Pharmacokinetics and pharmacodynamics of fenoldopam mesylate for blood pressure control in pediatric patients

Background

Intermittent measurement of cardiac output may be performed using a lithium dilution technique (LiDCO). This can then be used to calibrate a pulse power algorithm of the arterial waveform which provides a continuous estimate of this variable. The purpose of this study was to examine the duration of accuracy of the pulse power algorithm in critically ill patients with respect to time when compared to measurements of cardiac output by an independent technique.

Methods

Pulse power analysis was performed on critically ill patients using a proprietary commercial monitor (PulseCO). All measurements were made using an in-dwelling radial artery line and according to manufacturers instructions. Intermittent measurements of cardiac output were made with LiDCO in order to validate the pulse power measurements. These were made at baseline and then following 1, 2, 4 and 8 hours. The LiDCO measurement was considered the reference for comparison in this study. The two methods of measuring cardiac output were then compared by linear regression and a Bland Altman analysis. An error rate for the limits of agreement (LOA) between the two techniques of less than 30% was defined as being acceptable for this study.

Results

14 critically ill medical and surgical patients were enrolled over a three month period. At baseline patients showed a wide range of cardiac output (median 7.5 L/min, IQR 5.1 -9.0 L/min). The bias and limits of agreement between the two techniques was deemed acceptable for the first four hours of the study with percentage errors being 29%, 22%, and 285 respectively. The percentage error at eight hours following calibration increased to 36%. The ability of the PulseCo to detect changes in cardiac output was assessed with a similar analysis. The PulseCO tracked the changes in cardiac output with adequate accuracy for the first four hours with percentage errors being 20%, 24% and 25%. However at eight hours the error had increased to 43%.

Conclusion

The agreement between lithium dilution cardiac output and the pulse power algorithm in the PulseCO monitor remains acceptable for up to four hours in critically ill patients.     

Influence of hypoxia on cardiac functions in the grass shrimp (Palaemonetes pugio Holthuis)

Crustaceans frequently encounter hypoxic water and have evolved a variety of compensatory mechanisms to deal with low O₂ conditions. Typically, large decapod crustaceans attempt to maintain cardiac output by increasing stroke volume to compensate for the hypoxia-induced bradycardia. Grass shrimp (Palaemonetes pugio), small hypoxic tolerant decapod crustaceans, were used to investigate cardiac responses to hypoxia in a smaller crustacean using videomicroscopy and dimensional analysis techniques. In addition, these techniques were compared to the more established dye dilution technique for calculation of cardiac output. No significant difference was found between the two methods for determining cardiac output in grass shrimp. Cardiac parameters (heart rate f_H, stroke volume V_S, and cardiac output V_b) were monitored in grass shrimp exposed to progressive hypoxia (P_O2s=20, 13.3, 10, 5.3, and 2 KPa O₂). Shrimp exhibit a cardiac response to hypoxia that is atypical when compared to larger crustaceans. Cardiac output was maintained until water P_O2 fell below 10 KPa O₂. This maintenance of V_b is consistent in both large and small decapods, however the mechanism differs. In grass shrimp, V_S was P_O2 dependent and declined significantly while f_H increased significantly when P_O2 was reduced to 13.3 KPa O₂.     

Direct Fick application for measurement of cardiac output in rat.

The direct Fick procedure for cardiac output determination in rat was validated by simultaneous comparison with electromagnetic flowmeter techniques. Significant coefficients of correlation were obtained between absolute cardiac output values (r = 0.789, P less than 0.001), increases (r = 0.768, P less than 0.001) and decreases (r = 0.672, P less than 0.01) in cardiac output detected by the two methods. As demonstrated in other species, cardiac output values of the Fick procedure in the rat were between 40 and 58% greater than respective electromagnetic flow probe values; however, percent changes in cardiac output obtained by the two methods were similar. The larger values of cardiac output obtained by the direct Fick method may be related, to a great extent, to the distribution of blood flow to the coronary and bronchial circulations. Fick cardiac output measurements were reproducible within rats, and the degree of variation in values among rats was similar to that obtained with the flowmeter procedure. The result indicate that the Fick meth od provides a valid estimation of cardiac output in the rat, with the ability to detect moderate changes (22-36%) in cardiac output.     

