Pressure-rate Index Research Articles

Mechanical power ratio and respiratory treatment escalation in COVID-19 pneumonia: a secondary analysis of a prospectively enrolled cohort.

Under the hypothesis that mechanical power ratio could identify the spontaneously breathing patients with higher risk of respiratory failure, we assessed lung mechanics in non-intubated patients with COVID-19 pneumonia aimed at: 1) describe their characteristics; 2) compare lung mechanics between patients who received respiratory treatment escalation and those who did not; 3) identify variables associated with the need for respiratory treatment escalation. Secondary analysis of prospectively enrolled cohort involving 111 consecutive spontaneously breathing adults receiving continuous positive airway pressure, enrolled from September 2020 to December 2021. Lung mechanics, other previously reported predictive indices were calculated, as well as a novel variable: the mechanical power ratio (the ratio between the actual and the expected baseline mechanical power). Patients were grouped according to the outcome: 1) no-treatment escalation (patient supported in continuous positive airway pressure until improvement); 2) treatment escalation (escalation of the respiratory support to non-invasive or invasive mechanical ventilation); and the association between lung mechanics/predictive scores and outcome was assessed. At day 1, patients undergoing treatment escalation had similar spontaneous tidal volume than patients who did not (7.1 ± 1.9 vs 7.1 ± 1.4 mL/KgIBW; p=0.990). In contrast, they showed higher respiratory rate (20 ± 5 vs 18 ± 5 bpm; p=0.028), minute ventilation (9.2 ± 3.0 vs 7.9 ± 2.4 L/min; p=0.011), tidal pleural pressure (8.1 ± 3.7 vs 6.0 ± 3.1 cmH2O; p=0.003), mechanical power ratio (2.4 ± 1.4 vs 1.7 ± 1.5; p=0.042) and lower PaO2/FiO2 (174 ± 64 vs 220 ± 95; p=0.007). Mechanical power (AUC 0.738 [95%CI 0.636-0.839] p<0.001), the mechanical power ratio (AUC 0.734 [95%CI 0.625-0.844] p <0.001) and the pressure-rate index (AUC 0.733 [95%CI 0.631-0.835] p <0.001) showed the highest AUC. In this COVID-19 cohort, tidal volume was similar in patients undergoing treatment escalation and in patients who did not; mechanical power, its ratio, and pressure-rate index were the variables presenting the highest association with the clinical outcome.

Dynamics of Schoolchildren`s Spine Sagittal Curves, Parameters of Cardiovascular System and their Coherence

Objective. We aimed to investigate the peculiarities of cardiovascular system parameters and changes in spine sagittal curves with age in schoolchildren and also possible interrelation between parameters in those two systems. Material and methods. 124 schoolchildren (aged 7—18 years) were divided into three groups according to their age. For evaluation of cardiovascular system the bicycle ergometry test with modified Bruce protocol was performed and computerized functional test analysis system “Kaunas — Load” was used. Load, arterial blood pressure, ECG in 12 standard derivations were synchronously recorded at every step. Evaluation of spine sagittal plane was performed using flexible ruler-cirtometer. Angular values of thoracic kyphosis and lumbar lordosis were measured. Results. Parameters of sagittal spine had few differences according to gender and age. Changes in sagittal plane curves with age were greater in boys than in girls. In the group of boys the expression of both sagittal curves had decreasing tendencies with age. Changes in girls’ sagittal curves were inconsistent with age. However, we found many significant differences in the parameters of cardiovascular system’s depending on gender and age. Different correlations between spinal sagittal curves and cardiovascular parameters according to gender and age could beassociated with different state in musculoskeletal system and development, different physical activity level and manyother factors, which vary among girls and boys and also changes with age. Conclusions. There was no significant difference of lumbar lordosis according to gender in all age groups. The thoracic kyphosis had significant different expression only among boys and girls in 7—10 years age group. We found significant difference of such cardiovascular system parameters as index of health, maximal power, pressure rate index, half recovery period of heart rate and change of double product according to gender. Thoracic kyphosis had more correlations with cardiovascular system parameters than lumbar lordosis. Blood pressure reactions had more correlations with spine sagittal curves in older girls and younger boys.Keywords: sagittal spine curves, cardiovascular system, lumbar lordosis, thoracic kyphosis.

