Cardiotoxicity of environmental contaminant tributyltin involves myocyte oxidative stress and abnormal Ca2+ handling.

Tributyltin (TBT) is an organotin environmental pollutant widely used as an agricultural and wood biocide and in antifouling paints. Countries began restricting TBT use in the 2000s, but their use continues in some agroindustrial processes. We studied the acute effect of TBT on cardiac function by analyzing myocardial contractility and Ca2+ handling. Cardiac contractility was evaluated in isolated papillary muscle and whole heart upon TBT exposure. Isolated ventricular myocytes were used to measure calcium (Ca2+) transients, sarcoplasmic reticulum (SR) Ca2+ content and SR Ca2+ leak (as Ca2+ sparks). Reactive oxygen species (ROS), as superoxide anion (O2•-) was detected at intracellular and mitochondrial myocardium. TBT depressed cardiac contractility and relaxation in papillary muscle and intact whole heart. TBT increased cytosolic, mitochondrial ROS production and decreased mitochondrial membrane potential. In isolated cardiomyocytes TBT decreased both Ca2+ transients and SR Ca2+ content and increased diastolic SR Ca2+ leak. Decay of twitch and caffeine-induced Ca2+ transients were slowed by the presence of TBT. Dantrolene prevented and Tiron limited the reduction in SR Ca2+ content and transients. The environmental contaminant TBT causes cardiotoxicity within minutes, and may be considered hazardous to the mammalian heart. TBT acutely induced a negative inotropic effect in isolated papillary muscle and whole heart, increased arrhythmogenic SR Ca2+ leak leading to reduced SR Ca2+ content and reduced Ca2+ transients. TBT-induced myocardial ROS production, may destabilize the SR Ca2+ release channel RyR2 and reduce SR Ca2+ pump activity as key factors in the TBT-induced negative inotropic and lusitropic effects.

Testosterone deficiency prevents left ventricular contractility dysfunction after myocardial infarction.

Testosterone may affect myocardial contractility since its deficiency decreases the contraction and relaxation of the heart. Meanwhile, testosterone replacement therapy has raised concerns because it may worsen cardiac dysfunction and remodeling after myocardial infarction (MI). In this study, we evaluate cardiac contractility 60 days after MI in rats with suppressed testosterone. Male Wistar rats underwent bilateral orchidectomy one week before the ligation of the anterior descending left coronary artery. The animals were divided into orchidectomized (OCT); MI; orchidectomized + MI (OCT + MI); orchidectomized + MI + testosterone (OCT + MI + T) and control (Sham) groups. Eight weeks after MI, papillary muscle contractility was analyzed under increasing calcium (0.62, 1.25, 2.5 and 3.75 mM) and isoproterenol (10-8 to 10-2 M) concentrations. Ventricular myocytes were isolated for intracellular calcium measurements and assessment of Ca2+ handling proteins. Contractility was preserved in the orchidectomized animals after myocardial infarction and was reduced when testosterone was replaced (Ca2+ 3.75 mM: Sham: 608 ± 70 (n = 11); OCT: 590 ± 37 (n = 16); MI: 311 ± 33* (n = 9); OCT + MI: 594 ± 76 (n = 7); OCT + MI + T: 433 ± 38* (n=4), g/g *p < 0.05 vs Sham). Orchidectomy also increased the Ca2+ transient amplitude of the ventricular myocytes and SERCA-2a protein expression levels. PLB phosphorylation levels at Thr17 were not different in the orchidectomized animals compared to the Sham animals but were reduced after testosterone replacement. CAMKII phosphorylation and protein nitrosylation increased in the orchidectomized animals. Our results support the view that testosterone deficiency prevents MI contractility dysfunction by altering the key proteins involved in Ca2+ handling.

Low-salt diet increases NO bioavailability and COX-2 vasoconstrictor prostanoid production in spontaneously hypertensive rats.