Amiloride but Not Memantine Reduces Neurodegeneration,Seizures and Myoclonic Jerks in Rats with Cardiac Arrest-Induced Global Cerebral Hypoxia and Reperfusion

It has been reported that both activation of N-methyl-D-aspartate receptors and acid-sensing ion channels during cerebral ischemic insult contributed to brain injury. But which of these two molecular targets plays a more pivotal role in hypoxia-induced brain injury during ischemia is not known. In this study, the neuroprotective effects of an acid-sensing cation channel blocker and an N-methyl-D-aspartate receptor blocker were evaluated in a rat model of cardiac arrest-induced cerebral hypoxia. We found that intracisternal injection of amiloride, an acid-sensing ion channel blocker, dose-dependently reduced cerebral hypoxia-induced neurodegeneration, seizures, and audiogenic myoclonic jerks. In contrast, intracisternal injection of memantine, a selective uncompetitive N-methyl-D-aspartate receptor blocker, had no significant effect on cerebral hypoxia-induced neurodegeneration, seizure and audiogenic myoclonic jerks. Intracisternal injection of zoniporide, a specific sodium-hydrogen exchanger inhibitor, before cardiac arrest-induced cerebral hypoxia, also did not reduce cerebral hypoxia-induced neurodegeneration, seizures and myoclonic jerks. These results suggest that acid-sensing ion channels play a more pivotal role than N-methyl-D-aspartate receptors in mediating cerebral hypoxia-induced brain injury during ischemic insult.     

Exhaled NO is reduced at an early stage of hypoxia-induced pulmonary hypertension in newborn piglets

Altered nitric oxide (NO) production could contribute to the pathogenesis of hypoxia-induced pulmonary hypertension. To determine whether parameters of lung NO are altered at an early stage of hypoxia-induced pulmonary hypertension, newborn piglets were exposed to room air (control, n = 21) or 10% O(2) (hypoxia, n = 19) for 3-4 days. Some lungs were isolated and perfused for measurement of exhaled NO output and the perfusate accumulation of nitrite and nitrate (NOx-), the stable metabolites of NO. Pulmonary arteries (20-600-microm diameter) and their accompanying airways were dissected from other lungs and incubated for NOx- determination. Abundances of the nitric oxide synthase (NOS) isoforms endothelial NOS and neural NOS were assessed in homogenates of PAs and airways. The perfusate NOx- accumulation was similar, whereas exhaled NO output was lower for isolated lungs of hypoxic, compared with control, piglets. The incubation solution NOx- did not differ between pulmonary arteries (PAs) of the two groups but was lower for airways of hypoxic, compared with control, piglets. Abundances of both eNOS and nNOS proteins were similar for PA homogenates from the two groups of piglets but were increased in airway homogenates of hypoxic compared with controls. The NO pathway is altered in airways, but not in PAs, at an early stage of hypoxia-induced pulmonary hypertension in newborn piglets.     

Estimation of changes in instantaneous aortic blood flow by the analysis of arterial blood pressure

The purpose of this study was to introduce and validate a new algorithm to estimate instantaneous aortic blood flow (ABF) by mathematical analysis of arterial blood pressure (ABP) waveforms. The algorithm is based on an autoregressive with exogenous input (ARX) model. We applied this algorithm to diastolic ABP waveforms to estimate the autoregressive model coefficients by requiring the estimated diastolic flow to be zero. The algorithm incorporating the coefficients was then applied to the entire ABP signal to estimate ABF. The algorithm was applied to six Yorkshire swine data sets over a wide range of physiological conditions for validation. Quantitative measures of waveform shape (standard deviation, skewness, and kurtosis), as well as stroke volume and cardiac output from the estimated ABF, were computed. Values of these measures were compared with those obtained from ABF waveforms recorded using a Transonic aortic flow probe placed around the aortic root. The estimation errors were compared with those obtained using a windkessel model. The ARX model algorithm achieved significantly lower errors in the waveform measures, stroke volume, and cardiac output than those obtained using the windkessel model (P < 0.05).     

