Maximum Rate Of Pressure Development Research Articles

The effects of glycine, glutamate and their combination on cardiodynamics, coronary flow and oxidative stress in isolated rat hearts

Objectives: To examine the effects of glycine, glutamate and their combination on cardiac function, coronary flow and oxidative stress in isolated rat hearts, and to examine the effects of potential activation of N-methyl-Daspartate (NMDA) receptors in isolated rat hearts. Methods: The hearts of male Wistar albino rats were excised and perfused according to the Langendorff technique, and cardiodynamic parameters (maximum rate of pressure development in the left ventricle [dp/dt max]; minimum rate of pressure development in the left ventricle [dp/dt min], systolic left ventricular pressure, diastolic left ventricular pressure, heart rate) and coronary flow were determined during the subsequent administration of glycine, glutamate and their combination. Oxidative stress biomarkers, including thiobarbituric acid-reactive substances, nitrites (NO2 −), superoxide anion radical (O2 −) and hydrogen peroxide (H2O2), were each determined spectrophotometrically in coronary venous effluent. Results: Treatment with glycine and glutamate alone did not cause a statistically significant change in any of the observed parameters; however, their combined administration induced significant decreases in dp/dt max, dp/dt min, heart rate and coronary flow compared with the control conditions. Treatment with glycine and glutamate together induced significant increases in NO2 −, O2 − and H2O2 levels. After the washout period, all parameters that had changed (cardiodynamic parameters, coronary flow and levels oxidative stress biomarkers) returned to values that were not significantly different from controls. Conclusions: The results of the present study indicate that NMDA receptors likely have important roles in the function of the heart and coronary circulation. In addition, these results are suggestive of a damaging effect of NMDA receptor overstimulation in heart functioning, potentially mediated by oxidative stress.

Endurance exercise attenuates cardiotoxicity induced by androgen deprivation and doxorubicin.

Doxorubicin (DOX) is associated with cardiac dysfunction and irreversible testicular damage. Androgen deprivation therapy (ADT) is administered prior to DOX treatment to preserve testicular function. However, ADT may exacerbate DOX-induced cardiac dysfunction. Exercise is cardioprotective, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. In this study, male Sprague-Dawley rats were randomly assigned to experimental groups: control (CON), ADT, DOX, or ADT+DOX. Animals received ADT or control implants on days 1 and 29 of the 56-day protocol. Animals remained sedentary (SED) or engaged in treadmill endurance exercise (TM) beginning on day 1. On day 15, the animals received DOX at 1 mg·(kg body mass)(-1)·d(-1) by intraperitoneal injection for 10 consecutive days, or an equivalent volume of saline. On day 57, cardiac function was assessed in vivo and ex vivo. Animals treated with DOX alone, or with combined ADT+DOX, showed significant (P < 0.05) reductions in left ventricular developed pressure (-21% and -27%), maximal rate of pressure development (-29% and -32%), and maximal rate of pressure decline (25% and 31%), respectively when compared with the sedentary control animals. Endurance exercise training attenuated (P > 0.05) cardiac dysfunction associated with combined ADT+DOX treatment, indicating that exercise during simultaneous ADT+DOX treatment is cardioprotective.

The Effects of Diclofenac and Ibuprofen on Heart Function and Oxidative Stress Markers in the Isolated Rat Heart

ABSTRACT Eicosanoids lead to the promotion of inflammation, cause fever and pain and have many other eff ects. NSAIDs block the action of cyclooxygenase (COX) during the process of converting arachidonic acid into inflammatory mediators, thus reducing the symptoms of inflammation. Investigations focusing on nonselective COX inhibitors, used in high doses, revealed harmful eff ects on myocardial function. Th e aim of our study was to assess the eff ects of two nonselective NSAIDs, diclofenac and ibuprofen, on cardiodynamic parameters, coronary flow and oxidative stress biomarkers in isolated rat hearts. Th e hearts of male Wistar albino rats were excised and retrogradely perfused according to the Langendorff technique at gradually increased coronary perfusion pressures (40-120 cm H2O). Th e experiments were performed under controlled conditions (Krebs-Henseleit physiological solution). Th e hearts were perfused with 10 μmol/l diclofenac and 10 μmol/l ibuprofen. Th e heart function parameters, including the maximum rate of pressure development (dp/dt max), minimum rate of pressure development (dp/dt min), systolic left ventricular pressure (SLVP), diastolic left ventricular pressure (DLVP), mean perfusion pressure (MBP) and heart rate (HR), were continuously registered. Coronary flow (CF) was measured flowmetrically. Oxidative stress markers, including the index of lipid peroxidation measured as TBARS, nitric oxide measured through nitrites (NO2 -), superoxide anion radical (O2 -), and hydrogen peroxide (H2O2) in the coronary venous effluent, were assessed spectrophotometrically. Our results showed that diclofenac aff ected cardiodynamic parameters more significantly than did ibuprofen. Furthermore, the present data indicate that both estimated COX inhibitors do not promote the production of reactive oxygen species.

