Participation of the autonomic nervous system in the cardiovascular effects of milrinone

The cardiodynamic activity of intravenously administered milrinone was examined in alpha-chloralose anesthetized dogs. Two groups of dogs were used, one pretreated with hexamethonium to block autonomic reflexes, and a second group which received no pretreatment. In the untreated group milrinone produced dose-dependent increases in +dP/dt and heart rate while decreasing both systolic and diastolic blood pressure and left ventricular end diastolic pressure (LVEDP). After treatment with hexamethonium basal heart rate was significantly increased, whereas reflex changes in heart rate in response to i.v. norepinephrine or nitroglycerin were ablated. Systolic, but not diastolic blood pressure was also markedly reduced by hexamethonium. In the presence of hexamethonium responses to milrinone were qualitatively similar to milrinone responses in the absence of hexamethonium. However, the dose-response curves for milrinone were shifted dextrally for changes in +dP/dt and LVEDP, whereas the dose-response curve for blood pressure was shifted sinistrally. Thus, it appears that the autonomic nervous system enhances the effect of milrinone on +dP/dt and LVEDP, but attenuates its effect on blood pressure.     

Inotropic responses of the left ventricle to changes in heart rate in anesthetized rabbits

Factors known to influence left ventricular contractility include preload, afterload, circulating catecholamine concentration, efferent sympathetic discharge, and heart rate. Heart rate influences have been primarily determined in the dog, whereas the influence of heart rate in smaller mammals has not been determined. Eight pentobarbital-anesthetized rabbits were instrumented to measure electrocardiogram, heart rate, left ventricular pressure, end-diastolic pressure, dP/dt, and mean and pulsatile aortic pressures. Systematic bradycardia was induced by stimulating the peripheral end of the sectioned right vagus nerve. Between 293 and 235 beats/min, there was no change in (dP/dt)max as heart rate was decreased. Below this range there was a direct relationship between (dP/dt)max and heart rate. Preload remained unchanged down to 132 beats/min. There was a small but significant decrease in afterload (0.09 mmHg X beat-1 X min-1; 1 mmHg = 133.32 Pa) throughout the decrease in heart rate. Infusion of propranolol (2.0 mg/kg) produced no marked change in the heart rate - (dP/dt)max relationship, although both resting heart rate and (dP/dt)max were reduced. This study demonstrates that (dP/dt)max is not influenced by changes in heart rate above 235 beats/min in the pentobarbital-anesthetized rabbit. These results differ from findings in other animals, and demonstrate that species and heart rate ranges must be considered when drawing conclusions regarding (dP/dt)max as a reliable index of contractility.     

The effect of changes in cardiac frequency on left and right ventricular dP/dt max at different contractile states of the myocardium

In 17 canine heart-lung preparations the dependence of frequency potentiation of the right and left ventricular myocardium on the basic inotropic state of the heart was investigated. The effect of unipolar stimulation of the right atrium on dP/dt max in both ventricles was measured. The aortic pressure was maintained constant. Shortly after isolation of the heart, a stepwise increase of rate from 140 to 200 beats/min only had a very weak influence on left ventricular dP/dt max. With deterioration of the myocardium the frequency potentiation of dP/dt max increased considerably. End-diastolic pressure regularly decreased with rising cardiac frequency. Since the real positive inotropic effect is masked by the concomitant fall in diastolic loading, the end-diastolic pressure was maintained constant in a second group of 8 hearts during rate variation. The most pronounced inotropic effect was now found shortly after isolation of the heart. A rate increase of 30 beats/min resulted in a 20% rise of dP/dt max. The frequency potentiation decreased with deterioration of the heart resulting in a 12% dP/dt max increase at an estimated inotropic state of 50% of control. When the contractile state of the heart was improved above the control state by calcium application the frequency potentiation of the myocardium decreased. In the right ventricle similar results were obtained except for the fact that no significant correlation between the steepness of the frequency characteristics and the contractile state of the heart could be found when the end-diastolic pressure was kept constant.     

Assessing left ventricular systolic dysfunction after myocardial infarction: are ejection fraction and dP/dt(max) complementary or redundant?

