PurposeThe study aimed to compare the acute overall hemodynamic and oxidative stress effects of intravenous S-NO-human serum albumin (S-NO-HSA) infusion and inhaled nitric oxide (iNO) in a chronic left-to-right shunt-induced pulmonary arterial hypertension model.MethodsMale Wistar rats underwent surgical creation of aorto-caval fistula (Qp/Qs> 2.0). After 10 weeks they were randomly treated with human serum albumin (HSA) (controls; n. 25), S-NO-HSA (0.5 μmol/kg/h; n. 30) or iNO (20 ppm; n. 35) for 60 minutes. Right ventricular contractility, right ventricular-vascular coupling and ventricular interdependence were assessed in vivo at different preloads by biventricular conductance catheters prior and after 60 minutes treatment. Heart and lung biopsies were obtained to determine oxidative stress by oxidized to reduced glutathione (GSSG/GSH) ratio and high-energy phosphates content.ResultsBoth S-NO-HSA and iNO led to a significant reduction in right ventricular afterload expressed by effective pulmonary arterial elastance (Ea) (from 1.3 ±0.2 to 0.5 ±0.3 and 0.4 ±0.2 respectively; P< 0.001). Only S-NO-HSA significantly improved right ventricle diastolic function (slope of end-diastolic pressure-volume relation) and contractility indicated by end-systolic elastance (Ees). Therefore a significant increase in the efficiency of ventricular-vascular coupling (Ees/Ea) occurred after S-NO-HSA but not iNO treatment (from 0.33 ±0.15 to 0.98 ±0.21; P< 0.005 and from 0.35 ±0.16 to 0.45 ±0.18; P< 0.1 respectively) with significant increase in left ventricular stroke volume (58 ±7 vs 18 ± 9 %; P< 0.003). S-NO-HSA compared to iNO improved right ventricle phosphocreatine content (27.08 ±11.35 vs. 8.41 ±1.80 nmol/mg protein; P<0.001) and myocardial energy charge (0.85 ±0.03 vs. 0.78 ±0.03; P<0.01). Both S-NO-HSA and iNO decreased lung and right ventricular GSSG/GSH ratio (P<0.001).ConclusionS-NO-HSA is more effective than iNO in treating pulmonary hypertension, improving right ventricle diastolic function and right ventricular-arterial coupling with a positive effect on ventricular interdependence. This results in superior energetic reserve of the heart, despite similar reduction of lung and right ventricular oxidative stress. PurposeThe study aimed to compare the acute overall hemodynamic and oxidative stress effects of intravenous S-NO-human serum albumin (S-NO-HSA) infusion and inhaled nitric oxide (iNO) in a chronic left-to-right shunt-induced pulmonary arterial hypertension model. The study aimed to compare the acute overall hemodynamic and oxidative stress effects of intravenous S-NO-human serum albumin (S-NO-HSA) infusion and inhaled nitric oxide (iNO) in a chronic left-to-right shunt-induced pulmonary arterial hypertension model. MethodsMale Wistar rats underwent surgical creation of aorto-caval fistula (Qp/Qs> 2.0). After 10 weeks they were randomly treated with human serum albumin (HSA) (controls; n. 25), S-NO-HSA (0.5 μmol/kg/h; n. 30) or iNO (20 ppm; n. 35) for 60 minutes. Right ventricular contractility, right ventricular-vascular coupling and ventricular interdependence were assessed in vivo at different preloads by biventricular conductance catheters prior and after 60 minutes treatment. Heart and lung biopsies were obtained to determine oxidative stress by oxidized to reduced glutathione (GSSG/GSH) ratio and high-energy phosphates content. Male Wistar rats underwent surgical creation of aorto-caval fistula (Qp/Qs> 2.0). After 10 weeks they were randomly treated with human serum albumin (HSA) (controls; n. 25), S-NO-HSA (0.5 μmol/kg/h; n. 30) or iNO (20 ppm; n. 35) for 60 minutes. Right ventricular contractility, right ventricular-vascular coupling and ventricular interdependence were assessed in vivo at different preloads by biventricular conductance catheters prior and after 60 minutes treatment. Heart and lung biopsies were obtained to determine oxidative stress by oxidized to reduced glutathione (GSSG/GSH) ratio and high-energy phosphates content. ResultsBoth S-NO-HSA and iNO led to a significant reduction in right ventricular afterload expressed by effective pulmonary arterial elastance (Ea) (from 1.3 ±0.2 to 0.5 ±0.3 and 0.4 ±0.2 