Complex study of the rat heart at isoproterenol damage

Introduction of isoproterenol (an agonist of beta-adrenoreceptors) to rats is one of the widespread experimental models of cardiac failure. It is caused by damage of cardiomyocytes with the subsequent development of substitutive fibrosis. The purpose of the given work was the complex characteristic of cardiac function by means of invasive and noninvasive (echocardiography and impedansometry) methods of research. Isoproterenol was injected twice with a daily interval in dozes 85, 120, 150 or 180 mg/kg. Echocardiographic study of the heart in 2 weeks revealed obvious attributes of cardiac failure (left ventricular dilatation, lowered ejection fraction) in the groups which have received high cumulative dozes of isoproterenol (300-360 mg/kg). The catheterization of the left ventricle in these groups has shown raised enddiastolic pressure, decreased maximal rate of pressure development and fall, and also lowered indices of myocardial contractility and relaxability. In the groups which have received smaller isoproterenol dozes, apparent decrease in relaxability parameters (constants of isovolumic and auxovolumic relaxation) has been revealed at only slightly changed parameters of contractility. A strong correlation between echocardiographic and invasive parameters of myocardial contractility has been found. The phase analysis of the cardiac cycle has shown a lengthening of isometric phases of contraction and relaxation, as well as duration of ejection due to shortening duration of filling of both ventricles. Cardiomyocytes isolated from hearts with obvious cardiac failure responded to electrostimulation by arrhythmic contractions and also by much slowed and incomplete removal of free Ca++ from the myoplasm. Results allow to conclude that relatively smaller extent of myocardial damage is accompanied by decreased relaxability at slightly changed contractility, while at greater degree of damage both processes fail, but delay of relaxation still prevails.

Maximum Rate of Pressure Development and Maximal Relaxation Rate of Respiratory Muscles in Patients with Cystic Fibrosis

Respiratory muscle function in patients with cystic fibrosis (CF) has been studied by measurement of maximal inspiratory pressure (P(Imax)), maximal expiratory pressure (P(Emax)), and the pressure-time index of the respiratory muscles (PTI(mus)). The maximum rate of pressure development (MRPD) during P(Imax) (MRPD-P(Imax)), MRPD during P(Emax) (MRPD-P(Emax)), maximal relaxation rate (MRR) during P(Imax) (MRR-P(imax)), and MRR during P(Emax) (MRR-P(Emax)) have not been studied in CF. Our aim was to study MRPD and MRR and investigate their possible application as accessory indices of respiratory muscle function in patients with CF. FEVY, FVC, and maximal expiratory flow between 25% and 75% of vital capacity, body mass index (BMI), upper arm muscle area, P(imax), P(Emax), PTI(mus), MRPD-P(Imax), MRPD-P(Emax), MRR-P(imax), and MRR-P(Emax) were assessed in 123 CF patients and in a control group of 123 healthy subjects matched for age and sex. MRR-P(Emax) was significantly increased and MRPD-P(Emax) was significantly decreased in the CF patients, compared to the healthy controls. In the CF patients MRR-P(Imax) was significantly related to PTI(mus) (P = .02), FEV1 (P = .03), FVC (P = .001), BMI (P < .001), and upper arm muscle area (P < .001). In the CF patients, MRPD-P(Imax) and MRPD- P(Emax) were significantly related to upper arm muscle area (P < .001), BMI (P < .001 and P = .01, respectively), P(Imax) (P < .001), and P(Emax) (P < .001). The CF patients exhibited increased MRR and decreased MRPD during maximal respiratory effort, compared to controls. The differences in MRR-P(imax) and MRPD-P(Imax) between the controls and the complete group of CF patients were not significant. MRPD and MRR were significantly related to nutritional and pulmonary function impairment in CF patients. MRPD strongly correlated to maximal respiratory muscle pressures, and MRR strongly correlated to PTI(mus) in patients with CF. These findings suggest that CF patients are at increased risk of respiratory muscle fatigue. Regular determination of MRPD and MRR may be clinically useful in CF patients and help to initiate inspiratory muscle training and noninvasive ventilation.