Among the various cardiac contractility parameters, left ventricular (LV) ejection fraction (EF) and maximum dP/dt (dP/dt(max)) are the simplest and most used. However, these parameters are often reported together, and it is not clear if they are complementary or redundant. We sought to compare the discriminative value of EF and dP/dt(max) in assessing systolic dysfunction after myocardial infarction (MI) in swine. A total of 220 measurements were obtained. All measurements included LV volumes and EF analysis by left ventriculography, invasive ventricular pressure tracings, and echocardiography. Baseline measurements were performed in 132 pigs, and 88 measurements were obtained at different time points after MI creation. Receiver operator characteristic (ROC) curves to distinguish the presence or absence of an MI revealed a good predictive value for EF [area under the curve (AUC): 0.998] but not by dP/dt(max) (AUC: 0.69, P < 0.001 vs. EF). Dividing dP/dt(max) by LV end-diastolic pressure and heart rate (HR) significantly increased the AUC to 0.87 (P < 0.001 vs. dP/dt(max) and P < 0.001 vs. EF). In na?ve pigs, the coefficient of variation of dP/dt(max) was twice than that of EF (22.5% vs. 9.5%, respectively). Furthermore, in n = 19 pigs, dP/dt(max) increased after MI. However, echocardiographic strain analysis of 23 pigs with EF ranging only from 36% to 40% after MI revealed significant correlations between dP/dt(max) and strain parameters in the noninfarcted area (circumferential strain: r = 0.42, P = 0.05; radial strain: r = 0.71, P < 0.001). In conclusion, EF is a more accurate measure of systolic dysfunction than dP/dt(max) in a swine model of MI. Despite the variability of dP/dt(max) both in na?ve pigs and after MI, it may sensitively reflect the small changes of myocardial contractility.     

Effects of parathyroid hormone on the cardiovascular system

It has been well accepted that the bone and kidney are the principal organs of parathyroid hormone (PTH) actions, but there has been little work on the cardiovascular system. We evaluated the effect of PTH on the cardiovascular system of rats. In thiobutabarbital anesthetized rats, synthetic bovine parathyroid hormone, containing the amino acid (b-PTH 1-34) in dose of 0.1-10 micrograms/kg iv, caused dose related decrease in mean arterial blood pressure (MAP). On the other hand, there were significantly increase in heart rate (HR) and left ventricular contractile force. With the doses of 10 micrograms/kg, PTH decreased the MAP from 104.3 to 55.5 mmHg, left ventricular pressure (LVP) 122.1 to 96.4 mmHg, left ventricular end diastolic pressure (LVEDP) from 6.70 to 6.37 mmHg and LV dp/dt max 5,684 to 4,736 mmHg/sec. The HR, LV dp/dt/p and Vmax increase from 399.7 to 410.0 bpm, 95.5 to 108.4/sec, 98.2 to 107.4/sec, respectively. The propranolol, phentolamine, atropine and promethazine did not affect these actions of PTH. On the basis of these findings, we conclude that PTH has the directory vasodepressive action and the effect of augmentation of the left ventricular contractile force.     

Preserved ventricular contractility in infarcted mouse heart overexpressing beta(2)-adrenergic receptors

Effects of cardiac specific overexpression of beta(2)-adrenergic receptors (beta(2)-AR) on the development of heart failure (HF) were studied in wild-type (WT) and transgenic (TG) mice following myocardial infarction (MI) by coronary artery occlusion. Animals were studied by echocardiography at weeks 7 to 8 and by catheterization at week 9 after surgery. Post-infarct mortality, due to HF or cardiac rupture, was not different among WT mice, and there was no difference in infarct size (IS). Compared with the sham-operated group (all P < 0.01), WT mice with moderate (<36%) and large (>36%) IS developed lung congestion, cardiac hypertrophy, left ventricular (LV) dilatation, elevated LV end-diastolic pressure (LVEDP), and suppressed maximal rate of increase of LV pressure (LV dP/dt(max)) and fractional shortening (FS). Whereas changes in organ weights and echo parameters were similar to those in infarcted WT groups, TG mice had significantly higher levels of LV contractility in both moderate (dP/dt(max) 4,862 +/- 133 vs. 3,694 +/- 191 mmHg/s) and large IS groups (dP/dt(max) 4,556 +/- 252 vs. 3,145 +/- 312 mmHg/s, both P < 0.01). Incidence of pleural effusion (36% vs. 85%, P < 0.05) and LVEDP levels (6 +/- 0.3 vs. 9 +/- 0.8 mmHg, P < 0.05) were also lower in TG than in WT mice with large IS. Thus beta(2)-AR overexpression preserved LV contractility following MI without adverse consequence.     