AIMS: The ability of dietary sodium restriction to reduce the incidence of cardiovascular mortality and improve vascular function in hypertension still remains poorly understood. The aim of this study was to observe the effects of a long period of salt restriction on the vascular reactivity of mesenteric resistance arteries of SHRs. METHODS: Male SHRs received either standard-salt diet (0.3% NaCl) or low-salt diet (0.03% NaCl) for 28weeks. Vascular reactivity was studied in mesenteric artery segments and the influence of cyclooxygenase-2 (COX-2), reactive oxygen species (ROS) and participation of the renin-angiotensin system were analyzed. KEY FINDINGS: Decreased salt intake did not affect phenylephrine-induced vasoconstriction but increased acetylcholine-induced vasodilatation and also increased the response to phenylephrine after inhibition of NO synthase by L-NAME (100µM) and iNOS protein expression was elevated. Cyclooxygenase inhibitor indomethacin (10µM) and COX-2 inhibitor NS 398 (1µM) decreased the reactivity to phenylephrine in low-salt-treated group, and COX-2 protein expression was elevated in low-salt group. The effects of apocynin (10µM); superoxide anion scavenger, tiron (1mM); hydrogen peroxide scavenger, catalase (1000UmL(-1)); and ACE and AT1 receptor blockers, enalapril (10µM) and losartan (10µM) on vascular reactivity were not different between two groups. The levels of AT1 protein expression were similar in both groups. SIGNIFICANCE: Low-salt diet modulates mesenteric vascular responses via increased NO bioavailability suggested by increased iNOS protein expression and vasoconstrictor prostanoid production via COX-2 pathway, in SHRs. Neither ROS nor the local renin-angiotensin system is involved in these responses.

Eucalyptol, an essential oil, reduces contractile activity in rat cardiac muscle.

Eucalyptol is an essential oil that relaxes bronchial and vascular smooth muscle although its direct actions on isolated myocardium have not been reported. We investigated a putative negative inotropic effect of the oil on left ventricular papillary muscles from male Wistar rats weighing 250 to 300 g, as well as its effects on isometric force, rate of force development, time parameters, post-rest potentiation, positive inotropic interventions produced by Ca2+ and isoproterenol, and on tetanic tension. The effects of 0.3 mM eucalyptol on myosin ATPase activity were also investigated. Eucalyptol (0.003 to 0.3 mM) reduced isometric tension, the rate of force development and time parameters. The oil reduced the force developed by steady-state contractions (50% at 0.3 mM) but did not alter sarcoplasmic reticulum function or post-rest contractions and produced a progressive increase in relative potentiation. Increased extracellular Ca2+ concentration (0.62 to 5 mM) and isoproterenol (20 nM) administration counteracted the negative inotropic effects of the oil. The activity of the contractile machinery evaluated by tetanic force development was reduced by 30 to 50% but myosin ATPase activity was not affected by eucalyptol (0.3 mM), supporting the idea of a reduction of sarcolemmal Ca2+ influx. The present results suggest that eucalyptol depresses force development, probably acting as a calcium channel blocker.

Left ventricular length dependent activation in the isovolumetric rat heart.

STUDY OBJECTIVE: The aim of the study was to examine, in a whole heart preparation, the relationship between length changes in cardiac muscle and tension development and length dependent activation. DESIGN: Rat hearts were perfused by the Langendorff technique and isovolumetric pressure changes in the left ventricle, produced by increasing diastolic pressures (0, 5, 10, 15, 20, 25 mm Hg), were studied at different calcium concentrations (0.5, 1.25, 2.5, 3.75 mmol.litre-1). EXPERIMENTAL MATERIALS: 20 whole heart preparations were obtained from albino rats of either sex, weight 180-240 g (females) and 220-330 g (males). MEASUREMENTS AND MAIN RESULTS: In a comparison of ventricular diastolic upsilon systolic pressure curves, normalised with respect to maximum isovolumetric systolic pressure, there was a separation and an upward displacement of the curves with increments in calcium concentration in the perfusate. CONCLUSIONS: The results show, as in isolated preparations, that there is length dependent activation in the whole rat heart.

Changes in performance of the surviving myocardium after left ventricular infarction in rats.

