Cromakalim and cicletanine against pacing-induced myocardial ischemia in conscious rabbits

Myocardial ischemia assessed by intracavital ST-segment elevation, shortening of ventricular effective refractory period (VERP), and increase in left ventricular end-diastolic pressure (LVEDP) was provoked by ventricular overdrive pacing (VOP) in conscious rabbits. Cromakalim (10 μg/kg), an ATP-sensitive K⁺ channel opener, and cicletanine (30 mg/kg), a cGMP-phosphodiesterase inhibitor, reduced VOP-induced ST-segment elevation and LVEDP-increase. Under resting conditions, cromakalim lowered blood pressure, increased heart rate (HR), and shortened VERP, whereas cicletanine decreased HR, prolonged VERP without changing blood pressure. Co-administration of cromakalim and cicletanine additively reduced VOP-induced ST-segment elevation, shortening of VERP, and LVEDP-increase. Cicletanine did not change cromakalim-induced hypotension but abolished reflexogenic tachycardia. This suggests that VERP shortening is not a prerequisite for the anti-ischemic effect of cromakalim, and the combination of these drugs may afford a potent and safe anti-ischemic effect without affecting hypotension induced cromakalim.     

Regulation of cardiac sarcolemmal Ca2+ channels and Ca2+ transporters by thyroid hormone

In order to examine the regulatory role of thyroid hormone on sarcolemmal Ca²⁺-channels, Na⁺–Ca²⁺ exchange and Ca²⁺-pump as well as heart function, the effects of hypothyroidism and hyperthyroidism on rat heart performance and sarcolemmal Ca²⁺-handling were studied. Hyperthyroid rats showed higher values for heart rate (HR), maximal rates of ventricular pressure development+(dP/dt)max and pressure fall–(dP/dt)max, but shorter time to peak ventricular pressure (TPVP) and contraction time (CT) when compared with euthyroid rats. The left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP), as well as aortic systolic and diastolic pressures (ASP and ADP, respectively) were not significantly altered. Hypothyroid rats exhibited decreased values of LVSP, HR, ASP, ADP, +(dP/dt)max and –(dP/dt)max but higher CT when compared with euthyroid rats; the values of LVEDP and TPVP were not changed. Studies with isolated-perfused hearts showed that while hypothyroidism did not modulate the inotropic response to extracellular Ca²⁺ and Ca²⁺ channel blocker verapamil, hyperthyroidism increased sensitivity to Ca²⁺ and decreased sensitivity to verapamil in comparison to euthyroid hearts. Studies of [³H]-nitrendipine binding with purified cardiac sarcolemmal membrane revealed decreased number of high affinity binding sites (B_max) without any change in the dissociation constant for receptor-ligand complex (K_d) in the hyperthyroid group when compared with euthyroid sarcolemma; hypothyroidism had no effect on these parameters. The activities of sarcolemmal Ca²⁺-stimulated ATPase, ATP-dependent Ca²⁺ uptake and ouabain-sensitive Na⁺–K⁺ ATPase were decreased whereas the Mg²⁺-ATPase activity was increased in hypothyroid hearts. On the other hand, sarcolemmal membranes from hyperthyroid samples exhibited increased ouabain-sensitive Na⁺–K⁺ ATPase activity, whereas Ca²⁺-stimulated ATPase, ATP-dependent Ca²⁺ uptake, and Mg²⁺-ATPase activities were unchanged. The V_max and K_a for Ca²⁺ of cardiac sarcolemmal Na⁺–Ca²⁺ exchange were not altered in both hyperthyroid and hypothyroid states. These results indicate that the status of sarcolemmal Ca²⁺-transport processes is regulated by thyroid hormones and the modification of Ca²⁺-fluxes across the sarcolemmal membrane may play a crucial role in the development of thyroid state-dependent contractile changes in the heart.     