Ketamine-induced cardiac depression is associated with increase in [Mg2+]i and activation of p38 MAP kinase and ERK 1/2 in guinea pig

This study investigated the signaling pathways responsible for ketamine-induced cardiac depression in guinea pigs. The left ventricular development pressure (LVDP), velocity of the change in pressure (dP/dt), and heart rate (HR) accompanied with the total magnesium efflux ([Mg]e) were measured simultaneously in perfused hearts. The level of activation of the extracellular signal-regulated kinases 1/2 (ERK 1/2) and p38 mitogen-activated protein (MAP) kinase. The intracellular ionized magnesium concentration ([Mg2+]i) was measured using Mag-fura 2 AM in a single cardiomyocyte. Ketamine produced reversible decreases in the LVDP, dP/dt, and HR accompanied by increases in the [Mg]e. Ketamine also produced significant activation of p38 MAP kinase and ERK 1/2, and produced a dose-dependent increase in the [Mg2+]i, which was inhibited SB203580 and PD98059. These results suggest that ketamine-induced cardiac depression can be partly responsible for the increase in [Mg2+]i and [Mg]e, accompanied by the activation of p38 MAP kinase and ERK 1/2 in guinea pigs.     

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 avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (tau), and the first derivatives of LV pressure rise and fall (dP/dt(max) and dP/dt(min), respectively). During echocardiography, HR was lower in XK than AV mice (250 +/- 14 beats/min in XK vs. 453 +/- 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 +/- 0.08 mm in XK vs. 3.8 +/- 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 +/- 1.2% in XK vs. 40 +/- 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 +/- 24 beats/min) and XK (342 +/- 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 +/- 5 vs. 6.2 +/- 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/dt(max): 4,402 +/- 798 vs. 8,250 +/- 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (tau: 23 +/- 2 vs. 14 +/- 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.     

Frequency-dependent left ventricular performance in women and men

We aimed to determine whether sex differences in humans extend to the dynamic response of the left ventricular (LV) chamber to changes in heart rate (HR). Several observations suggest sex influences LV structure and function in health; moreover, this physiology is also affected in a sex-specific manner by aging. Eight postmenopausal women and eight similarly aged men underwent a cardiac catheterization-based study for force-interval relationships of the LV. HR was controlled by right atrial (RA) pacing, and LV +dP/dt(max) and volume were assessed by micromanometer-tipped catheter and Doppler echocardiography, respectively. Analysis of approximated LV pressure-volume relationships was performed using a time-varying model of elastance. External stroke work was also calculated. The relationship between HR and LV +dP/dt(max) was expressed as LV +dP/dt(max) = b + mHR. The slope (m) of the relationship was steeper in women compared with men (11.8 ± 4.0 vs. 6.1 ± 4.1 mmHg·s(-1)·beats(-1)·min(-1), P = 0.01). The greater increase in contractility in women was reproducibly observed after normalizing LV +dP/dt(max) to LV end-diastolic volume (LVVed) or by measuring end-systolic elastance. LVVed and stroke volume decreased more in women. Thus, despite greater increases in contractility, HR was associated with a lesser rise in cardiac output and a steeper fall in external stroke work in women. Compared with men, women exhibit greater inotropic responses to incremental RA pacing, which occurs at the same time as a steeper decline in external stroke work. In older adults, we observed sexual dimorphism in determinants of LV mechanical performance.     