Investigations concerning the application of the cross-correlation method in cardiac output measurements

ABSTRACT: BACKGROUND: In spite of numerous non-invasive examinations the "gold clinical standard" of cardiac output measurements is the invasive pulmonary artery catheterization by means of the Swan-Ganz catheter and the application of the thermodilution method to estimate the blood flow. The results obtained by means of thermodilution are sensitive to many physical and biological disturbances. The unreliability of this method amounts to 20-45% and depends on the given variant of the method. Therefore some other method, more accurate and resistant to disturbances, was looked for. This paper presents a new approach to cardiac output measurements, based on cross-correlation signal analysis. The goal of investigations was to verify experimentally the application of the cross-correlation method of cardiac output measurements. RESULTS: In 99.2% of the examined cases the extreme of the cross-correlation function was easy to be estimated by numerical algorithms. In 0,8% of the remaining cases (with a plateau region adjacent to the maximum point) numerical detection of the extreme was inaccurate. The typical unreliability of the investigated method amounted o 5.1% (9.8% in the worst case). Investigations performed on a physical model revealed that the unreliability of cardiac output measurements by means of the cross-correlation method is 3-5 times better than in the case of thermodilution. CONCLUSIONS: The performed investigations and theoretical analysis have shown, that the cross-correlation method may be applied in cardiac output measurements. This kind of measurements seems to be more accurate and disturbance-resistant than clinically applied thermodilution.     

Measuring stroke volume of the ascending aorta with an extravascular Doppler ultrasound probe in comparison with aortic thermodilution]

Currently, no reliable minimally invasive method of measuring cardiac output continuously in neonates and children undergoing cardiac surgery is available. An extravascular Doppler probe was used to measure cardiac output in 15 New Zealand White rabbits (average weight 3.5 kg, range 2.5-4.5 kg). The results obtained were compared with cardiac outputs determined using the aortic thermodilution principle. The mean cardiac outputs measured with the extravascular Doppler probe was 0.37 +/- 0.01 l/min as compared with 0.39 +/- 0.01 l/min with aortic thermodilution. Regression analysis revealed a close correlation (r = 0.973) between the two techniques. The extravascular Doppler techniques is an option for continuous and reliable cardiac output measurement in small animals used in surgical experiments (open chest models) and in neonates or children during surgical repair of complicated congenital heart conditions.     

Non-invasive assessment of cardiac output and stroke volume in patients during exercise. Evaluation of a CO2-rebreathing method

A one-step CO2 rebreathing method for the determination of cardiac output and stroke volume (SV) has been evaluated by comparison with the direct Fick technique during recumbent exercise (10-90 W) in 13 patients. In an initial analysis, the influence of different rebreathing times and of correction for haemoglobin concentration was studied. The best correlation with the direct Fick technique was obtained with the longest analysis time, i.e. 21 s, and correction for variations in haemoglobin concentration further improved the correlation. Consequently, an analysis time of 21 s and correction for haemoglobin have been used. At low cardiac outputs, the CO2-rebreathing method overestimated the flow compared to the Fick technique. The correlation between the methods, however, was so good that a valid estimate of cardiac output could be obtained from the CO2 rebreathing method with appropriate corrections (Cardiac output, CO2 method = 2.7 + 0.77. Cardiac output, Fick; r = 0.91; Residual Standard deviation (SD res) = 0.77 l X min-1). Stroke volumes measured with the CO2 rebreathing method did not differ significantly from those obtained with the direct Fick technique, although there was a tendency to overestimate stroke volume with the CO2 rebreathing method (SV, CO2 method = 12 + 0.89 X SV, Fick; r = 0.82; SD res = 11 ml).     

Measurement of cardiac output by electrical impedance plethysmography

There are many potential applications for cardiac output measurement in clinical and experimental medicine. The most commonly used techniques are invasive procedures, requiring cardiac or arterial catheterization, a disadvantage that has restricted their wider application. Impedance plethysmography has been developed as a non-invasive, beat-by-beat method of cardiac output measurement, which provides an estimate of stroke volume from changes in the electrical impedance of the thorax during cardiac systole. The values for cardiac output obtained by this technique have been extensively compared with values obtained by other methods, both in experimental animals and in the human subject. In the majority of studies high correlation coefficients have been obtained, although impedance plethysmography has tended to give higher absolute values than most other methods. Values for cardiac output obtained by impedance plethysmography are best assessed by comparison with a series of normal values obtained by this technique, rather than with values obtained by other methods. We discuss the results of an investigation of normal cardiac output by impedance plethysmography; theoretical objections to impedance cardiography are considered, and various methods of determining the specific resistivity of blood are reviewed.     

