing alternative approaches that are safer and more effective. These new approaches include, among others, the development of alternative low-energy defibrillation waveforms, methods for optimizing the timing for attempting defibrillation, and the use of vasopressor agents devoid of beta-agonist effects. There is also interest in understanding the role that activation of pathways of ischemic and reperfusion injury could play during resuscitation from cardiac arrest. To this end, activation of the sarcolemmal sodium-hydrogen exchanger isoform 1 seems to play an important role. Other potentially important pathways involve adenosine metabolism, activation of potassium ATP channels, and generation of oxygen radical species. These pathways may become novel pharmacologic targets for cardiac resuscitation. SUMMARY: The growing body of research in these areas is bringing hope that in a not so distant future new approaches and interventions for cardiac resuscitation could be available for resuscitation of humans in various clinical settings.

Anti-Arrhythmia Agents↗
PubMed2003

Optimal timing for electrical defibrillation after prolonged untreated ventricular fibrillation.

OBJECTIVE: It currently is recommended that electrical shocks be delivered immediately on recognition of ventricular fibrillation. However, decreased effectiveness of this approach has been reported after prolonged intervals of untreated ventricular fibrillation. We investigated the optimal strategy for successful defibrillation after prolonged untreated ventricular fibrillation by using a rat model of ventricular fibrillation and closed-chest resuscitation. DESIGN: Controlled, randomized, laboratory study. SETTING: Research laboratory at a VA hospital. SUBJECTS: Seventy pentobarbital anesthetized Sprague-Dawley rats. INTERVENTIONS: After 10 mins of untreated ventricular fibrillation, four groups of rats were randomized to receive electrical shocks (which we designated as "experimental shocks") immediately before or at 2, 4, or 6 mins of chest compression. Unsuccessfully defibrillated rats received additional shocks (which we designated as "rescue shocks") after 8 mins of chest compression. MEASUREMENTS AND MAIN RESULTS: The number of rats that restored spontaneous circulation after the experimental shocks increased with increasing duration of the predefibrillatory interval of chest compression (0 of 8, 0 of 8, 2 of 8, and 7 of 8, respectively, p <.005). Two additional groups then were randomized to receive repetitive experimental shocks at 2, 4, and 6 mins or a single attempt at 6 mins of chest compression. Although a comparable number of rats restored spontaneous circulation in each group, rats subjected to repetitive defibrillation attempts had more intense postresuscitation ectopic activity and worse survival. Two final groups were used to investigate whether inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) could facilitate return of spontaneous circulation during repetitive defibrillation attempts. Although spontaneous circulation was restored earlier in more rats subjected to NHE-1 inhibition, the differences were statistically insignificant. NHE-1 inhibition, however, replicated previously reported resuscitation and postresuscitation benefits. The optimal predefibrillation interval of chest compression was approximately 6 mins, and this coincided with partial return of the amplitude and frequency characteristics of the ventricular fibrillation waveform to those present immediately after induction of ventricular fibrillation. CONCLUSIONS: Improved outcome after prolonged untreated ventricular fibrillation may result from strategies that provide chest compression before attempting defibrillation and avoid early and repetitive defibrillation attempts. The amplitude and frequency characteristics of the ventricular fibrillation waveform could help identify the optimal timing for attempting electrical defibrillation.

Animals↗
PubMed2002

Myocardial protection during ventricular fibrillation by inhibition of the sodium-hydrogen exchanger isoform-1.

Activation of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) in response to the intense intracellular acidosis that develops during ischemia has been identified as an important mechanism of myocardial cell injury. NHE-1 inhibition in the quiescent (nonfibrillating) heart ameliorates functional manifestation of ischemia and reperfusion injury. We investigated in isolated heart and intact rat models of ventricular fibrillation whether NHE-1 inhibition, by using the selective inhibitor cariporide, could ameliorate myocardial abnormalities that develop during ventricular fibrillation and limit resuscitability and survival. In the isolated rat heart, cariporide significantly reduced the magnitude of ischemic contracture during ventricular fibrillation and the accompanying increases in coronary vascular resistance. Hearts that had received cariporide during ventricular fibrillation had no diastolic dysfunction after resuscitation and recovered their systolic function earlier. In intact rats, cariporide given immediately before starting chest compression allowed generation of a coronary perfusion pressure and end-tidal Pco2 comparable with control rats but with significantly less depth of compression. Cariporide had an unprecedented effect in this rat model, prompting spontaneous defibrillation after approximately 8 mins of chest compression. After resuscitation, rats treated with cariporide had significantly less ventricular ectopic activity, better hemodynamic function, and higher survival rates (22 of 24 [94%] vs. 15 of 24 [63%] in control rats, p <.05). We conclude that NHE-1 inhibition may represent a novel and highly effective form of treatment for resuscitation from ventricular fibrillation.

Animals↗