Effects of estrogen on venous function in rats with chronic heart failure

The effect of 17beta-estradiol on venous function was investigated in ovariectomized rats with heart failure. Rats (50-60 days old) were ovariectomized and implanted with 60-day-release pellets that contain 17beta-estradiol (1.5 mg) or vehicle. The left coronary artery was ligated 7 days later. Another group of ovariectomized rats was given vehicle pellets and then a sham operation was performed. The rats were studied while under pentobarbital anesthesia at 7 wk after ligation. Ligated rats, relative to sham groups, had lower mean arterial pressure (MAP, -34 mmHg) and cardiac output (CO, -38%); higher arterial resistance (R(A), +12%) and venous resistance (R(V), +116%); mean circulatory filling pressure (MCFP, +40%) and left ventricular end-diastolic pressure (LVEDP, +11 mmHg); and similar cardiovascular responses to norepinephrine (NE). Treatment of ligated rats with 17beta-estradiol increased CO (+16%); reduced R(A) (-16%), R(V) (-35%), MCFP (-23%), and LVEDP (-3 mmHg); and augmented MAP, R(V,) and MCFP responses to NE. Therefore, 17beta-estradiol reduced MCFP, and this reduced preload (LVEDP). 17beta-Estradiol decreased R(V), which, along with decreased R(A) (afterload), led to an increase in CO. 17beta-Estradiol likely augmented vasoconstriction to NE through an improvement on the cardiovascular status.     

Cardiac response to submaximal exercise in dogs susceptible to sudden cardiac death

The hemodynamic response to submaximal exercise was investigated in 38 mongrel dogs with healed anterior wall myocardial infarctions. The dogs were chronically instrumented to measure heart rate (HR), left ventricular pressure (LVP), LVP rate of change, and coronary blood flow. A 2 min coronary occlusion was initiated during the last minute of an exercise stress test and continued for 1 min after cessation of exercise. Nineteen dogs had ventricular fibrillation (susceptible) while 19 animals did not (resistant) during this test. The cardiac response to submaximal exercise was markedly different between the two groups. The susceptible dogs exhibited a significantly higher HR and left ventricular end-diastolic pressure (LVEDP) but a significantly lower left ventricular systolic pressure (LVSP) in response to exercise than did the resistant animals. (For example, response to 6.4 kph at 8% grade; HR, susceptible 201.4 +/- 5.1 beats/min vs. resistant 176.2 +/- 5.6 beats/min; LVEDP, susceptible 19.4 +/- 1.1 mmHg vs. resistant 12.3 +/- 1.7 mmHg; LVSP, susceptible 136.9 +/- 7.9 mmHg vs. resistant 154.6 +/- 9.8 mmHg.) beta-Adrenergic receptor blockade with propranolol reduced the difference noted in the HR response but exacerbated the LVP differences (response to 6.4 kph at 8% grade; HR, susceptible 163.4 +/- 4.7 mmHg vs. resistant 150.3 +/- 6.4 mmHg; LVEDP susceptible 28.4 +/- 2.1 mmHg vs. resistant 19.6 +/- 3.0 mmHg; LVSP, susceptible 122.2 +/- 8.1 mmHg vs. resistant 142.8 +/- 10.7 mmHg). These data indicate that the animals particularly vulnerable to ventricular fibrillation also exhibit a greater degree of left ventricular dysfunction and an increased sympathetic efferent activity.     

左心室脱血回注循环辅助法对急性心肌梗死血流动力学的改善作用

目的:实验观察左心室脱血回注循环辅助法对急性心肌梗死血流动力学的改善作用.方法:18只杂种犬分两组制作急性心肌梗死泵衰竭模型,治疗组给予左心室脱血回注循环辅助,对照组不进行治疗.观察比较两组间心律失常、死亡率、外周动脉压、肺动脉毛细血管楔嵌压(PCWP)、左心室舒张末期压(LVEDP)、左心室内径的变化.结果:治疗组室性期外收缩、心室纤颤发生率和死亡率显著低于对照组;对照组的外周动脉收缩压低于80 mmHg以下,治疗组维持在100mmHg以上(P＜0.01);治疗组PCWP和LVEDP值在45 min以后的各时段低于对照组(P＜0.01);治疗组的左室舒张末期内径小于对照组(P＜0.01).结论:左心室脱血回注循环辅助法能够减少急性心肌梗死泵衰竭的心室纤颤发生率和死亡率,有显著改善血流动力学、防止梗死后心肌扩张和有效的左心室辅助作用.     