Abstract P234: 2-Methoxyestradiol Attenuates Angiotensin II Induced Hypertension: A Novel Paradigm

Estrogen metabolite 2-methoxyestradiol (2ME2) has therapeutic potential in a number of cardiovascular disorders, including hypertension. However, specific or potential targets remains to be determined. In this study, animals were surgically implanted with PA-C40 telemetry in the intra-aortic vessel and 2ME2 (20 mg/kg/day, i.p. injection) effects in AngII infused Wistar-Koyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were determined. In WKY rats 2ME2 treatment resulted in significant reduction in AngII induced blood pressure (BP) compared to vehicle control (systolic; 143.69 ± 2.68 vs. 169.75 ± 1.93 mm Hg, diastolic; 99.91 ± 2.49 vs. 120.16 ± 1.25 mm Hg, and mean arterial pressure; 118.94 ± 2.52 vs. 142.73 ± 1.47 mm Hg). We observed a decrease in heart rate in 2ME2 exposed animals compared to control group (272.67 ± 9.88 vs. 329.12 ± 6.14 BPM). In addition, 2ME2 mediated reduction in workload of the heart when we calculated the rate pressure product or pressure rate index by 13.46 ± 2.32 indicating that 2ME2 can reduce AngII induced hemodynamic stress of the heart. [ 3 H]AngII binding studies showed that in kidney cortex AT1R expression was inhibited by 2ME2 treatment compared to control (2112 ± 71 vs. 3341 ± 248 DPM/mg protein). In a separate 5-week study, 2ME2-treated SHRs displayed significant reduction in diastolic BP (114.31 ± 0.66 vs. 123.28 ± 0.70 mm Hg) and mean arterial pressure (146.35 ± 0.67 vs. 151.54 ± 0.89 mm Hg) without significant change in systolic BP compare to the vehicle treated animals. Moreover, we found significant decrease in heart rate in 2ME2-treated animals (290.03 ± 2.69 vs. 312.92 ± 1.50 BPM). Analyses of kidney cortical tissue revealed downregulation of AT1R expression after 2ME2 treatments (20227 ± 2211 vs. 9515 ± 2115 DPM/mg protein). Consistent with the reduction in BP, the indicators of cardiac hypertrophy including heart weight (1.28 ± 0.08 vs. 0.99 ± 0.02 gram), cardiac collagen deposit and α-smooth muscle actin (α-SMC) positive myofibroblasts were decreased. The data demonstrate for the first time that 2ME2 control BP through downregulation of AT1R in kidney and heart rate, which may provide an insight to the mechanism(s) of cardioprotective effects of 2ME2 through the blockade of AngII induced hypertension.

Cardioprotective and Antihypertensive Potential of Morus alba L. in Isoproterenol-Induced Myocardial Infarction and Renal Artery Ligation-Induced Hypertension

The present study was aimed to evaluate the cardioprotective and antihypertensive effect of ethyl acetate soluble fraction of Morus alba L. in rats. Rats were orally treated with the ethyl acetate soluble fraction of methanol extract of Morus alba leaves (EASF 25, 50, and 100 mg/kg) for three weeks. Isoproterenol (85 mg/kg, s.c.) was administered at an interval of 24 h for two days for induction of myocardial infarction. The parameters like ST segment, heart rate, mean arterial blood pressure, pressure-rate index, vascular reactivity, heart weight, cardiac markers, and antioxidant enzymes were measured. Hypertension was induced by left renal artery ligation method. The effect of EASF was evaluated on blood pressure and cumulative concentration response curve (CCRC) of CaCl 2 on phenylephrine pre-ontracted isolated rat aortas. Oral administrati on of EASF signifi cantly reduced ST segment, heart rate, arterial pressure, pressure-rate index, heart weight, LDH, CK-MB, and SGOT, whereas the levels of antioxidant enzymes were increased significantly. EASF reduced the pressor response to catecholamines and also showed protection from hypertrophy and degenerative changes on myocardial muscles. The ligation of renal artery significantly increased the blood pressure and CCRC of CaCl 2 shifted to the left. EASF significantly reversed these changes. The observations propose that Morus alba may possess beneficial role in the treatment of myocardial infarction and hypertension through the regulation of antioxidant defensive mechanisms and blockade of calcium channels, respectively.