respectively; P< 0.001). Only S-NO-HSA significantly improved right ventricle diastolic function (slope of end-diastolic pressure-volume relation) and contractility indicated by end-systolic elastance (Ees). Therefore a significant increase in the efficiency of ventricular-vascular coupling (Ees/Ea) occurred after S-NO-HSA but not iNO treatment (from 0.33 ±0.15 to 0.98 ±0.21; P< 0.005 and from 0.35 ±0.16 to 0.45 ±0.18; P< 0.1 respectively) with significant increase in left ventricular stroke volume (58 ±7 vs 18 ± 9 %; P< 0.003). S-NO-HSA compared to iNO improved right ventricle phosphocreatine content (27.08 ±11.35 vs. 8.41 ±1.80 nmol/mg protein; P<0.001) and myocardial energy charge (0.85 ±0.03 vs. 0.78 ±0.03; P<0.01). Both S-NO-HSA and iNO decreased lung and right ventricular GSSG/GSH ratio (P<0.001). Both S-NO-HSA and iNO led to a significant reduction in right ventricular afterload expressed by effective pulmonary arterial elastance (Ea) (from 1.3 ±0.2 to 0.5 ±0.3 and 0.4 ±0.2 respectively; P< 0.001). Only S-NO-HSA significantly improved right ventricle diastolic function (slope of end-diastolic pressure-volume relation) and contractility indicated by end-systolic elastance (Ees). Therefore a significant increase in the efficiency of ventricular-vascular coupling (Ees/Ea) occurred after S-NO-HSA but not iNO treatment (from 0.33 ±0.15 to 0.98 ±0.21; P< 0.005 and from 0.35 ±0.16 to 0.45 ±0.18; P< 0.1 respectively) with significant increase in left ventricular stroke volume (58 ±7 vs 18 ± 9 %; P< 0.003). S-NO-HSA compared to iNO improved right ventricle phosphocreatine content (27.08 ±11.35 vs. 8.41 ±1.80 nmol/mg protein; P<0.001) and myocardial energy charge (0.85 ±0.03 vs. 0.78 ±0.03; P<0.01). Both S-NO-HSA and iNO decreased lung and right ventricular GSSG/GSH ratio (P<0.001). ConclusionS-NO-HSA is more effective than iNO in treating pulmonary hypertension, improving right ventricle diastolic function and right ventricular-arterial coupling with a positive effect on ventricular interdependence. This results in superior energetic reserve of the heart, despite similar reduction of lung and right ventricular oxidative stress. S-NO-HSA is more effective than iNO in treating pulmonary hypertension, improving right ventricle diastolic function and right ventricular-arterial coupling with a positive effect on ventricular interdependence. This results in superior energetic reserve of the heart, despite similar reduction of lung and right ventricular oxidative stress.

Purpose: To compare the effect of cannabinoid receptor agonist WIN55,212-2 with mild hypothermia and normothermic control on post resuscitation outcome in a rat model of cardiac arrest. Methods: Ventricular fibrillation (VF) was induced and untreated for 10 min in adult male Sprague-Dawley rats (400-450 g). Defibrillation was attempted and resuscitated animals were randomized to three groups of ten: (a) normothermia; (b) mild therapeutic hypothermia (32°C) and (c) normothermia with WIN55,212-2 intravenous infusion (1 mg/kg/h). Cooling to 32°C and drug infusion were started at the beginning of return of spontaneous circulation and lasted for the 6 hours. The functional cardiac and neurological outcome, activated caspase-3 immunoreactivity, TUNEL and cold-inducible RNA-binding protein RBM3 were assessed at 6, 12 and 24h. Results: WIN55,212-2 administration produced pharmacologic hypothermia (32-34°C) and improved myocardial systolic and diastolic functions. Neurological deficit scores and 24-hour survival were significantly better in animals treated with WIN55,212-2 than mild therapeutic hypothermia. RNM3 expression was 5-fold after WIN,212-2 and 3-fold after mild therapeutic hypothermia compared to normothermic control (p<0.01). Cardiomyocyte apoptotic index (TUNEL) and neuronal activated caspase-3 immunoreactivity were reduced (p<0.01 and p=0.03, respectively) after WIN55,212-2 administration compared to both hypothermia and normothermia. Conclusions: Pharmacologically induced hypothermia with WIN55,212-2 induced after restoration of spontaneous circulation improved postresuscitation myocardial and neurological functions, and survival than mild therapeutic hypothermia after cardiac arrest.