The effects of homocysteine-related compounds on cardiac contractility, coronary flow, and oxidative stress markers in isolated rat heart

Research on the effects of homocysteine on the vascular wall, especially in endothelial and smooth muscle cells, has indicated that increased homocysteine levels lead to cellular stress and cell damage. Considering the adverse effects of homocysteine on vascular function and the role of oxidative stress in these mechanisms, the aim of this study was to estimate the influence of different homocysteine isoforms on cardiac contractility, coronary flow, and oxidative stress markers in isolated rat heart. The hearts of male Wistar albino rats (n = 36, age 8 weeks, body mass 180-200 g), were excised and retrogradely perfused according to the Langendorff technique at a constant perfusion pressure (70 cmH(2)O) and administered with three isoforms of 10 μM homocysteine [DL-Hcy, DL-Hcy thiolactone-hydrochloride (TLHC) and L-Hcy TLHC). After the insertion and placement of the sensor in the left ventricle, the parameters of heart function: maximum rate of pressure development in the left ventricle (dP/dt max), minimum rate of pressure development in the left ventricle (dP/dt min), systolic left ventricular pressure (SLVP), diastolic left ventricular pressure (DLVP), mean blood pressure (MBP) and heart rate (HR)] were continuously registered. Flowmetry was used to evaluate the coronary flow. Markers of oxidative stress: index of lipid peroxidation measured as TBARS, nitric oxide measured through nitrites (NO(2)(-)), superoxide anion radical (O(2)(-)), and hydrogen peroxide (H(2)O(2)) in the coronary venous effluent were assessed spectrophotometrically. Our results showed that administration of Hcy compounds in concentration of 10 μM induced depression of cardiac contractility, manifested by a decrease in dp/dt max after administration of any Hcy compound, decrease in dp/dt min after administration of L-Hcy TLHC, decrease in SLVP after administration of DL-Hcy TLHC and DL-Hcy, and the drop in CF after administration of any Hcy compound. Regarding the effects of Hcy on oxidative stress parameters, only L-Hcy TLHC significantly affected O(2)(-) release. L-Hcy TLHC showed a cardiotoxic effect by affecting heart contractility, but surprisingly, it decreased the release of O(2)(-).

Test/Retest Reliability of Maximum Mouth Pressure Measurements With the MicroRPM in Healthy Volunteers

Respiratory muscle strength is an important part of lung function. Assessment of the respiratory muscles' ability to generate force is important for recognizing respiratory muscle weakness in both sick and healthy people. To assess the test/retest reliability of the MicroRPM portable manometer's measurements of maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) in the sitting and standing positions; the number of expiratory maneuvers needed with the MicroRPM for reliability in MIP and MEP measurement; and the MicroRPM's test/retest reliability in other respiratory function indices, such as the maximum rate of pressure development (MRPD), the time constant of relaxation (tau), and the maximum relaxation rate (MRR). We recruited 15 healthy volunteers (mean age 21.6 ± 1.1 years). We assessed respiratory muscle strength on 3 separate occasions, each a week apart. We calculated reliability with the intraclass correlation coefficient (ICC), the standard error of measurement (SEM) and the smallest detectable difference (SDD). MicroRPM reliably measured MIP and MEP in both the sitting position (ICC 0.86-0.90, SEM 9-10, SDD 18-22) and standing position (ICC 0.78-0.83, SEM 12-14, SDD 23-26). After a 5-breath practice, 2 expiratory/inspiratory maneuvers on each testing occasion gave adequate MIP and MEP reliability (ICC > 0.90). MRR reliability was moderate to excellent (ICC 0.58-0.87), MRPD reliability was moderate (ICC 0.59-0.64), and tau reliability was insufficient (ICC 0.27-0.67). The MicroRPM reliably measures MIP and MEP, but its MRPD, MRR, and tau measurements should be considered with caution.