Assessment of health benefits from a nutrition program aimed at inmates with cardiovascular risk factors at Huelva Prison

Diet and lifestyle are important factors in improving cardiovascular health and preventing chronic diseases. Assessment of changes brought about in cardiovascular risk (CVR) and metabolic syndrome (MS) after inclusion in a nutritional program. Intervention, nonrandomized prospective cohort study carried out at Huelva prison in a one year period. Information about quarterly and bi-annual anthropometric and blood biochemical variables was obtained to assess changes in diet. A descriptive analysis with LC 95% and pre-post study was also completed, using T-Student quantitative variables and Wilcoxon test averages. Qualitative testing was performed using the Chi-square test. The sample consisted of 139 subjects, 44 patients were lost in the follow-up study and 95 completed the program. Diet modification took place in 86.3% of the cases. We obtained significant improvements in weight, body mass, fat mass, abdominal perimeter and diastolic blood pressure rate index variables (Table 3). We see a reduction in high and low CVR vs. medium CVR according to features of Framingham and REGICOR (without significance), remaining stable in the SCORE model (Table 4). Health education and proper diet improved anthropometric and biochemical parameters in these patients. This may imply a new tool in the health care repertoire that can be applied to other centres.

Cardioprotective potential of Punica granatum extract in isoproterenol-induced myocardial infarction in Wistar rats

Objective:To determine the protective role of Punica granatum L. (Punicaceae) seed juice extract and its butanolic fraction on heart rate, electrocardiographic patterns, vascular reactivity to catecholamines, cardiac marker enzymes, antioxidant enzymes together with morphologic and histopathological changes in isoproterenol-induced myocardial infarction in male Wistar rats.Materials and Methods:The effects of Punica granatum seed juice extract (100 mg/kg, p.o. and 300 mg/kg, p.o.) and butanolic fraction of Punica granatum seed juice extract (100 mg/kg., p.o.) on cardiac parameters were studied. Isoproterenol hydrochloride was used to induce myocardial infarction in Wistar rats. At the end of the experiment, heart rate, ECG, pressure rate index and cardiac marker enzyme levels were assessed.Results:Rats treated with isoproterenol (85 mg/kg, administered subcutaneously twice at an interval of 24 h) showed a significant increase in heart rate, ST elevation in ECG, pressure rate index and a significant increase in the levels of cardiac marker enzymes- lactate dehydrogenase, and creatine kinase in serum. Isoproterenol significantly reduced superoxide dismutase and catalase activity and increased vascular reactivity to various catecholamines. Pretreatment with PJ (100 mg/kg, p.o. and 300 mg/kg, p.o.) and B-PJ (100 mg/kg., p.o.) for a period of 21 days significantly inhibited the effects of ISO on heart rate, PRI, ECG patterns, levels of LDH, CK, SOD, CAT, and vascular reactivity changes. Treatment with PJ (100 mg/kg and 300 mg/kg) and B-PJ (100 mg/kg., p.o.) alone did not alter any of the parameters as compared to vehicle-treated Wistar rats. Punica granatum-treated animals showed a lesser degree of cellular infiltration in histopathological studies.Conclusion:Punica granatum ameliorates cardiotoxic effects of isoproterenol and may be of value in the treatment of MI.

Tempol reduces reperfusion-induced arrhythmias in anaesthetized rats

The generation of reactive oxygen species (ROS) contributes to reperfusion-induced arrhythmias. In the present study, the antiarrhythmic effects of tempol and tiron, two membrane-permeable radical scavengers, on reperfusion-induced arrhythmias in rats in vivo were investigated. The anaesthetized rats were subjected to 5 min of left descending coronary artery (LAD) occlusion followed by 30 min of reperfusion. All rats pretreated with saline developed ventricular tachycardia (VT) and ventricular fibrillation (VF) at the onset of reperfusion, and most of the rats died from irreversible VF at the end of reperfusion. However, pretreatment with tempol (30 or 100 mg kg −1) 5 min before reperfusion reduced mortality, arrhythmia score and the incidence and duration of VT and VF. In the rats pretreated with high dose of tempol (100 mg kg −1), no VF happened and all rats were alive at the end of the experiment. The arrhythmia score was also significantly decreased compared with that of rats pretreated with saline (0.80 ± 0.4 versus 5.6 ± 0.4, P < 0.01). Tiron also provided nearly complete protection against reperfusion-induced arrhythmias when given 2 min before reperfusion. On the other hand, intravenous administration of tempol induced decreases in mean arterial pressure (MAP), heart rate (HR) and pressure rate index (PRI), a relative indicator of myocardial oxygen consumption. In order to determine whether the antiarrhythmic effects of tempol were secondary to the reduction of myocardial oxygen consumption, continuous electrical stimulation of the aortic depressor nerve (3 V, 10 ms and 10 Hz) was carried out in a group of rats to induce decreases in MAP, HR and PRI similar to those in the high dose of Tempol group. However, these rats did not show significant changes in the severity of reperfusion-induced arrhythmias. We conclude that both tempol and tiron significantly reduce reperfusion-induced arrhythmias in rats, and this protective action is independent of hemodynamic effects.