Adenosine A(2a)-receptor activation increases contractility in isolated perfused hearts

Adenosine A(2a)-receptor activation enhances shortening of isolated cardiomyocytes. In the present study the effect of A(2a)-receptor activation on the contractile performance of isolated rat hearts was investigated by recording left ventricular pressure (LVP) and the maximal rate of LVP development (+dP/dt(max)). With constant-pressure perfusion, adenosine caused concentration-dependent increases in LVP and +dP/dt(max), with detectable increases of 4.1 and 4.8% at 10(-6) M and maximal increases of 12.0 and 11.1% at 10(-4) M, respectively. The contractile responses were prevented by the A(2a)-receptor antagonists chlorostyryl-caffeine and aminofuryltriazolotriazinyl-aminoethylphenol (ZM-241385) but were not affected by the beta(1)-adrenergic antagonist atenolol. The adenosine A(1)-receptor antagonist dipropylcyclopentylxanthine and pertussis toxin potentiated the positive inotropic effects of adenosine. The A(2a)-receptor agonists ethylcarboxamidoadenosine and dimethoxyphenyl-methylphenylethyl-adenosine also enhanced contractility. With constant-flow perfusion, 10(-5) M adenosine increased LVP and +dP/dt(max) by 5.5 and 6.0%, respectively. In the presence of the coronary vasodilator hydralazine, adenosine increased LVP and +dP/dt(max) by 7.5 and 7.4%, respectively. Dipropylcyclopentylxanthine potentiated the adenosine contractile responses with constant-flow perfusion in the absence and presence of hydralazine. These increases in contractile performance were also antagonized by chlorostyryl-caffeine and ZM-241385. The results indicate that adenosine increases contractile performance via activation of A(2a) receptors in the intact heart independent of beta(1)-adrenergic receptor activation or changes in coronary flow.     

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).     

Effects of sequential biventricular pacing during acute right ventricular pressure overload

Temporary sequential biventricular pacing (BiVP) is a promising treatment for postoperative cardiac dysfunction, but the mechanism for improvement in right ventricular (RV) dysfunction is not understood. In the present study, cardiac output (CO) was optimized by sequential BiVP in six anesthetized, open-chest pigs during control and acute RV pressure overload (RVPO). Ventricular contractility was assessed by the maximum rate of increase of ventricular pressure (dP/dt(max)). Mechanical interventricular synchrony was measured by the area of the normalized RV-left ventricular (LV) pressure diagram (A(PP)). Positive A(PP) indicates RV pressure preceding LV pressure, whereas zero indicates complete synchrony. In the control state, CO was maximized with nearly simultaneous stimulation of the RV and LV, which increased RV (P = 0.006) and LV dP/dt(max) (P = 0.002). During RVPO, CO was maximized with RV-first pacing, which increased RV dP/dt(max) (P = 0.007), but did not affect LV dP/dt(max), and decreased the left-to-right, end-diastolic pressure gradient (P = 0.023). Percent increase of RV dP/dt(max) was greater than LV dP/dt(max) (P = 0.014). There were no increases in end-diastolic pressure to account for increases in dP/dt(max). In control and RVPO, RV dP/dt(max) was linearly related to A(PP) (r = 0.779, P < 0.001). The relation of CO to A(PP) was curvilinear, with a peak in CO with positive A(PP) in the control state (P = 0.004) and with A(PP) approaching zero during RVPO (P = 0.001). These observations imply that, in our model, BiVP optimization improves CO by augmenting RV contractility. This is mediated by changes in mechanical interventricular synchrony. Afterload increases during RVPO exaggerate this effect, making CO critically dependent on simultaneous pressure generation in the RV and LV, with support of RV contractility by transmission of LV pressure across the interventricular septum.     

Effects of naloxone on systemic and regional hemodynamic responses to exercise in dogs

To determine whether endogenous opiates have a role in circulatory regulation during mild to moderate exercise, 11 chronically instrumented dogs were exercised on a treadmill up a 6% incline at 2.5 and 5.0 mph, each for 20 min, after treatment with either the opiate receptor antagonist naloxone (1 mg/kg bolus and 20 micrograms.kg-1.min-1 infusion) or normal saline. Naloxone increased plasma beta-endorphin and adrenocorticotropic hormone at rest but had no effect on resting heart rate, aortic pressure, cardiac output, left ventricular time derivative of pressure (dP/dt) and ratio of dP/dt at a developed pressure of 50 mmHg and the developed pressure (dP/dt/P), or plasma catecholamines. Plasma beta-endorphin and adrenocorticotropic hormone increased during exercise. In addition, graded treadmill exercise produced proportional increases in heart rate, cardiac output, aortic pressure, left ventricular dP/dt and dP/dt/P, and blood flow to exercising muscles, right and left ventricular myocardium, and adrenal glands. However, there were no differences in the circulatory responses to exercise between animals receiving naloxone and normal saline. Thus the endogenous opiate system probably does not play an important role in regulating the systemic hemodynamic and blood flow responses to mild and moderate exercise.     