Endurance Exercise Attenuates Cardiotoxicity Induced by Androgen Deprivation and Doxorubicin

Besides doxorubicin's (DOX) well known cardiotoxic effects, it is associated with irreversible testicular damage. In an attempt to preserve testicular function during DOX treatment, androgen deprivation therapy (ADT) using goserelin acetate is gaining clinical popularity as it temporarily suppresses gonadal function thereby minimizing DOX's gonadal damage. However, DOX's cardiac dysfunction is a major clinical concern as well, and evidence suggests that ADT may exacerbate DOX-induced cardiac dysfunction. Exercise has been shown to protect against DOX-induced cardiac dysfunction, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. PURPOSE: To determine whether exercise training can attenuate the combined cardiotoxic effects of ADT and DOX. METHODS: Male Sprague Dawley rats were randomly assigned to experimental groups: control implants (CON), androgen deprivation therapy (ADT), doxorubicin (DOX), or (ADT+DOX). Animals received ADT or control implants on day 1 and 29 of the 56 day protocol. Animals were then assigned to either sedentary activity (SED) or forced treadmill endurance exercise (TM). Exercise commenced the day after initial implants. On day 15, animals received 1 mg/kg/d DOX i.p. for 10 consecutive days or an equivalent volume of 0.9% saline. On day 57, cardiac function was assessed using an isolated perfused working heart model. RESULTS: When compared to sedentary CON, DOX and ADT+DOX treated animals possessed significantly depressed left ventricular developed pressure (-21% and -27%, respectively, P<0.05), maximal rate of pressure development (-29% and -32%, respectively, P<0.05), and maximal rate of pressure decline (25% and 31%, respectively, P<0.05). Exercise training during ADT+DOX treatment, however, attenuated the depression in left ventricular developed pressure, maximal rate of pressure development, and maximal rate of pressure decline (-9%, -8%, and 2%, respectively when compared to CON, P>0.05). CONCLUSIONS: Treadmill training protected against combined ADT+DOX dysfunction, suggesting that cardiac function can be preserved in the clinical setting if cancer survivors concurrently endurance train while undergoing ADT and DOX treatment.

Exercise Preconditioning Provides Long-Term Protection Against Early Chronic Doxorubicin Cardiotoxicity

Acute doxorubicin (DOX) cardiotoxicity can be attenuated by exercise preconditioning, but little is known of whether this cardioprotection continues beyond 10 days post-DOX administration. The purpose of this study was to determine the effects of exercise preconditioning on early chronic DOX-induced cardiotoxicity. Male rats were randomly assigned to sedentary, treadmill, or wheel running groups. Treadmill and wheel running animals participated in a progressive treadmill training protocol or voluntary wheel running, respectively, for 10 weeks. Following the intervention, animals were further randomized to receive either DOX (sedentary + DOX, treadmill + DOX, wheel running + DOX) or saline (sedentary + saline, treadmill + saline, wheel running + saline). All animals then remained sedentary for 4 weeks. A 22% reduction in fractional shortening was observed in left ventricles from previously sedentary animals receiving DOX when compared with sedentary + saline. This degree of decline was not observed in treadmill + DOX and wheel running + DOX. Sedentary + DOX possessed significantly depressed mitral and aortic valve blood flow velocities when compared with sedentary + saline, but these decrements were not observed in treadmill + DOX and wheel running + DOX. Ex vivo analysis revealed that left ventricular developed pressure and maximal rate of pressure development were significantly lower in sedentary + DOX when compared to sedentary + saline. Treadmill and wheel running prior to DOX treatment protected against these decrements. Exercise cardioprotection was associated with preserved myosin heavy chain but not sarcoendoplasmic reticulum Ca(2+) ATPase 2a expression. In conclusion, 10 weeks of prior exercise protected against early chronic DOX cardiotoxicity suggesting that training status may be a determining factor in the degree of late-onset cardiotoxicity experienced by cancer patients undergoing treatment with DOX.

Effect of simvastatin on collagen I deposition in non-infarcted myocardium: role of NF-κB and osteopontin