Myocardial protection of MCI-186 in rabbit ischemia–reperfusion

We observed that 3-methyl-1-1phenyl-2-pyrazolin-5-one (MCI-186), a newly-developed free radical scavenger, attenuated necrosis in the in vivo rabbit hearts upon reperfusion after prolonged ischemia. In rabbits undergoing 1 hour ligation of the anterior ventricular coronary artery, a single bolus injection of MCI-186 (1.5 mg/kg) was introduced into the post-ischemic heart immediately before 4 hour reperfusion. Compared to negligible necrosis in sham-operated control animals and 33.81 ± 13.50% necrosis in the area at risk for the saline control group (n = 8), the MCI-186 - treated group (n = 8) had a necrosis of 13.27 ± 4.60% (p < 0.05 vs saline control group). The pressure-rate index had a slight decrease in MCI-186 treated group compared to the control group (p > 0.05). However, the blood levels of malondialdehyde (MDA) in MCI-186 treated group (2.08 ± 0.23 μM) was significantly smaller than that of 2.65 ± 0.31 μM in control animals (p < 0.01), while sham control had an average MDA level of 1.91 ± 0.40 μM, with p > 0.05 relative to that in the MCI-186 treated group. These data support our contention that MCI-186 reduces reperfusion injury in perfused hearts with prolonged ischemia and the mechanism for the in vivo efficacy of MCI-186 is predominantly related to its antioxidant activities.

Protective effects of poly (adp-ribose) synthase inhibitors on digoxin-induced cardiotoxicity in guinea-pig isolated hearts

Reactive oxygen species, generated and released during digoxin-induced cardiotoxicity, can produce an activation of poly (ADP-ribose) synthase (PARS). Our objective was to examine the effects of PARS inhibitors, 3-aminobenzamide (3-AB ) and nicotinamide, on digoxin-induced arrhythmias in guinea-pig isolated hearts. 3-AB (0.1–0.3 mM) and nicotinamide (0.3 mM) were added to the perfusion solution starting 10 min before digoxin infusion (8 μg ml −1min −1reaching the heart) and maintained throughout the experiments. Electrocardiograms and coronary perfusion pressure were recorded continuously, and digoxin-induced arrhythmias were determined. Nicotinamide markedly inhibited ventricular tachycardia (VT) incidence (from 100%, n= 7, to 29%, n= 7), and abolished ventricular fibrillation (VF) incidence. 3-AB (0.1 mM, n= 9) significantly decreased VT incidence from 100% ( n= 7) to 22% ( n= 9) and VF incidence from 86% ( n= 7) to 11% ( n= 9). Both nicotinamide and 3-AB (0.1 mM) markedly decreased number of ventricular ectopic beats (VEBs) and arrhythmia score. 3-AB at 0.3 mM ( n= 8) appeared to decrease the VT (to 63%) and VF incidence (to 38%), but these reductions did not reach statistically significance levels. Moreover, 3-AB at high concentration (0.3 mM) did not significantly modify the number of VEBs and arrhythmia score. There were no significant changes in coronary perfusion pressure, heart rate or pressure rate index measured at certain time points throughout the experiment in all groups. Our results suggest that PARS activation plays a role in the digitalis-induced cardiotoxicity in guinea-pig isolated hearts.

Increased resistance to ischaemic injury in the isolated perfused atherosclerotic heart of the cholesterol-fed rabbit.