Atrial natriuretic peptide lowers pulmonary arterial pressure in hypoxia-adapted rats

To test the hypothesis that atrial natriuretic peptide (ANP) has a direct vasodilator effect on the pulmonary vasculature that is enhanced in hypoxia-induced pulmonary hypertension in the rat, we determined the effects of ANP on mean pulmonary (MPAP) and systemic arterial pressure (MSAP) in intact conscious Sprague-Dawley rats exposed to 10% O2 or room air for 4 wk. Catheters were placed in the pulmonary artery through the right jugular vein by means of a closed-chest technique. MPAP and MSAP were monitored before and after intravenous injections of graded doses of ANP. ANP produced dose-related decreases in MPAP that were greater in the hypoxic group than in air controls. There were no significant between-group differences in the systemic depressor responses to ANP or in the ANP-induced reduction in cardiac output. ANP lowered MPAP significantly in isolated perfused lungs from both hypoxia-adapted and air control rats, and this effect was significantly greater in the hypoxic than the air control lungs. These data indicate that ANP lowers pulmonary arterial pressure in rats with hypoxia-induced pulmonary hypertension, mainly by a direct vasodilator effect on the pulmonary vasculature.     

PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats.

Chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodeling in rats. Because platelet-activating factor (PAF) levels increase in lung lavage fluid and in plasma from chronically hypoxic rats, we examined the effect of two specific, structurally unrelated PAF antagonists, WEB 2170 and BN 50739, on hypoxia-induced pulmonary vascular remodeling. Treatment with either agent reduced hypoxia-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk of hypoxic exposure (simulated altitude 5,100 m) but did not affect cobalt (CoCl2)-induced pulmonary hypertension. The PAF antagonists had no effect on the hematocrit of normoxic or chronically hypoxic rats or CoCl2-treated rats. Hypoxia-induced pulmonary hypertension was associated with an increase in the vessel wall thickness of the muscular arteries and reduction in the number of peripheral arterioles. In WEB 2170-treated rats, these changes were significantly less severe than those observed in untreated chronically hypoxic rats. PAF receptor blockade had no acute hemodynamic effects; i.e., it did not affect pulmonary arterial pressure or cardiac output nor did it affect the magnitude of acute hypoxic pulmonary vasoconstriction in awake normoxic or chronically hypoxic rats. Isolated lungs from chronically hypoxic rats showed a pressor response to the chemotactic tripeptide N-formyl-Met-Leu-Phe (fMLP) and an increase in the number of leukocytes lavaged from the pulmonary circulation. In vivo treatment with WEB 2170 significantly reduced the fMLP-induced pressor response compared with that observed in isolated lungs from untreated chronically hypoxic rats. These results suggest that PAF contributes to the development of chronic pulmonary hypertension induced by chronic hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypoxia induces activation and subcellular translocation of focal adhesion kinase (p125(FAK)) in cultured rat cardiac myocytes.

We previously reported that hypoxia caused rapid activation of RAS/mitogen-activated protein kinase (MAPK) pathway, two other stress-activated MAPK family members, stress-activated protein kinase (SAPK) and p38MAPK, and Src family tyrosine kinases, p60(c-src) and p59(c-fyn) in cultured rat cardiac myocytes. In this study, to elucidate how hypoxia affects adhesive interaction between cardiac myocytes and extracellular matrix (ECM), we investigated the molecular mechanism of the activation of focal adhesion-associated tyrosine kinases p125(FAK) and paxillin. Here, we show that hypoxia induced tyrosine phosphorylation of p125(FAK) and paxillin and that hypoxia-induced activation of p125(FAK) was accompanied by its increased association with adapter proteins Shc and GRB2, and non-receptor type tyrosine kinase p60(c-src). Furthermore, hypoxia caused subcellular translocation of p125(FAK) from perinuclear sites to the focal adhesions. These results strongly suggest that p125(FAK) is one of the most important components in hypoxia-induced intracellular signaling in cardiac myocytes and may play a pivotal role in adhesive interaction between cardiac myocytes and ECM.     