Cardioprotective effects of stretch are mediated by activation of sarcolemmal, not mitochondrial, ATP-sensitive potassium channels

To determine whether sarcolemmal and/or mitochondrial ATP-sensitive potassium (K(ATP)) channels (sarcK(ATP), mitoK(ATP)) are involved in stretch-induced protection, isolated isovolumic rat hearts were assigned to the following protocols: nonstretched hearts were subjected to 20 min of global ischemia (Is) and 30 min of reperfusion, and before Is stretched hearts received 5 min of stretch + 10 min of no intervention. Stretch was induced by a transient increase in left ventricular end-diastolic pressure (LVEDP) from 10 to 40 mmHg. Other hearts received 5-hydroxydecanoate (5-HD; 100 microM), a selective inhibitor of mitoK(ATP), or HMR-1098 (20 microM), a selective inhibitor of sarcK(ATP), before the stretch protocol. Systolic function was assessed through left ventricular developed pressure (LVDP) and maximal rise in velocity of left ventricular pressure (+dP/dt(max)) and diastolic function through maximal decrease in velocity of left ventricular pressure (-dP/dt(max)) and LVEDP. Lactate dehydrogenase (LDH) release and ATP content were also measured. Stretch resulted in a significant increase of postischemic recovery and attenuation of diastolic stiffness. At 30 min of reperfusion LVDP and +dP/dt(max) were 87 +/- 4% and 92 +/- 6% and -dP/dt(max) and LVEDP were 95 +/- 9% and 10 +/- 4 mmHg vs. 57 +/- 6%, 53 +/- 6%, 57 +/- 10%, and 28 +/- 5 mmHg, respectively, in nonstretched hearts. Stretch increased ATP content and did not produce LDH release. 5-HD did not modify and HMR-1098 prevented the protection achieved by stretch. Our results show that the beneficial effects of stretch on postischemic myocardial dysfunction, cellular damage, and energetic state involve the participation of sarcK(ATP) but not mitoK(ATP).     

Divergent changes in the rate of development of pressure in the left ventricle and in the performance of the heart as a pump.

Dog hearts were prepared in situ so that heart rate (HR), left ventricular end diastolic pressure (LVEDP) and mean aortic pressure (MAP) could be controlled separately during computation of left ventricular dP/dt max and external stroke work (SW). Progressive increases in HR consistently raised dP/dt max over a wide range, and consistently lowered SW except at low rates. Progressive increases in LVEDP or MAP consistently raised both dP/dt max and SW. Infusion of noradrenaline consistently raided both dP/dt max and SW, except at very high HR when only dP/dt max was consistently raised. Our results lead us to question the validity of equating changes in pre-ejection measurements with changes in performance of the heart as a pump under abnormal conditions and in the assessment of inotropic agents.     

Effect of cicletanine on reperfusion-induced arrhythmias and its relation to 6-keto-PGF1 alpha and thromboxane B2 release

Isolated hearts, excised from spontaneously hypertensive male rats treated orally with cicletanine, a new furopyridine anti-hypertensive drug, were subjected to 30 min of global ischemia followed by 10 min of reperfusion. The effect of cicletanine on reperfusion-induced arrhythmias in relation to 6-keto-PGF1 alpha and thromboxane (TXB2) release was studied. After 30 min of global ischemia, the incidence (total) of ventricular fibrillation (VF) and ventricular tachycardia (VT) was reduced by 2-week pretreatment of the rats with 30 and 100 mg/kg of cicletanine (VF, 33% at 30 mg/kg and 25% at 100 mg/kg vs. 91% in untreated rats; VT, 42% at 30 mg/kg and 42% at 100 mg/kg vs. 100% in untreated rats), while lower doses of cicletanine (3 and 10 mg/kg) failed to reduce the incidence of reperfusion-induced rhythm disturbances. Reperfusion of the ischemic myocardium resulted in a fivefold increase of 6-keto-PGF1 alpha and TXB2 release in the perfusion effluent of fibrillated hearts but not in the perfusion effluent of nonfibrillated hearts. Cicletanine failed to influence the reperfusion-stimulated release of 6-keto-PGF1 alpha and TXB2. These results indicate that the anti-arrhythmic effect of cicletanine in the reperfused myocardium is not related to PGI2 and thromboxane A2 release.     