In isolated, Langendorff-perfused hearts in the early stages of atherosclerosis from rabbits exposed to hypercholesterolaemia induced by 2% cholesterol feeding for 6 weeks (n = 23), and age-matched normal controls fed standard chow (n = 12), we studied baseline cardiac haemodynamics and the susceptibility of these hearts to 30 min global, normothermic ischaemia and 90 min reperfusion. Spontaneously beating hearts were perfused with oxygenated Krebs buffer (pH 7.4) at constant pressure, and were enclosed in a thermostated water jacket at 37 degrees C. Isovolumetric left ventricular (LV) pressure was measured by means of a balloon placed in the LV cavity. An electromagnetic flow probe placed around the perfusion cannula determined coronary flow. At the end of an initial 30 min stabilisation period, several baseline cardiodynamic variables were measured, just before subjecting the hearts to 30 min ischaemia. Recovery of mechanical function and lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) activities in the coronary effluent were recorded throughout 90 min reperfusion. Baseline spontaneous heart rate, LV developed pressure (LVDP), coronary flow and pressure-rate index (PRI) were all significantly lower in hearts from cholesterol-fed rabbits (CFR) than in age-matched controls (P < 0.01). Although large differences in several baseline haemodynamic parameters in hearts from CFR and controls were evident before ischaemia, no statistically significant differences were discernible in these parameters between the two groups from 60 min reperfusion onwards (p = NS). Furthermore, CPK and, to a lesser extent, LDH release during reperfusion was attenuated in hearts from CFR compared to controls. Hearts from CFR exhibited markedly improved recovery upon reperfusion compared to age-matched controls, strongly suggesting increased myocardial resistance to ischaemic injury.

Effects of platelet-activating factor antagonists WEB 2086 and BN 50730 on digoxin-induced arrhythmias.

Effects of platelet-activating receptor antagonists WEB 2086 (1.0-30.0 mg.kg-1 intravenously) and BN 50730 (10.0 mg.kg-1 intravenously) alone or in combination with CGS 8515 (a specific 5-lipoxygenase inhibitor, 0.3 mg.kg-1 intravenously) and Dazmegrel (a thromboxane synthase inhibitor, 1.0 mg.kg-1.hr-1 intravenous infusion) on digoxin-induced arrhythmias were investigated in anaesthetised guinea-pigs. ECG, mean arterial blood pressure, heart rate and arrhythmias were recorded, starting 30 min. before digoxin administration and continuing for 60 min. afterwards. WEB 2086 (10.0 mg.kg-1 intravenously) reduced the mortality rate and arrhythmia score significantly compared to the control values. However, in combination with CGS 8515, it did not affect the mortality rate. BN 50730 (10.0 mg.kg-1) reduced the incidence of ventricular fibrillation and also arrhythmia score. BN 50730 in combination with Dazmegrel was reduced the arrhythmia score, incidence of ventricular fibrillation and mortality rate significantly, compared to control values. Digoxin-induced acute rise in mean arterial blood pressure was not affected by any of drug treatment except WEB 2086 (10.0 mg.kg-1) in combination with CGS 8515. Heart rate values did not differ between groups. However, pressure-rate index was reduced by WEB 2086 alone or in combination with CGS 8615. Results showed that although two different platelet-activating factor antagonists have different effects on the incidence of ventricular fibrillation and mortality, they improved the digoxin-induced arrhythmias when they were used either separately or in combination with CGS 8515 or Dazmegrel by implicating that platelet-activating factor has a role on digoxin-induced arrhythmias.

Tumour necrosis factor mediates e-selectin production and leukocyte accumulation in myocardial ischaemia-reperfusion injury

The aim of our study was to examine the mechanism of E-selectin production and leukocyte accumulation in myocardial ischaemia-reperfusion injury. Myocardial injury was induced in anaesthetized rats by the clamping of the left main coronary artery followed by reperfusion. After thoracotomy a silk suture was placed under the left coronary artery. The ligature was tied for a period of 1 h and after this period it was untied and the ischaemic myocardium was reperfused for 1 h (MI/R rats) or removed (SHAM MI/R rats). Myocardial ischaemia plus reperfusion in untreated rats decreased survival rate, produced a marked myocardial necrosis, enhanced cardiac myeloperoxidase activity (a marker enzyme commonly used to assess polymorphonuclear leukocyte infiltration) and increased serum creatinephosphokinase (CPK) activity, serum levels of tumour necrosis factor-α (TNF-α) and serum levels of soluble Eselectin (sE-selectin). Furthermore, MI/R rats had an increased pressure rate index studied as a quantitative means for assessing myocardial oxygen demand. Administration of cloricromene, an inhibitor of TNF-α, reduced TNF-α production, significantly lowered serum sE-selectin levels, blunted leukocyte accumulation in the ischaemic myocardium and protected the myocardium from injury due to ischaemia and reperfusion. The results of the present study show an involvement of E-selectin in vivo in the pathogenesis of myocardial ischaemia and reperfusion and suggest that TNF-α may induce in vivo the production of a specific adhesion mechanism which sustains leukocyte infiltration.