STUDY OBJECTIVE: The aim was to investigate left ventricular performance of infarcted hearts during scar formation and development of hypertrophy in the surviving myocardium. DESIGN: Hearts were perfused according to the Langendorff technique and left ventricular function curves were obtained by inserting a distensible balloon into the ventricular cavity. The isovolumetric systolic pressure was measured as diastolic pressure was changed from 0 to 25 mm Hg and during inotropic interventions produced by Ca and isoprenaline. EXPERIMENTAL MATERIALS: Hearts were obtained from albino rats of either sex, 180-250 g, killed 1, 3, 7 or 14 d after left coronary artery ligation (n = 24) or sham operation (n = 26). Normal rats (n = 6) were used as additional controls. MEASUREMENTS AND MAIN RESULTS: After infarction, there was a progressive and almost parallel displacement of the ventricular function curves toward higher diastolic pressures. The positive chronotropic response to isoprenaline was similar in infarcted and non-infarcted hearts. The inotropic response to Ca and isoprenaline, however, was significantly depressed in the infarcted hearts throughout the observation period. CONCLUSIONS: Hypertrophy in the surviving myocardium did not result in improvement of the left ventricular systolic function assessed under in vitro conditions during the first two weeks after infarction. The decreased inotropic response of the infarcted left ventricle to isoprenaline is likely to be dependent on the reduced Ca sensitivity of the surviving myocardium.

A single resistance exercise session improves myocardial contractility in spontaneously hypertensive rats.

Resistance training evokes myocardial adaptation; however, the effects of a single resistance exercise session on cardiac performance are poorly understood or investigated. This study aimed to investigate the effects of a single resistance exercise session on the myocardial contractility of spontaneously hypertensive rats (SHRs). Male 3-month-old SHRs were divided into two groups: control (Ct) and exercise (Ex). Control animals were submitted to sham exercise. Blood pressure was measured in conscious rats before the exercise session to confirm the presence of arterial hypertension. Ten minutes after the exercise session, the animals were anesthetized and killed, and the hearts were removed. Cardiac contractility was evaluated in the whole heart by the Langendorff technique and by isometric contractions of isolated left ventricular papillary muscles. SERCA2a, phospholamban (PLB), and phosphorylated PLB expression were investigated by Western blot. Exercise increased force development of isolated papillary muscles (Ex=1.0±0.1 g/mg vs Ct=0.63±0.2 g/mg, P<0.05). Post-rest contraction was greater in the exercised animals (Ex=4.1±0.4% vs Ct=1.7±0.2%, P<0.05). Papillary muscles of exercised animals developed greater force under increasing isoproterenol concentrations (P<0.05). In the isolated heart, exercise increased left ventricular isovolumetric systolic pressure (LVISP; Δ +39 mmHg; P<0.05) from baseline conditions. Hearts from the exercised rats presented a greater response to increasing diastolic pressure. Positive inotropic intervention to calcium and isoproterenol resulted in greater LVISP in exercised animals (P<0.05). The results demonstrated that a single resistance exercise session improved myocardial contractility in SHRs.

Electromechanical effects of urea on the isolated rat heart.

1. Langendorff-perfused isolated hearts and left ventricle papillary muscles from 3-month-old albino rats of both sexes were studied before and after a 30-min treatment with 17 mM urea added to the medium, a concentration equivalent to a plasma level of 100 mg/dl. To determine whether the effects observed after the addition of urea were produced by an increase in tonicity, the study was repeated using 17 mM sucrose. 2. Mechanical studies on the papillary muscles showed that isometric force development and its first time derivative decreased after washing out urea from the bath (F = 9.73 +/- 1.02 g/mm2 to 7.47 +/- 0.72 and dF/dt = 66.8 +/- 6.43 to 56.7 +/- 4.60 g (mm2)-1 s-1, respectively; P < 0.05). Inotropic responses to isoproterenol and increased extracellular calcium after urea treatment reached values similar to those obtained before urea treatment. Thus, the effect of isoproterenol and calcium was stronger than that obtained before urea treatment. 3. In Langendorff-perfused hearts, the spontaneous heart rate did not change after urea or sucrose treatment. Urea promoted a decrease in the left ventricle isovolumic systolic pressure (39.7 +/- 4.05 to 26.1 +/- 2.69 mmHg, P < 0.05) and a reduction of total QRS amplitude. 4. In both papillary muscles and isovolumic perfused hearts, contractile responses resulting from changes in extracellular sodium concentration were reduced after urea treatment. The increased osmolarity due to sucrose did not produce any changes in electromechanical activities. 5. Although 17 mM, which reduces isometric force and isovolumic pressure development and modifies the ECG, is well below the concentration required to modify protein conformation in vitro, the present results suggest that its action could be explained by an effect at the sarcolemmal level.