心肌梗死患者择期行PCI治疗对左心室重构和收缩功能的影响

目的:研究心肌梗死患者择期行经皮冠状动脉介入(PCI)治疗对左心室重构和收缩功能的影响。方法:选取2009年12月到2014年12月我院收治的心肌梗死择期行PCI治疗的患者60例(研究组),另选同期单纯心绞痛行PCI治疗的患者60例(对照组)。比较治疗前、后两组左心室舒张末期容积(LVEDV)、收缩末期容积(LVESV)、每搏量(SV)、左室射血分数(LVEF)、左室收缩末期压(LVESP)和左心室舒张末压(LVEDP)。结果:治疗后研究组LVEDV、LVESV、SV、LVEF、LVESP和LVEDP均显著优于治疗前,比较差异均具有统计学意义(P0.05),对照组治疗前、后LVEDV、LVESV、SV、LVEF、LVESP和LVEDP比较差异均无统计学意义(P0.05)。结论:心肌梗死患者行PCI治疗具有较好的效果,能显著改善患者的左心室重构和收缩功能。     

激动乙醛脱氢酶2对抗糖尿病大鼠心肌缺血/再灌注损伤的作用

目的:探讨激动乙醛脱氢酶2(ALDH2)在糖尿病大鼠心肌损伤中的作用。方法:腹腔注射55 mg/kg链脲佐菌素复制糖尿病大鼠模型,分为糖尿病组和乙醇+糖尿病组(n=8)。8周后行离体心肌缺血/再灌注(I/R),测定心室动力学指标和复灌期间冠脉流出液中乳酸脱氢酶(LDH)含量。测定空腹血糖、糖化血红蛋白(HbA1c)水平。RT-PCR和Western blot测定左心室前壁心尖组织线粒体ALDH2 mRNA和蛋白表达。结果:与正常大鼠心肌I/R相比,糖尿病大鼠左室发展压、左心室最大上升和下降速率、左室做功进一步下降,左室舒张末压抬高,复灌期冠脉流出液中LDH释放增多,心室ALDH2 mRNA和蛋白表达降低;与糖尿病大鼠心肌I/R相比,ALDH2激动剂乙醇明显促进左室发展压、左心室最大上升和下降速率、左室做功的恢复,降低左室舒张末压,同时降低HbA1c水平和LDH的释放,ALDH2 mRNA和蛋白表达增高。结论:糖尿病大鼠心肌缺血/再灌注时,心肌ALDH2表达降低;增强ALDH2在糖尿病大鼠心肌中的表达可发挥保护作用。     

Cardioprotection from ischemia and reperfusion injury by Withania somnifera: a hemodynamic, biochemical and histopathological assessment

The efficacy of Withania somnifera (Ws) to limit myocardial injury after ischemia and reperfusion was explored and compared to that of Vit E, a reference standard known to reduce mortality and infarct size due to myocardial infarction. Wistar rats (150-200 g) were divided into six groups and received orally saline (sham, control group), Ws-50/kg (Ws control and treated group) and Vit E-100 mg/kg (Vit E control and treated group) respectively for 1 month. On the 31st day, rats of the control, Vit E and Ws treated groups were anesthetized and subjected to 45 min occlusion of the LAD coronary artery followed by 60 min reperfusion. Hemodynamic parameters: systolic, diastolic and mean arterial pressure (SAP, DAP, MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), left ventricular peak (+)LVdP/dt and (-)LVdP/dt were monitored. Hearts were removed and processed for histopathological and biochemical studies: Myocardial enzyme viz, creatin phosphokinase (CPK), and antioxidant parameters: malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx) were estimated. Postischemic reperfusion produced significant cardiac necrosis, depression of left ventricular functions (MAP, LVEDP, (+) and (-)LVdP/dt) and a significant fall in GSH (p < 0.01), SOD, CAT (p < 0.05), LDH and CPK (p < 0.01) as well as an increase in MDA level (p < 0.05) in the control group rats as compared to sham group. The changes in levels of protein and GPx was however, not significant. Ws and Vit E favorably modulated most of the hemodynamic, biochemical and histopathological parameters though no significant restoration in GSH, MAP (with Vit E) were observed. Ws on chronic administration markedly augmented antioxidants (GSH, GSHPx, SOD, CAT) while Vit E did not stimulate the synthesis of endogenous antioxidants compared to sham. Results indicate that Ws significantly reduced myocardial injury and emphasize the beneficial action of Ws as a cardioprotective agent.     