Antibodies against intercellular adhesion molecule 1 protect against myocardial ischaemia-reperfusion injury in rat

In this study we have assayed the pathophysiological role of intercellular adhesion molecule (ICAM-1), a cytokine-inducible adhesion molecule, in a model of ischaemia reperfusion in the rat. Anaesthetized rats were subjected to occlusion (1 h) of the left main coronary artery followed by reperfusion (1 h). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial ischaemia plus reperfusion in untreated rats decreased survival rate, produced a marked myocardial necrosis, increased serum creatine phosphokinase activity, and cardiac myeloperoxidase activity (a marker enzyme commonly used to assess polymorphonuclear leukocyte accumulation). Furthermore, rats subjected to myocardial ischaemia-reperfusion showed an increased pressure rate index, studied as a quantitative means for assessing myocardial oxygen demand. Treatment with monoclonal anti-rat ICAM-1 (1 mg/kg i.v.), 3 h before occlusion of the left main coronary artery, significantly lowered serum creatine phosphokinase activity, blunted leukocyte accumulation and protected the myocardium from injury subsequent to ischaemia and reperfusion injury. These investigations have revealed that ICAM-1 is a critical adhesion molecule in the pathogenesis of ischaemia-reperfusion injury. In addition these results suggest that the use of monoclonal antibodies raised against ICAM-1 can represent a useful tool for the prevention of ischaemia-reperfusion damage.

Protective effects of IRFI-016, a new antioxidant agent, in myocardial damage, following coronary artery occlusion and reperfusion in the rat.

The new free radical scavenger IRFI-016 [2(2,3-dihydro-5-acetoxy 4,6,7-trimethyl-benzofuranyl) acetic acid] was assessed in a rat model of myocardial injury induced by 1 h of left coronary artery occlusion followed by 30 min of reperfusion. Myocardial ischaemia plus reperfusion (MI/R) produced severe cardiac necrosis, neutrophil infiltration in the jeopardized tissue, increased serum creatine kinase (CK) and ST segment of the electrocardiogram (ECG), lowered the pressure rate index (PRI), increased serum levels of tumour necrosis factor (TNF-alpha) and caused a decrease in the survival rate. Administration of IRFI-016 (100 and 200 mg/kg i.p.) 30 min before occlusion resulted in a significant protective effect in post-ischaemic reperfusion. Compared with untreated rats, IRFI-016, in particular the dose of 200 mg/kg, caused a reduction of the necrotic zone whether the necrotic area was expressed as a percentage of the area at risk (55 +/- 4% in the MI/R vehicle group and 24 +/- 2.5% in the MI/R treated group; p < 0.001) or as a percentage of the total left ventricle (23 +/- 3.4% in the MI/R vehicle group and 8 +/- 2.1% in the MI/R treated group; p < 0.005), reduced the myeloperoxidase activity, an index of neutrophil infiltration in the necrotic area (from 4.8 +/- 0.8 to 1.6 +/- 0.4 U/g tissue; p < 0.005), reduced the serum levels of TNF-alpha (from 216 +/- 13 to 45 +/- 7 U/ml; p < 0.001), blunted the rise of the ST segment of the ECG (from 0.47 +/- 0.13 mV in the vehicle group to 0.3 +/- 0.18 mV in the treated group; p < 0.001), reduced the loss of CK (from 220 +/- 15 to 88 +/- 13 IU/ml of blood; p < 0.001) and improved the depressed PRI (from 56 +/- 4% to 78 +/- 3% mm Hg/beats/min; p < 0.005). Finally, IRFI-016 significantly enhanced the survival rate evaluated at the end of the experiment. The results strongly indicate that IRFI-016 is a promising drug for cardiac ischaemia and reperfusion.