The novel biological effect of statins in alleviating myocardium fibrosis following infarction has been increasingly recognized, yet the underlying mechanisms are not fully understood. The purpose of this study was to characterize the effect of simvastatin on myocardial fibrosis and collagen I deposition in the non-infarcted region after myocardial infarction (MI) and to identify the role of NF-κB and osteopontin in simvastatin-mediated inhibition of post-MI collagen over-expression. A rat model of MI was generated by ligating the left anterior descending coronary artery. The rats surviving the MI operation were randomly divided into the following 3 groups: myocardial infarction (MI, vehicle), simvastatin (Sim, 30 mg·kg-1·day-1), and pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB, 100 mg·kg-1·day-1). Four weeks after MI, cardiac function, mRNAs, and protein expression in non-infarcted myocardium were analyzed. Myocardial fibrosis and collagen I over-expression were observed following MI, accompanied by an increase of NF-κB and osteopontin. Simvastatin improved post-MI left ventricular dysfunction and ameliorated post-MI associated changes to several cardiac parameters, including the left ventricular end diastolic pressure (LVEDP), the maximal rate of pressure development (+dP/dtmax), and the maximal rate of pressure decline (-dP/dtmax). Concurrently, simvastatin significantly suppressed the over-expression of NF-κB, osteopontin, and collagen I in the non-infarcted region following MI. Inhibition of NF-κB by PDTC also reduced osteopontin over-expression and excessive collagen I production and improved the above functional myocardial parameters. These results show that post-MI myocardial fibrosis and collagen I over-expression in the non-infarcted region is associated with activation of NF-κB and osteopontin up-regulation. The anti-fibrotic effect of simvastatin following MI is associated with the attenuation of the expression of osteopontin and NF-κB. The inhibition of NF-κB activation could be the process upstream of osteopontin suppression in the simvastatin-mediated effect.

Effect of Hemidesmus indicus on ischemia–reperfusion injury in the isolated rat heart

The root extract of Hemidesmus indicus (Linn.) R. Br. (Asclepiadaceae) (HI) was studied for its cardioprotective effect in Langendorff-perfused rat hearts. HI was perfused for 15 min at a concentration of 0.09 g/L prior to 30 min global ischemia/120 min reperfusion (I/R). Recovery of functional parameters, reperfusion arrhythmias, and infarct size (TTC staining) served as the end-points. After 15 min of perfusion with HI, the left ventricular developed pressure (LVdevP) and HR (heart rate) were not altered significantly (p > 0.05), as compared with the pre-drug values. During R, HI showed a significantly higher (p < 0.05) recovery of LVdevP at nearly all time points. The recovery of maximal rate of pressure development (+dP/dtmax) and left ventricular end-diastolic pressure (LVEDP) at 40 min of R were significantly better than in non-treated controls. There was also a significant reduction in the total number of ventricular premature beats (VPB) and duration of ventricular tachycardia (VT). HI can protect ischemic myocardium against contractile dysfunction and reperfusion-induced arrhythmias and reduce the extent of irreversible tissue damage following I/R in rat hearts.

Proinflammatory Events in Right Ventricular Damage During Pulmonary Embolism: Effects of Treatment With Ketorolac in Rats

Right ventricular (RV) damage contributes to poor clinical outcome after pulmonary embolism (PE). Our studies show that neutrophils contribute to RV dysfunction in rat PE. Present studies examine effects of the nonsteroidal anti-inflammatory drug, ketorolac, upon RV inflammation and dysfunction. RV inflammatory gene expression significantly increased 6 and 18 hours after PE [cytokine-induced neutrophil chemoattractant-1 (CINC-1) 18-fold and 24-fold; cyclooxygenase-2 21-fold and 32-fold]. Eighteen hours after PE, there was significant upregulation of adhesion molecules (selectin E 18-fold; intercellular adhesion molecule 1 14-fold), influx of neutrophils (myeloperoxidase activity 21-fold), depressed RV function (RV peak systolic pressure = 24 +/- 3 vs. 40 +/- 1 mm Hg; maximum rate of pressure development = 444 +/- 79 vs. 1533 +/- 146; maximum rate of pressure decrease = -357 +/- 50 vs. -651 +/- 44), and release of cardiac troponin I (7.8 +/- 1.9 ng/mL) compared with vehicle. Ketorolac (10 mg/kg, intraperitoneally) significantly reduced expression of CINC-1, cyclooxygenase-2, selectin E, and intercellular adhesion molecule 1, lowered neutrophil influx, improved RV function (RV peak systolic pressure was 34 +/- 3 mm Hg; maximum rate of pressure development = 1288 +/- 146; maximum rate of pressure decrease = -611 +/- 92), and marginally reduced cardiac troponin I release (P < 0.07) compared with PE alone. Ketorolac reduced CINC-1 stimulated chemotaxis of isolated neutrophils. PE converted cardiac tissue into a proinflammatory phenotype. Ketorolac reduced RV inflammatory genes, reduced neutrophil influx, and improved RV function in rat PE.