Effects of mercury on the mechanical and electrical activity of the Langendorff-perfused rat heart.

The effects of increasing concentrations of mercury (Hg2+) chloride (0.5, 1, 2 and 10 microM) on the myocardial electromechanical activity were studied on 10 Langendorff-perfused rat hearts. Hg2+ decreased the development of isovolumic systolic pressure from 20.3 +/- 2.13 mmHg under control conditions to 6.25 +/- 1.32 mmHg at 10 microM HgCl2 (P < 0.01) (diastolic pressure = 0 mmHg). The atrial and ventricular rates also decreased at 0.5 microM, 1 microM and 2 microM HgCl2 when compared to the Hg(2+)-free solution (from 201 +/- 4 to 126 +/- 15 bpm). However, at 10 microM Hg2+ the atrial rate increased (155 +/- 19 bpm) whereas the ventricular rate did not change significantly (119 +/- 13 bpm). A delay in atrioventricular conduction occurred at 0.5 microM Hg2+ (64 +/- 4 ms in the Hg(2+)-free solution to 91 +/- 14 ms in the presence of 0.5 microM Hg2+, P < 0.05) with no further changes at higher Hg2+ concentrations. The QRS-T duration also increased as a function of increasing Hg2+ concentrations (58 +/- 5.5 ms in the Hg(2+)-free solution to 123 +/- 15 ms in the presence of 10 microM Hg2+, P < 0.01). Qualitative changes of ECG such as extrasystoles, atrial or ventricular arrhythmias and A-V blocks were also observed. The inhibitory action of Hg2+ on ATP hydrolysis and on Ca2+ and Na(+)-K+ ATPases suggested to occur in other tissues could be the mechanism responsible for the observations reported here.

Time-dependent changes of left ventricular contractility in Langendorff perfused hearts from renovascular hypertensive rats.

1. The contractile activity of the hypertrophied myocardium was investigated in Langendorff perfused hearts from one-kidney one-clip (1K1C) renovascular hypertensive rats. 2. Hearts obtained from control and renovascular hypertensive animals were studied 15, 30 and 60 days after sham operation (SO) or renovascular hypertension induction. Rats were anesthetized with ether and mean blood pressure (MBP) and heart rate (HR) were measured. The hearts were then excised and perfused with Krebs solution and bicarbonate buffer, at 31 degrees C, with a perfusion pressure of 75 mmHg, beating spontaneously. The left ventricular function curves were evaluated by measuring the isovolumic systolic pressure (ISP) obtained at diastolic pressures (DP) of 0, 10, 20 and 30 mmHg in 0.62, 1.25 and 2.5 mM extracellular calcium. After the experiments the left ventricle (LV) was dissected, blotted and dried to obtain the dry and wet weights. 3. The 1K1C animals were hypertensive and displayed LV hypertrophy. The LV function curves showed the expected behavior, being similar for all 3 calcium concentrations used for the 15-day groups. However, at 30 days, ISPs were lower than those from the SO control group. Moreover, after 60 days ISPs from 1K1C rat ventricles were higher than controls in 0.62 mM calcium for all DPs. For all other DPs, ISP from 1K1C and control ventricles were similar. Normalization of ISP to LV dry weight showed that the hypertrophied ventricles, at any time and at all calcium concentrations used, developed less pressure by ventricular mass than SO controls. 4. Absolute ISP results suggest changes in the contractile machinery characteristics, not only as a function of the pressure overload but also as a function of the hypertension time course, and that ISP normalization to ventricular mass demonstrated the lower capacity of the hypertrophied muscle to generate force and pressure.