E-selectin in the pathogenesis of experimental myocardial ischemia-reperfusion injury

The role of E-selectin in the pathogenesis of an experimental model of myocardial ischemia-reperfusion injury was investigated. Pentobarbital anesthetized rats underwent left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham operated rats were used as controls (sham MI/R). Myocardial ischemia-reperfusion injury reduced survival rate (50%), caused severe myocardial damage (necrotic area/area-at-risk 69.8 ± 5%; necrotic area/total=area = 56 ± 7.6%), increased serum creatine phosphokinase activity (sham MI/R = 33 ± 3 U/ml; MI/R = 215 ± 13 U/ml) and elevated myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation; sham MI/R = 0.11 ± 0.02 U × 10 −3/g tissue) in the area-at-risk (7.5 ± 1.7 U × 10 −3/g tissue) and in the necrotic area (7.8 ± 2.2 U × 10 −3/g tissue). Furthermore, MI/R rats had an increased pressure rate index, studied as a quantitative means for assessing myocardial oxygen demand. Administration of a hyperimmune serum containing antibodies against E-selectin significantly improved survival rate (80%), reduced myocardial injury (necrotic area/area-at-risk = 26.4 ± 7%, P < 0.005; necrotic area/total area 19.1 ± 2.8%, P < 0.005), lowered serum creatine phospokinase activity (85 ± 5 U/ml, P < 0.001) and decreased myeloperoxidase actibity in the area at risk (3.7 ± 1.3 U × 10 −3/g tissue, P < 0.001) and in the necrotic area (3.0 ± 0.7 U × 10 −3/g tissue). Finally, the administration of anti E-selection antibodies improved the PRI in MI/R rats. The present data suggest that E-selectin in vivo plays a key role in the pathogenesis of myocardial ischemia/reperfusion injury.

The opposing effects of an inhibitor of nitric oxide synthesis and of a donor of nitric oxide in rabbits undergoing myocardial ischemia reperfusion

We observed that N-nitro-L-arginine (NOLA), a nitric oxide biosynthesis inhibitor, exacerbated necrosis in the rabbit heart during ischemia-reperfusion while 3-morpholino-sydnonimine-hydrochloride (SIN-1) (a nitric oxide donor) reduced myocardial damage in the same model. In rabbits undergoing 1-h ligation of the anterior ventricular coronary artery, a single bolus injection of NOLA (30 mg/kg) or continuous infusion of SIN-1 (3 mg/kg) were introduced into the post-ischemic heart immediately before 4-h reperfusion. Against negligible necrosis in 6 sham-operated control animals, and 33.8 (SD 13.5)% necrosis in the area at risk for the saline control group (n=8), the NOLA-treated group (n=8) had a necrosis of 44.3 (SD 8.6)% whereas the SIN-1-treated group (n=10) showed a necrosis of 16.8 (SD 4.9)% (both with p<0.05 vs saline control group). The pressure-rate index increased in the NOLA-treated group but decreased in the SIN-1-treated group. These data support the contention that a nitric oxide donor is an effective cardioprotector during ischemia-reperfusion in vivo .

Peptide leukotriene receptor antagonism in myocardial ischaemia and reperfusion.

The aim was to investigate the role of peptide leukotrienes in the pathophysiology of myocardial injury during reperfusion of previously ischaemic myocardium. Adult male cats (2.9-5.4 kg) were subjected to left anterior descending coronary artery occlusion for 3 h followed by 3 h of reperfusion. The peptide leukotriene receptor antagonist, LY-171883, was given intravenously only during the reperfusion period (3 mg.kg-1 bolus; 3 mg.kg-1 x h-1 infusion). Ischaemic injury was assessed by nitroblue tetrazolium staining and tissue creatine kinase activity; neutrophil infiltration was determined by myeloperoxidase activity of myocardial homogenates. There was no significant difference at any time point in the experimental protocol between mean arterial blood pressure or pressure-rate index in cats given LY-171883 (3 mg.kg-1) and cats given vehicle. The area at risk of infarction (AAR) was 24(SEM 2)% for vehicle treated cats and 22(2)% for the drug treated cats. The necrotic area was 48(5)% of the AAR for the vehicle group but only 29(5)% of the AAR for the group given LY-171883 (p < 0.02). Left ventricular maximum +dP/dt tended to be higher with drug treatment compared to vehicle at the end of the reperfusion period. Tissue from the area at risk was assayed for creatine kinase activity and neutrophil specific myeloperoxidase activity as an index of the accumulation of neutrophils in this region. Creatine kinase activity was significantly higher (p < 0.05) in the AAR for drug nu vehicle treated cats following reperfusion, confirming the histochemical analysis. Myeloperoxidase activity increased approximately 12-fold in the AAR of cats receiving vehicle. LY-171883 did not reduce the myeloperoxidase activity significantly in the area at risk. LY-171883 has a protective effect in ischaemia-reperfusion injury to the myocardium. These findings suggest a role for peptide leukotrienes both in the extension of ischaemic damage and in post-ischaemic ventricular dysfunction during reperfusion.