Effects Of Low Vs. High Intensity Short-term Exercise On Doxorubicin-induced Cardiotoxicity

Previously, we reported that short-term voluntary wheel running activity prior to doxorubicin (DOX) treatment protects against DOX cardiotoxicity. However, very little is known regarding the effect of exercise intensity on DOX-induced cardiac dysfunction. PURPOSE: To determine if short-term treadmill training at low or high intensity can attenuate the cardiac dysfunction that accompanies DOX in mature female rats. METHODS: Six month old female Sprague-Dawley rats (n=24) were randomly assigned to either sedentary (SED) or treadmill (TM) groups. TM animals participated in either a low intensity (TML) or a high intensity (TMH) progressive treadmill training protocol for 5 days. Following the activity period, animals in each group were randomly assigned to receive either a 15 mg·kg-1 cumulative dose of DOX (SED+DOX, TML+DOX, TMH+DOX) or saline (SED+SAL, TML+SAL, TMH+SAL). Left ventricle (LV) function was assessed ex vivo using an isolated working heart model 5 days post DOX exposure. RESULTS: A 44% reduction in end systolic pressure (ESP) was observed in SED+DOX when compared to SED+SAL (p<0.001). This degree of decline, however, was not observed in TML+DOX (-9%, p>0.05) and TMH+DOX (-13%, p>0.05) when compared to SED+SAL. Similarly, SED+DOX had significantly depressed LV developed pressure (-42%, p<0.001) when compared to SED+SAL, but this diminution was not observed in TML+DOX and TMH+DOX (p>0.05 vs. SED+SAL). LV maximal rate of pressure development (dP/dtmax) was significantly reduced after exposure to DOX in sedentary animals when compared to SED+SAL (p<0.001), however, prior treadmill training at either intensity TML+DOX or TMH+DOX attenuated the observed decrement induced by DOX (p>0.05). Likewise, lusitropic properties (dP/dtmin) were impaired in SED+DOX when compared to SED+SAL (p<0.01). However, this impairment was not evident in TML+DOX and TMH+DOX when compared to SED+SAL (p>0.05). CONCLUSION: Five days of treadmill preconditioning performed at either low or high intensity protected against DOX-induced cardiotoxicity possibly suggesting that cancer patients may benefit from variable exercise intensities prior to undergoing treatment with DOX.

Protective effect of total aralosides of Aralia elata (Miq) Seem (TASAES) against diabetic cardiomyopathy in rats during the early stage, and possible mechanisms

Total aralosides of Aralia elata (Miq) Seem (TASAES) from Chinese traditional herb Longya Aralia chinensis L was found to improve cardiac function. The present study was to determine the protective effects of TASAES on diabetic cardiomyopathy, and the possible mechanisms. Therefore, a single dose of streptozotocin was used to induce diabetes in Wister rats. Diabetic rats were immediately treated with low, medium and high doses of TASAES at 4.9, 9.8 mg/kg and 19.6 mg/kg body weight by gavage, respectively, for eight weeks. Cardiac function was evaluated by in situ hemodynamic measurements, and patch clamp for the L-type Ca2+ channel current I(Ca(2+)-L) and transient outward K+ channel current (I(to)). Histopathological changes were observed under light and electron microscope. The expression of pro-fibrotic factor, connective tissue growth factor (CTGF) was monitored using immunohistochemistry staining. Compared with diabetic group, medium and high doses, but not low dose, of TASAES showed a significant protection against diabetes-induced cardiac dysfunction, shown by increased absolute value of left ventricular systolic pressure (LVSP) and maximum rates of pressure development (+/-dp/dt(max)), and enhanced amplitude of I(Ca(2+)-L) (P<0.05). Histological staining indicated a significant inhibition of diabetes-caused pathological changes and up-regulation of CTGF expression (P< 0.05). The results suggest that TASAES prevents diabetes-induced cardiac dysfunction and pathological damage through up-regulating I(Ca(2+)-L) in cardiac cells and decreasing CTGF expression.