Contractility changes of the right and ventricular muscle after chronic myocardial infarction.

Contractility changes and adaptive responses resulting from acute left ventricular (LV) myocardial infarction are not restricted to the LV myocardium. The reduced LV function increased the right ventricular (RV) pressure load and neurohumoral factors, activated by the infarction

Heterometric regulation and calcium sensitivity of the infarcted rat heart.

1. The surviving hypertrophied muscle remaining after myocardial infarction in rats is less sensitive to extracellular Ca2+ than the normal myocardium. Since the inotropic effect of Ca2+ is modulated by sarcomere length, the present study was undertaken to determine if Ca2+ desensitization of infarcted left ventricles (LV) can be modulated by increasing the diastolic pressure (DP). 2. Rats submitted to left coronary artery ligation (N = 11) or sham-operation (N = 9) were killed 8-10 days later and their hearts perfused by the Langendorff technique. A balloon was introduced into the LV cavity to measure the isovolumic systolic pressure (ISP) produced by DP changes (0 to 25 mmHg) at three Ca2+ concentrations (0.8, 1.25 and 2.5 mM). 3. In control hearts submitted to a DP of 5 mmHg, the ISP increased from 36 +/- 3 to 63 +/- 4 and to 74 +/- 4 mmHg as external Ca2+ was changed from 0.8 to 1.25 and to 2.5 mM, respectively. In contrast, in infarcted hearts submitted to the same DP and Ca2+ concentrations, the ISP increased from 19 +/- 2 to 26 +/- 2 and to 27 +/- 3 mmHg. The depressed response to Ca2+ was not modified by increasing DP up to 25 mmHg, the greatest DP tested. At this DP, ISP increased from 75 +/- 4 to 103 +/- 5 and to 114 +/- 5 mmHg in control hearts and from 45 +/- 2 to 54 +/- 3 and to 55 +/- 4 mmHg in infarcted hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of right and left ventricular performance of the rat heart with chronic myocardial infarction.

1. The rat heart develops a compensatory hypertrophy after infarction which is secondary to volume overload in the left ventricle (LV) and to pressure overload in the right ventricle (RV). This study was undertaken to determine whether the reduced inotropic response to Ca2+ presented by the LV of infarcted rats extends to the RV and whether this hemodynamic profile in vivo affects the contractile performance of the ventricles assessed in vitro. 2. Male adult rats were submitted to left coronary artery ligation to produce infarction (Inf) or to a sham surgery (SO) and used 4 to 5 weeks later. The hemodynamic data were recorded in the anesthetized animals and the systolic performance of both ventricles was evaluated in vitro in the hearts perfused by the Langendorff technique. The isovolumic systolic pressure (ISP) developed by both ventricles was measured at various diastolic pressures (0 to 30 mmHg) and Ca2+ concentrations (0.62, 1.25, and 2.50 mM). 3. The RV systolic pressure was higher in Inf (N = 12) than in SO (N = 12) rats (42 +/- 5 vs 26 +/- 1 mmHg, P < 0.05). A positive and linear correlation (r = 0.86, P < 0.01) between RV systolic pressure and the RV weight to body weight ratio in Inf rats was observed. 4. Length-dependent activation, evaluated by using normalized ventricular function curves, was unchanged in the RV of Inf hearts. In the Inf LV, however, a slight improvement of the normalized systolic performance was observed in relation to SO hearts for diastolic pressures higher than 15 mmHg. 5. A similar depression of the inotropic response to Ca2+ was observed in both ventricles of Inf hearts. Moreover, for Inf hearts the increase of the ISP to Ca2+ flattened at lower Ca2+ concentrations in relation to the SO group. 6. The present results demonstrate that LV infarction in rats depresses the contractile performance of both ventricles. The reduced inotropic response to Ca2+ presented by both ventricles may contribute to the reduced capacity of the Inf heart to generate external work under conditions of higher metabolic demand.

Effect of urea on the mechanical and electrical activity of the perfused rat heart.