Effect of cicletanine on renal cGMP production.

The aim of the present study was to assess the effect of cicletanine on renal cGMP production. To do so we measured mean arterial pressure (MAP), creatinine clearance (CC), and urinary excretion of electrolytes and cGMP under basal conditions and after 6 h of cicletanine administration (10 and 15 mg/kg body weight by oral gavage) in conscious Wistar rats. Also, the in vitro effect of cicletanine was assessed by incubating renal slices and isolated rat glomeruli with two concentrations of cicletanine (0.1 and 1 mM) for different times (1, 2, 5, and 30 min) in the presence of 3-isobutyl-1-methylxanthine. Oral administration of cicletanine induced an increase in urinary flow (V) and the urinary excretion of electrolytes and cGMP, with no changes in CC. In addition, a significant decrease in MAP was observed, but only with the lower dose. Incubation with cicletanine did not induce significant changes in cGMP production in glomeruli or renal slices. These results show that cicletanine, administered in vivo at diuretic and antihypertensive doses, induces an increase in urinary cGMP excretion.     

慢性缺氧对大鼠左右心室功能、心肌肌原纤维Ca~（2＋），Mg~（2＋）－ATP

模拟５０００ｍ中度缺氧时,大鼠右室功能显著加强,而左室功能加强不显著;左右心室肌原纤维Ｃａ２＋,Ｍｇ２＋－ＡＴＰ酶活性下降,肌球蛋白同功酶Ｖ２和Ｖ３百分含量增加,Ｖ１百分含量减少。８０００ｍ重度缺氧时,右室功能减弱,但无统计学意义,左室功能减弱有显著性;ＡＴＰ酶活性和同功酶的变化超过５０００ｍ组。此外,右室ＡＴＰ酶活性与ＰＡＰ呈反比且有显著性,左室ＡＴＰ酶活性与ＣＡＳＰ虽也呈反比但无显著性;右室同功酶Ｖ３百分含量与ＰＡＰ呈正比,左室同功酶Ｖ３百分含量与ＣＡＳＰ不呈比例。上述结果表明,因短期突发严重缺氧引起的心肌供氧不足对左心室心肌的直接损伤作用大于右心室心肌。     

降钙素基因相关肽对不同程度冠脉狭窄时的心脏功能的影响

本实验观察了冠脉内注射降钙素基因相关肽（ＣＧＲＰ０．３μｇ／ｋｇ）对正常及不同程度冠脉狭窄犬的心功能的影响。结果表明正常犬冠脉内注射ＣＧＲＰ后,平均动脉压（ＭＡＰ）下降１．２ｋＰａ（Ｐ＜０．０５）,同时,心率（ＨＲ）、心输出量（ＣＯ）、左室收缩压峰值（ＬＶＳＰ）均不同程度增加;左室舒张末压（ＬＶＥＤＰ）轻度降低。在中度狭窄３０ｍｉｎ后,冠脉内注射ＣＧＲＰ对ＨＲ、ＭＡＰ无明显影响;而重度狭窄后注射ＣＧＲＰ,ＭＡＰ由狭窄时降低逐渐增高,ＨＲ由增快而变慢。ＣＯ、ＬＶＳＰ均显著增高,ＬＶＥＤＰ降低,此作用较冠脉狭窄前更为明显。提示ＣＧＲＰ扩张冠脉动脉,增加冠脉血流量和心排血量,增强心肌收缩力,对缺血心脏功能有保护作用。     