离体大鼠心肌内质网应激模型构建条件的优化

目的探讨构建体外心肌内质网应激（endoplasmic reticulum stress,ERS）模型的方法及实验条件。方法应用Langendorff灌流装置制作大鼠心脏离体缺血/再灌注模型,采用PowerLab系统持续监测血流动力学参数,Western blot检测缺血（停止灌流）不同时间/再灌注120 min后心肌ERS标志性分子糖调节蛋白（GRP）78的表达,并检测C/EBP同源蛋白（CHOP）的表达;逆转录-聚合酶链反应（RT-PCR）检测二者mRNA的表达;体外孵育心肌组织切片,分别应用不同浓度的衣霉素（tunicamycin,Tm）和二硫苏糖醇（dithiothreitol,DTT）处理3 h和6 h,Western-blot检测心肌GRP78及CHOP的表达。结果与对照组相比,离体灌注心脏缺血40 min/再灌注120 min时,心肌GRP78表达最高（P〈0.01）,CHOP蛋白、GRP78 mRNA及CHOP mRNA表达均明显升高（P〈0.01,P〈0.05和P〈0.05）,同时,各项血流动力学参数受损（均P〈0.01）;Tm 10μg/mL和DTT 2 mmol/L孵育心肌组织切片3 h时,GRP78表达较对照组显著升高（均P〈0.001）,CHOP表达亦均明显升高（P〈0.05和P〈0.01）。结论使用离体大鼠心脏缺血/再灌注和孵育心肌组织切片的方法,均可成功构建体外心肌ERS模型。     

Changes in biomechanical parameters during heart perfusion and after midazolam pre-medication--experimental pilot study

Background: Midazolam is a frequently used benzodiazepine in anaesthesiology and intensive care. Aim: The aim of pilot study was to monitor its effect during heart perfusion in the laboratory rat. Methods: The same groups of animals (n = 10). The 1(st) group was treated with midazolam in a dose of 0.5mg/kg i.p. The 2(nd) group was a placebo. After i.p. administration of heparine injection of 500 IU dose, the hearts were excised and perfused (modified Langendorf's method). Working schedule: stabilization/ischaemia/reperfusion proceed at intervals of 20/30/60 min. Monitored parameters in isolated heart: left ventricle pressure (LVP), end-diastolic pressure (LVEDP), contractility (+dP/dt(max)). Results: The treated hearts showed improved postischemic recovery, reaching LVP values of 92 +/- 6 % at the end of the reperfusion, placebo only 61 +/- 7 %. In placebo hearts LVEDP rose from 10.0 +/- 0.5 mmHg to 43 +/- 4 mmHg after, in treated animals only about 25 mmHg. The treated hearts improved +dP/dt(max) recovery during reperfusion to 91 +/- 8 %. These values were significantly greater than those obtained from the placebo hearts. Conclusions: Positive changes in monitored parameters were found in this experimental pilot study. We conclude that the administration of midazolam in laboratory rats has a cardioprotective potential against ischemia-reperfusion induced injury.     