Modelflow underestimates cardiac output in heat-stressed individuals

An estimation of cardiac output can be obtained from arterial pressure waveforms using the Modelflow method. However, whether the assumptions associated with Modelflow calculations are accurate during whole body heating is unknown. This project tested the hypothesis that cardiac output obtained via Modelflow accurately tracks thermodilution-derived cardiac outputs during whole body heat stress. Acute changes of cardiac output were accomplished via lower-body negative pressure (LBNP) during normothermic and heat-stressed conditions. In nine healthy normotensive subjects, arterial pressure was measured via brachial artery cannulation and the volume-clamp method of the Finometer. Cardiac output was estimated from both pressure waveforms using the Modeflow method. In normothermic conditions, cardiac outputs estimated via Modelflow (arterial cannulation: 6.1 ± 1.0 l/min; Finometer 6.3 ± 1.3 l/min) were similar with cardiac outputs measured by thermodilution (6.4 ± 0.8 l/min). The subsequent reduction in cardiac output during LBNP was also similar among these methods. Whole body heat stress elevated internal temperature from 36.6 ± 0.3 to 37.8 ± 0.4°C and increased cardiac output from 6.4 ± 0.8 to 10.9 ± 2.0 l/min when evaluated with thermodilution (P < 0.001). However, the increase in cardiac output estimated from the Modelflow method for both arterial cannulation (2.3 ± 1.1 l/min) and Finometer (1.5 ± 1.2 l/min) was attenuated compared with thermodilution (4.5 ± 1.4 l/min, both P < 0.01). Finally, the reduction in cardiac output during LBNP while heat stressed was significantly attenuated for both Modelflow methods (cannulation: -1.8 ± 1.2 l/min, Finometer: -1.5 ± 0.9 l/min) compared with thermodilution (-3.8 ± 1.19 l/min). These results demonstrate that the Modelflow method, regardless of Finometer or direct arterial waveforms, underestimates cardiac output during heat stress and during subsequent reductions in cardiac output via LBNP.     

Gender-related differences in proliferative response of cardiac fibroblasts to hypoxia

Ischemic heart disease is more prevalent in men than in women. The remodeling of extracellular matrix, is a structural correlate of heart failure of ischemic origin and proliferation of cardiac fibroblasts is a key factor in this remodeling. We asked if proliferative response of male and female cardiac fibroblasts is differentially susceptible to hypoxia. DNA synthesis, using 3H-thymidine incorporation was compared under hypoxia (2% O₂) in cardiac fibroblasts obtained from adult, age-matched male and female rat heart. In female cells DNA synthesis remained unchanged under hypoxia and this resistance was dependent on tyrosine kinase activation, as it was abolished in the presence of genistein, a tyrosine kinase inhibitor. Male cells, on the other hand, were susceptible to hypoxia and their DNA synthesis was reduced significantly (70%, (p < 0.0001). This effect was partially reversed by inhibition of tyrosine kinase. Western analysis showed a higher abundance of tyrosine phosphorylated proteins in male cells compared to female cells as well as differences in molecular weight of basal and hypoxia-induced tyrosine-phosphorylated proteins between male and female cells. The presence of estrogen (17- estradiol, 10 nM) altered the response of both cells to hypoxia. In female cells the combined effect of hypoxia and estrogen led to inhibition of DNA synthesis, whereas in male cells estrogen partially reversed the hypoxia-induced inhibition of DNA synthesis (37% (p < 0.01) inhibition in the presence of estrogen vs. 70% (p < 0.0001) inhibition in the absence of estrogen). The effects of estrogen in male and female cells were mediated via estrogen receptors as they were reversed by the pure anti-estrogen, ICI 182,780. Western analysis of cell lysate showed hypoxia-induced increase in the level of estrogen receptor in both male and female cells. Gel shift analysis showed hypoxia-induced increase in cytoplasmic ERE (estrogen response element)-binding activity and decrease in nuclear ERE-binding in male cells. In female cells cytoplasmic and nuclear ERE-binding activities remained unchanged under hypoxia. Together, these data demonstrate that while female cells are resistant to hypoxia-induced inhibition in DNA synthesis, male cells are susceptible; intracellular pathways involving tyrosine phosphorylation are involved in the response of both cells; and estrogen, via estrogen-receptor-dependent mechanisms, differentially alters the response of male and female cells to hypoxia.     

Methods for global sensitivity analysis in life cycle assessment

Purpose

Input parameters required to quantify environmental impact in life cycle assessment (LCA) can be uncertain due to e.g. temporal variability or unknowns about the true value of emission factors. Uncertainty of environmental impact can be analysed by means of a global sensitivity analysis to gain more insight into output variance. This study aimed to (1) give insight into and (2) compare methods for global sensitivity analysis in life cycle assessment, with a focus on the inventory stage.

Methods

Five methods that quantify the contribution to output variance were evaluated: squared standardized regression coefficient, squared Spearman correlation coefficient, key issue analysis, Sobol’ indices and random balance design. To be able to compare the performance of global sensitivity methods, two case studies were constructed: one small hypothetical case study describing electricity production that is sensitive to a small change in the input parameters and a large case study describing a production system of a northeast Atlantic fishery. Input parameters with relative small and large input uncertainties were constructed. The comparison of the sensitivity methods was based on four aspects: (I) sampling design, (II) output variance, (III) explained variance and (IV) contribution to output variance of individual input parameters.