Poor Agreement between Pulmonary Capillary Wedge Pressure and Left Ventricular End-Diastolic Pressure in a Veteran Population

Background

Accurate determination of left ventricular filling pressure is essential for differentiation of pre-capillary pulmonary hypertension (PH) from pulmonary venous hypertension (PVH). Previous data suggest only a poor correlation between left ventricular end-diastolic pressure (LVEDP) and its commonly used surrogate, the pulmonary capillary wedge pressure (PCWP). However, no data exist on the diagnostic accuracy of PCWP in veterans. Furthermore, the effects of age and comorbidities on the PCWP-LVEDP relationship remain unknown.

Methods

We investigated the PCWP-LVEDP relationship in 101 patients undergoing simultaneous right and left heart catherization at a large VA hospital. PCWP performance was evaluated using correlation and Bland-Altman analyses. Area under Receiver Operating Characteristics curves (AUROC) for PCWP were determined.

Results

PCWP-LVEDP correlation was moderate (r = 0.57). PCWP-LVEDP calibration was poor (Bland-Altman limits of agreement −17.2 to 11.4 mmHg; mean bias −2.87 mmHg). 59 patients (58.4%) had pulmonary hypertension; 15 (25.4%) of those met pre-capillary PH criteria based on PCWP. However, if LVEDP was used instead of PCWP, 7/15 patients (46.6%) met criteria for PVH rather than pre-capillary PH. When restricting analysis to patients with a mean pulmonary artery pressure of ≥25 mmHg and pulmonary vascular resistance of >3 Wood units (n = 22), 10 patients (45.4%) were classified as pre-capillary PH based on PCWP ≤15 mmHg. However, if LVEDP was used, 4/10 patients (40%) were reclassified as PVH. Among patients with any type of pulmonary hypertension, PCWP discriminated moderately between high and normal LVEDP (AUROC, 0.81; 95%CI 0.69–0.94). PCWP-LVEDP correlation was particularly poor in patients with COPD or obesity.

Conclusion

Reliance on PCWP rather than LVEDP results in misclassification of veterans as having pre-capillary PH rather than PVH in almost 50% of cases. This is clinically relevant, as misclassification may lead to inappropriate therapies and adverse events.     

丹酚酸B对大鼠离体工作心脏血流动力学的影响

目的 研究丹酚酸B对离体大鼠工作心脏血流动力学的影响.方法 采用Langendorff离体心脏灌流的方法,以左室内压( LVSP)、左室舒末压(LVEDP)、室内压最大上升速率(+dp/dtmax)、室内压最大下降速率(- dp/dtmax)、心率(HR)等血流动力学参数为指标,观察丹酚酸B对心肌收缩性能的影响.结果 不同剂量(10、5、2.5 mg/L)的丹酚酸B可使LVSP、±dp/dtmax明显升高,同时使HR减慢,并呈剂量依赖性,但对LVEDP无明显作用.结论 丹酚酸B对离体工作心脏有剂量依赖性正性肌力作用.     

Cardioprotection from ischemia and reperfusion injury by Withania somnifera: A hemodynamic,biochemical and histopathological assessment