Cardioprotection by Inula racemosa Hook in experimental model of myocardial ischemic reperfusion injury

To evaluate the cardioprotective potential of Inula racemosa in myocardial ischemic-reperfusion injury, Wistar male albino rats were randomly divided into four groups. The group I and II animals were administered saline orally {(sham, ischemia- reperfusion (I-R) control group)} and animals of group III and group IV received I. racemosa extract (100 mg/kg) for 30 days. On the 30th day, animals of I-R control and I. racemosa treated groups were underwent 45 min of ligation of left anterior descending coronary artery and were thereafter re-perfused for 60 min. In the I-R control group, a significant decrease of mean arterial pressure (MAP), heart rate (HR), contractility, (+)LVdP/dt and relaxation, (-)LVdP/dt and an increase of left ventricular end diastolic pressure (LVEDP) were observed. Subsequent to haemodynamic impairment and left ventricular contractile dysfunction, a significant decline was observed in endogenous myocardial antioxidants; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH). Increased lipid peroxidation characterized by malonaldialdehyde (MDA) formation along with depletion of cardiomyocytes specific enzymes, creatine phosphokinase-MB (CK-MB) isoenzyme and lactate dehydrogenase (LDH) in I-R control group compared to sham group revealed I-R injury of heart. However, treatment with I. racemosa significantly restored the myocardial antioxidant status evidenced by increased SOD, CAT, GPx and GSH and prevented leakage of cardio-specific enzymes; CK-MB and LDH and favorably modulated the altered MAP, HR, (+)LVdP/dt, (-)LVdP/dt and LVEDP as compared to I-R control. Furthermore, I-R induced lipid peroxidation was significantly inhibited by I. racemosa treatment. These beneficial cardioprotective effects translated into significant improvement in cardiac function. In conclusion, our study has demonstrated that the cardioprotective effect of I. racemosa likely resulted to improved antioxidant status, haemodynamic and left ventricular contractile function subsequent to suppression of oxidative stress.     

Determination of cardiac contractility in awake unsedated mice with a fluid-filled catheter

Today, cardiac contractility in mice is exclusively measured under anesthesia or in sedated animals because the catheters available are too rigid to be used in awake mice. We therefore developed a new catheter (Pebax 03) to measure cardiac contractility in conscious mice. In this study, we evaluated the accuracy and utility of this new catheter for assessment of cardiac contractility in anesthetized and conscious mice. With the use of a balloon-pop test, the Pebax catheter with an inner diameter of 0.3 mm was found to exhibit a high natural frequency, a low damping coefficient, and a flat frequency of up to 50.5 +/- 0.6 Hz. Under anesthesia (0.5% or 1.0% halothane), no difference was found in heart rate (HR), left ventricular (LV) systolic pressure (LVSP), the maximum rates of LV pressure rise and fall (LV dP/dt(max) and LV dP/dt(min), respectively), ejection time (ET), and isovolumic relaxation time constant (tau) when measured with either the 1.4-Fr Millar or Pebax 03 catheter. However, when HR, LVSP, LV dP/dt(max), and LV dP/dt(min) were recorded with the Pebax catheter in awake mice, values were significantly higher, and ET and tau were lower, than under anesthesia, suggesting a major impact of anesthesia on these parameters. The Pebax catheter was also used in a normotensive one-renin gene mouse model of cardiac hypertrophy induced by DOCA and salt. In this model, DOCA-salt induced a severe decrease in cardiac contractility in the absence of changes in blood pressure. These data demonstrate that cardiac contractility can be measured very accurately in conscious mice. This new device can be of great help in the investigation of cardiac function in normal and genetically engineered mice.     

Comparative evaluation of pressure and time factors in estimating left ventricular performance.

Left ventricular and ascending aortic pressures were measured in open chest mongrel dogs under pentobarbital anesthesia. The data were digitized, averaged, and subgrouped by mean systolic aortic pressures (MSAP), end-diastolic pressure (EDP), and heart rate (HR). Seven raw and 32 derived variable from the pressure, as a function of time, wave forms were analyzed in each subgroup in the control state and following the infusion of catecholamines. A plot of control variability versus sensitivity to norepinephrine indicates that time to peak ventricular pressure (PVP time) is a more sensitive indicator of changes in the inotropic state than such other commonly used variables as max dP/dt, integrated isometric tension, and (max dP/dt)/developed pressure. PVP time also showed less variability with HR, EDP, and MSAP. Regression lines were also fit to the data using a second-order model. This permitted evaluation of experimentally varying either HR, EDP, or MSAP while maintaining the other two constant. PVP time was again one of the better variables in terms of sensitivity to HR, EDP, or MSAP. Vmax, fractional rate of change of power, preejection period, and systolic time were also analyzed and compared with PVP time using averaged data.     

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.