Results and discussion

The evaluation of the sampling design (I) relates to the computational effort of a sensitivity method. Key issue analysis does not make use of sampling and was fastest, whereas the Sobol’ method had to generate two sampling matrices and, therefore, was slowest. The total output variance (II) resulted in approximately the same output variance for each method, except for key issue analysis, which underestimated the variance especially for high input uncertainties. The explained variance (III) and contribution to variance (IV) for small input uncertainties were optimally quantified by the squared standardized regression coefficients and the main Sobol’ index. For large input uncertainties, Spearman correlation coefficients and the Sobol’ indices performed best. The comparison, however, was based on two case studies only.

Conclusions

Most methods for global sensitivity analysis performed equally well, especially for relatively small input uncertainties. When restricted to the assumptions that quantification of environmental impact in LCAs behaves linearly, squared standardized regression coefficients, squared Spearman correlation coefficients, Sobol’ indices or key issue analysis can be used for global sensitivity analysis. The choice for one of the methods depends on the available data, the magnitude of the uncertainties of data and the aim of the study.

     

Hemodynamic effects of arginine vasopressin in rats adapted to chronic hypoxia

Acute and chronic pulmonary and systemic hemodynamic responses to arginine vasopressin (AVP) were examined in 4-wk hypoxia-adapted and air control rats. AVP, administered intravenously as bolus injections or sustained infusions, produced major dose-dependent V1-receptor-mediated reductions in mean pulmonary arterial pressure in hypoxia-adapted rats. These effects were comparable in pentobarbital-anesthetized, thoracotomized animals and in conscious, intact rats. Chronic infusions of AVP induced a sustained reduction in mean pulmonary arterial pressure and partially prevented the development of pulmonary hypertension without changing systemic arterial pressure. AVP induced significant decreases in cardiac output in both groups; the cardiac output response was not significantly different in hypoxia-adapted and air control animals. AVP induced almost no change in MPAP in air control rats. Furthermore the systemic pressor effects of AVP were significantly blunted in hypoxia-adapted rats compared with air controls. We conclude that the pulmonary depressor and blunted systemic pressor effects of AVP observed in hypoxia-adapted rats may be related to release of a vasodilator, such as endothelium-derived relaxing factor, vasodilator prostaglandins, or atrial natriuretic peptides. Further study is needed to elucidate these mechanisms and assess the usefulness of AVP and/or its analogues in the treatment and prevention of hypoxia-induced pulmonary hypertension.     

Haemodynamic Effects of Salbutamol in Patients Needing Circulatory Support after Open-heart Surgery

The effects of substituting an infusion of salbutamol for isoprenaline were studied in 12 patients needing circulatory support after valve replacement surgery. The cardiac output rose while the heart rate remained unaltered. There was a reduction in systemic vascular resistance, and though the oxygen uptake tended to rise the increase in cardiac output was proportionately greater so that the arteriovenous oxygen difference fell.It is suggested that the drug is of value for two reasons. It causes a selective reduction in peripheral arteriolar resistance, which avoids peripheral pooling, but permits limited myocardial work to be used to generate flow rather than pressure, and the increase in cardiac output is not accompanied by a corresponding rise in oxygen uptake.     

Thiamine attenuates hypoxia-induced cell death in cultured neonatal rat cardiomyocytes

Previous studies have demonstrated that thiamine (vitamin B1) has a cytoprotective effect against ischemic damage to the heart, and that heat shock protein 70 (Hsp70) is capable of protecting cardiac cells from lethal ischemia/hypoxia. We show here that thiamine has a cytoprotective effect on cultured neonatal rat cardiomyocytes under hypoxic insult, and also protects the cardiomyocytes against hypoxia-induced apoptosis; caspase-3 activation, PARP cleavage and DNA fragmentation are all inhibited. Moreover, it increases the level of Hsp70 protein in the cardiomyocytes even under prolonged hypoxic stress and its effects on hypoxia-induced cardiac cell death are antagonized by an Hsp70 inhibitor. These results suggest that the cytoprotective effect of thiamine in cardiomyocytes under hypoxic stress is due to its ability to induce Hsp70.