Moderate Acute Isovolemic Hemodilution Alters Myocardial Function in Patients with Coronary Artery Disease

Although moderate hemodilution is usually well tolerated in coronary artery surgery patients, this may not be the case when myocardial oxygen demand is increased. We hypothesized that, in these patients, hemodilution in the presence of an increased heart rate could be associated with an impairment of myocardial function. Forty coronary surgery patients were randomly assigned to two groups (n=20), according to the rate of atrioventricular pacing [70 bpm (Group 70) or 90 bpm (Group 90)]. While paced at the fixed heart rate, hemodilution was performed before the start of cardiopulmonary bypass. Data were obtained from a pulmonary artery, a PiCCO catheter and a left ventricular pressure catheter. Measurements were obtained in steady-state conditions before and after isovolemic hemodilution. Hemodilution from 40%+/-2% to 30%+/-1% in Group 70, and from 39%+/-4% to 30%+/-2% in Group 90 resulted in a decrease in systemic vascular resistance and an increase in end-diastolic volume in both groups. This was associated with an increase in stroke volume in Group 70 but not in Group 90. In this latter group, the maximal rate of pressure development decreased significantly after hemodilution [from 856+/-93 to 716+/-80 mm Hg/s (P<0.01)], whereas it remained unchanged in Group 70 (843+/-86 mm Hg/s before and 832+/-79 mm Hg/s after hemodilution). In the conditions of the present study, increased heart rate during moderate hemodilution was associated with a depression of myocardial function.

Slow contractions characterize failing rat hearts

The reduced power of the failing heart can be ascribed to a combination of reduced force and slower contraction. We hypothesized that these two properties are due to different cellular mechanisms. We measured contraction parameters both in vivo and in isolated left ventricular (LV) cardiomyocytes from a rat model of post infarction congestive heart failure (CHF). ECG was measured simultaneously with echocardiography and LV pressure, respectively. Shortening and shortening velocity (SV) in isolated cardiomyocytes were measured during different stimulation protocols. LV end diastolic pressure (LVEDP) was 24.6 +/- 0.7 mmHg in CHF. LV systolic pressure was decreased by 20%, maximum rate of pressure development in the LV (+dP/dtmax) by 36% and time in systole increased by 20% in CHF compared to sham. Electrical remodelling occurred in CHF cells, which were depolarized and had prolonged action potentials (AP) compared to sham cells. Fractional shortening (FS) was increased in CHF compared to sham independent of stimulation protocol. Larger FS was accompanied by increased sarcoplasmic reticulum (SR) Ca2+ load and depended on the electrical remodelling. Time to peak contraction (TTP) was increased in CHF compared to sham cells, but in contrast to FS, TTP was only slightly affected when the cells were stimulated with sham APs and sham diastolic membrane potential (DMP). Contraction duration (corresponding to systolic duration) was 25% longer in CHF than in sham independent on stimulation protocol. We conclude that electrical remodelling affecting DMP and AP duration (APD) significantly affects the size of contraction, whereas the mechanism for slowing of contraction in CHF is different.

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive C-fiber and Adelta-fiber sensory nerves, has been suggested to play a beneficial role in myocardial ischemia-reperfusion (I/R) injury. Because most previous studies showing a cardioprotective role of CGRP employed pharmacological experiments, the purpose of this study was to utilize a genetic approach by using mice with a targeted deletion of the alpha-CGRP gene to determine whether this neuropeptide had a modulatory function on the severity of I/R injury. To accomplish this goal, isolated, perfused hearts from alpha-CGRP knockout (KO) and wild-type (WT) mice were subjected to 30 min of ischemia followed by 5, 15, and 30 min of reperfusion. Cardiac functional parameters, including coronary flow rates, left ventricular developed pressure, maximum rates of pressure development, and left ventricular end-diastolic pressure, were measured before and after I/R injury, as were levels of creatine kinase, to assess myocardial damage, and malonaldehyde, to assess oxidative stress. Following I/R injury, cardiac performance was significantly reduced in the hearts from the alpha-CGRP KO mice compared with their WT counterparts. The marked reduction in myocardial function in the alpha-CGRP KO hearts compared with WT hearts after I/R injury was associated with a significant elevation in creatine kinase release into the perfusates and malonaldehyde production in the cardiac tissue. Therefore, these data indicate that, in this in vitro setting, deletion of alpha-CGRP makes the heart more vulnerable to I/R injury, possibly due, at least in part, to increased oxidative stress.