The efficacy of Withania somnifera (Ws) to limit myocardial injury after ischemia and reperfusion was explored and compared to that of Vit E, a reference standard known to reduce mortality and infarct size due to myocardial infarction. Wistar rats (150–200 g) were divided into six groups and received orally saline (sham, control group), Ws-50/kg (Ws control and treated group) and Vit E-100 mg/kg (Vit E control and treated group) respectively for 1 month. On the 31st day, rats of the control, Vit E and Ws treated groups were anesthetized and subjected to 45 min occlusion of the LAD coronary artery followed by 60 min reperfusion. Hemodynamic parameters: systolic, diastolic and mean arterial pressure (SAP, DAP, MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), left ventricular peak (+) LVdP/dt and (–) LVdP/dt were monitored. Hearts were removed and processed for histopathological and biochemical studies: Myocardial enzyme viz, creatin phosphokinase (CPK), and antioxidant parameters: malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx) were estimated. Postischemic reperfusion produced significant cardiac necrosis, depression of left ventricular functions (MAP, LVEDP, (+) and (–) LVdP/dt) and a significant fall in GSH (p < 0.01), SOD, CAT(p < 0.05), LDH and CPK (p < 0.01) as well as an increase in MDA level (p < 0.05) in the control group rats as compared to sham group. The changes in levels of protein and GPx was however, not significant. Ws and Vit E favorably modulated most of the hemodynamic, biochemical and histopathological parameters though no significant restoration in GSH, MAP (with Vit E) were observed. Ws on chronic administration markedly augmented antioxidants (GSH, GSHPx, SOD, CAT) while Vit E did not stimulate the synthesis of endogenous antioxidants compared to sham. Results indicate that Ws significantly reduced myocardial injury and emphasize the beneficial action of Ws as a cardioprotective agent.     

Salutary effects of moderate hypothermia on the circulatory and myocardial consequences of acute coronary occlusion in dogs

The efficacy of moderate hypothermia with rewarming in attenuating the myocardial and circulatory consequences of acute coronary ligation was studied in open-chest, anesthetized dogs. Thirty minutes after ligation of the proximal left anterior descending coronary artery, 14 dogs were surface-cooled to 27 degrees C, maintained at this temperature for 2 hr, rewarmed to normothermic levels, and monitored for an additional hour. Fifteen dogs were maintained for a corresponding time period after coronary ligation at normothermic levels. Dogs maintained normothermic demonstrated significant depression (from preligation values) of dP/dt, cardiac output (CO), stroke volume (SV), and left ventricular stroke work and power (LVSW, LVSP) at elevated levels of left ventricular end-diastolic pressure (LVEDP). Dogs subjected to the hypothermic procedure demonstrated decreased inotropic status during hypothermia, but with rewarming, exhibited significantly greater values of left ventricular pressure, dP/dt, CO, SV, LVSW, and LVSP at lower values of LVEDP than observed in dogs maintained normothermic. Increased dysrhythmic activity was not observed during hypothermia. Hearts from dogs subjected to the hypothermic protocol demonstrated qualitatively greater dehydrogenase activity both at the periphery and in the center of the nonperfused region. The results suggest that moderate hypothermia during evolving myocardial infarction may preserve left ventricular cardio- and hemodynamics and thus may be useful in delaying morphological and functional deterioration until definitive treatment can be instituted.     

Fosinopril Attenuates the Doxorubicin-induced Cardiomyopathy by Restoring the Function of Sarcoplasmic Reticulum

Fosinopril, an angiotensin-converting enzyme inhibitor, is known to attenuate cardiomyopathy induced by doxorubicin (DOX); however, the mechanisms of this cardioprotection are not fully elucidated yet. In the present study, experimental cardiomyopathy was induced in rats by administration of DOX with or without co-treatment with fosinopril. Fosinopril was utilized on day 1 or 14 of the treatment with DOX to compare efficacies of early versus late co-treatments. We observed that fosinopril attenuated changes induced by DOX (e.g., less increased heart and left ventricular weights, diminished lung congestion and ascites, attenuated LVEDP and LVSP, and less decreased +dP/dt and ?dP/dt). Further, fosinopril diminished the levels of markers of cardiac toxicity (i.e., plasma levels and activities of cardiac enzymes and proteins AST, LDH, CPK, cTnI, and BNP). Fosinopril also prevented DOX-induced decreases in Ca²⁺ uptake and restored activity of Ca²⁺-stimulated ATPase in left ventricular sarcoplasmic reticulum. We next tested whether the improved Ca²⁺ transport activity in sarcoplasmic reticulum was due to modulation of SERCA2 and phospholamban expressions by fosinopril. Fosinopril attenuated the decrease in SERCA2 and phospholamban expressions caused by DOX. In conclusion, cardioprotective effects of fosinopril in the DOX-induced cardiomyopathy appear to be due to its ability to prevent remodeling of the cardiac sarcoplasmic reticulum membrane.