Effects of cyclooxygenase and lipoxygenase inhibitors on digoxin-induced arrhythmias and haemodynamics in guinea-pigs

Effects of cyclooxygenase and lipoxygenase inhibitors of digoxin-induced arrhythmias and haemodynamics were studied in guinea-pigs. ECG, mean arterial blood pressure heart rate, pressure rate index and arrhythmias were recorded, starting 15 min before digoxin administration and continuing for 30 min afterwards. The cyclooxygenase inhibitor aspirin (50 mg kg −1) and the dual cyclooxygenase/lipoxygenase inhibitor BW 755C (0.25–10.0 mg kg −1) were found to produce a significant protection against the arrhythmias, whereas aspirin (100 mg kg −1) and CGS 8515 were found to be irreffective. SK&F 104 353, a potent and selective peptidoleukotriene receptor antagonist significantly attenuated the arrhythmias and mortality in a dose-dependent manner. It is concluded that production of both cyclooxygenase and lipoxygenase metabolites could favour the occurrence and/or the maintenance of digoxin-induced cardiac toxicity.

Beneficial effects of SPM-5185, a cysteine-containing NO donor in myocardial ischemia-reperfusion.

Intravenous administration of SPM-5185 [N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester], a cysteine-containing nitric oxide (NO) donor, or SPM-5267 [pivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester], an analogue of SPM-5185 that lacks the NO moiety, was studied in a feline myocardial ischemia-reperfusion model. Administration of SPM-5185 (1 mg/kg), followed by a 2-mg.kg-1.h-1 infusion starting 10 min before reperfusion, resulted in significant protection 4.5 h postreperfusion. In the myocardial ischemia (MI)+SPM-5267 group, 38 +/- 4% of the area at risk was necrotic, whereas the necrotic area/area at risk was only 7 +/- 2% in the MI+SPM-5185 group (P less than 0.01). Moreover, SPM-5185 treatment markedly attenuated the endothelial dysfunction observed in the left anterior descending coronary artery after reperfusion by 50%. These beneficial effects occurred despite the absence of a significant change in myocardial oxygen demand, as measured by the pressure-rate index. In vitro experiments demonstrated that SMP-5185, but not SPM-5267, decreased adherence of neutrophils to the coronary vascular endothelium and decreased production of superoxide radicals. Therefore, a likely mechanism of the observed cardioprotection by SPM-5185 involves attenuation of polymorphonuclear leukocyte-induced endothelial dysfunction.

Converting Enzyme Inhibitors and the Role of the Sulfhydryl Group in the Potentiation of Exo- and Endogenous Nitrovasodilators

In this study, the effect of bradykinin on coronary flow in the isolated rat heart was significantly potentiated when cysteine or the sulfhydryl-containing converting enzyme inhibitors captopril and zofenoprilat were administered simultaneously. In contrast, the effect of concomitant administration of enalaprilat only slightly increased the effect of bradykinin on coronary flow. In nitrate-tolerant hearts of rats pretreated with isosorbide dinitrate (15 mg daily), the increase in coronary flow by nitroglycerin and bradykinin was significantly less when compared to control hearts. The effect of captopril was not affected by pretreatment. The involvement of endothelium-derived relaxing factor (EDRF) in the effect of captopril was apparent from experiments with L-arginine, the precursor of EDRF, and L-NMMA, the "false" precursor of EDRF. L-Arginine increased the effect of captopril, whereas L-NMMA showed a competitive antagonism for the effect of captopril on coronary flow in the isolated rat heart. Clinically, the effect of captopril was studied in 10 patients with stable, exercise-induced angina pectoris that had been treated for 3 weeks with slow-release isosorbide dinitrate (20 mg four times daily). At day 7, a baseline exercise test was obtained. Subsequently, patients with chest pain and at least 1-mm ST-segment depression on the ECG during exercise were included. They received on day 14 and 21 either captopril (25 mg) or placebo 1 h before exercise testing in a randomized, double-blind, crossover design. Captopril significantly improved the combined score of maximal ST-segment depression, maximal workload, and time to angina when compared to placebo. No differences in the pressure-rate index at rest and during exercise were seen. These results indicate that the sulfhydryl group of certain angiotensin converting enzyme inhibitors can potentiate their effect on the endogenous nitrovasodilator EDRF. In the clinical situation, this may lead to an improved exercise performance in patients with stable angina pectoris during chronic nitrate treatment, independent of its systemic vascular effects.