Effects of voluntary wheel running on cardiac function and myosin heavy chain in chemically gonadectomized rats

Reducing testosterone and estrogen levels with a luteinizing hormone-releasing hormone agonist such as Zoladex (i.e., chemical gonadectomy) is a common treatment for many prostate and breast cancer patients, respectively. There are reports of surgical gonadectomy inducing cardiac dysfunction, and exercise has been shown to be cardioprotective under these circumstances. Minimal research has been done investigating the effects of chemical gonadectomy and increased physical activity on cardiac function. The purpose of this investigation was to examine the effects of chemical gonadectomy and physical activity on cardiac function. Male (M) and female (F) Sprague-Dawley rats received either Zoladex treatment (Zol) that suppressed gonadal function for 8 wk or control implants (Con) and either were allowed unlimited access to voluntary running wheels (WR) or remained sedentary (Sed) throughout the treatment period. In vivo and ex vivo left ventricle (LV) function were then assessed, and myosin heavy chain (MHC) expression was analyzed to help explain LV functional differences. Hearts from M Sed+Zol exhibited significantly lower aortic blood flow velocity, developed pressure, and maximal rate of pressure development and higher beta-MHC expression than M Sed+Con. Hearts from F Sed+Zol exhibited significantly lower LV wall thicknesses, fractional shortening, and developed pressure and higher beta-MHC expression than F Sed+Con. This cardiac dysfunction was not evident in hearts from M or F WR+Zol, and this was associated with a preservation of the MHC isoform distribution. Thus an 8-wk chemical gonadectomy with Zoladex promoted cardiac dysfunction in male and female rats, and voluntary wheel running protected against this cardiac dysfunction.

Effects of Thalidomide on Isoprenaline‐Induced Acute Myocardial Injury: A Haemodynamic, Histopathological and Ultrastructural Study

In the present study, we investigated the cardioprotective effects of thalidomide in a rat model of acute myocardial injury, induced by subcutaneous injection of isoprenaline hemisulphate (85 mg/kg per day for 2 days). Thalidomide (75/150/300 mg/kg) or vehicle (dimethylsulphoxide) or saline (0.9% NaCl) was administered orally for 14 days and isoprenaline injection on the 12th and 13th days. Cardiovascular responses (arterial and left ventricular haemodynamic parameters and heart rate) were obtained in anaesthetized rats on the 14th day. Histopathological and electronmicroscopical analysis of myocardial injury was done. The results showed that thalidomide 300 mg/kg per day orally caused significant improvement in isoprenaline-induced reduction of cardiac function with increases in maximum rate of pressure development (+LVdP/dt, P < 0.001) and maximum rate of pressure decline (-LVdP/dt, P < 0.001) and decreases in left ventricular end-diastolic pressure (P < 0.01), systolic arterial pressure (P < 0.001), diastolic arterial pressure (P < 0.001), mean arterial pressure (P < 0.001) and heart rate (P < 0.001). The myocardial injury caused by isoprenaline was significantly reduced by thalidomide treatment as judged by the reduction of myocardial necrosis, ultrastructural changes such as mitochondria and myofibril damage, 300 mg/kg being the most effective dose. In conclusion, oral administration of thalidomide is able to ameliorate isoprenaline-induced myocardial injury and impaired myocardial function in spite of decreases in systolic arterial pressure, diastolic arterial pressure and mean arterial pressure, which may be due to its depressant effect on the sino-atrial node and sedative action.

Role of endogenous hydrogen peroxide in cardiovascular ischaemia/reperfusion function: Studies in mouse hearts with catalase-overexpression in the vascular endothelium

Hydrogen peroxide (H 2O 2) has been implicated as a component of oxidative ischaemia/reperfusion stress. We investigated the role of H 2O 2 in cardiovascular ischaemia/reperfusion stress in hearts from mice overexpressing catalase in their endothelial cells. Hearts of transgenic (TG, n = 9) and age-matched wild-type (WT, n = 7) mice were perfused at constant flow (2.2 ml min −1) and subjected to brief ischaemia and reperfusion. Intrinsic function and the effects of norepinephrine (3 nM–3 μM) were determined. Left ventricular pressure (LVDevP; balloon method), end-diastolic pressure (LVEDP), maximum rates of pressure development (+d P/d t, −d P/d t), coronary perfusion pressure (index of vascular function) and heart rate were recorded. Apart from a slightly higher recovery of LVDevP during reperfusion (+6 mmHg), neither systolic nor diastolic function was improved during ischaemia or reperfusion in TG hearts. However, hearts from TG mice exhibited a significantly better contractile response to noradrenergic stimulation (LVDevP: +20 mmHg or 1.15-fold increase; +d P/d t: +1476 mm Hg s −1 or 1.2-fold increase) ( P < 0.05). Norepinephrine relaxed the coronary microvasculature and increased heart rate, but no differences were detected between groups. We conclude that overexpressing catalase in endothelial cells is only weakly protective against myocardial or vascular ischaemia/reperfusion injury, but preserves the responsiveness of the heart to adrenergic stimulation.