The mechanical and electrical activities of Langendorff perfused isolated hearts from albino female rats were studied before and after the addition of 17 mM urea to the medium. The effect of urea on the osmolarity of the perfusing solution was evaluated by also carrying out the measurement in 17 mM saccharose. The rate of the spontaneously beating hearts did not change after urea or saccharose treatment. However, urea promoted a decrease in the left ventricle isovolumic systolic pressure and a reduction of the total QRS amplitude. Saccharose did not alter mechanical or electrical characteristics. Although the concentration of urea which reduced systolic isovolumic pressure development and altered the ECG is well below that required to modify protein conformation in vitro, our results suggest that its action could be at the sarcolemmal level.

The relationship between extracellular calcium and isovolumic systolic pressure in the Langendorff-perfused rat heart.

The relationship between extracellular calcium concentration and isovolumic systolic pressure developed by left ventricles was studied in Langendorff-perfused rat hearts. At diastolic pressure lower than 15 mmHg the isovolumic systolic pressure increased when external calcium was changed from 0.5 to 1.25 mM. Pressure stabilized when external calcium was increased to 3.5 mM but then declined at 5 mM Ca2+. At higher diastolic pressures (20 and 25 mmHg) systolic pressure increased only up to 1.25 mM Ca2+, and declined with further increases in external calcium concentration. This behavior is probably related to "calcium overload" of the preparations at external calcium concentrations greater than 3.5 mM associated with a decreased perfusion pressure gradient at higher diastolic pressures.

Activation of the Langendorff perfused rat heart under depolarizing conditions.

Myocardial activation under depolarized conditions was studied in spontaneously beating Langendorff perfused hearts from albino rats. Depolarization was obtained increasing external potassium concentration in steps (5.4, 7.4, 10, 10.5, 11, 11.5 mM) in the perfusing solution. Left ventricular isovolumic systolic pressure and coronary flow did not change as external potassium increased, but the atrial and ventricular beat rates decreased, the latter showing a larger decline. In the electrocardiogram, the P-R interval increased as a function of external potassium and the amplitude of the QRS complex diminished as its duration increased. The majority of perfused hearts stopped pumping when external potassium was raised to 11.5 mM.

The left ventricular contractility of the rat heart is modulated by changes in flow and alpha 1-adrenoceptor stimulation.

Myocardial contractility depends on several mechanisms such as coronary perfusion pressure (CPP) and flow as well as on alpha 1-adrenoceptor stimulation. Both effects occur during the sympathetic stimulation mediated by norepinephrine. Norepinephrine increases force development in the heart and produces vasoconstriction increasing arterial pressure and, in turn, CPP. The contribution of each of these factors to the increase in myocardial performance needs to be clarified. Thus, in the present study we used two protocols: in the first we measured mean arterial pressure, left ventricular pressure and rate of rise of left ventricular pressure development in anesthetized rats (N = 10) submitted to phenylephrine (PE) stimulation before and after propranolol plus atropine treatment. These observations showed that in vivo alpha 1-adrenergic stimulation increases left ventricular developed pressure (P < 0.05) together with arterial blood pressure (P < 0.05). In the second protocol, we measured left ventricular isovolumic systolic pressure (ISP) and CPP in Langendorff constant flow-perfused hearts. The hearts (N = 7) were perfused with increasing flow rates under control conditions and PE or PE + nitroprusside (NP). Both CPP and ISP increased (P < 0.01) as a function of flow. CPP changes were not affected by drug treatment but ISP increased (P < 0.01). The largest ISP increase was obtained with PE + NP treatment (P < 0.01). The results suggest that both mechanisms, i.e., direct stimulation of myocardial alpha 1-adrenoceptors and increased flow, increased cardiac performance acting simultaneously and synergistically.

Effects of aluminum on the mechanical and electrical activity of the Langendorff-perfused rat heart.

The effect of aluminum (Al3+) chloride (1, 5, 10, 50 and 100 microM) on myocardial electromechanical activity was studied in 10 Langendorff-perfused hearts from adult female Wistar rats. Al3+ decreased the development of isovolumic systolic pressure from 34.3 +/- 2.95 mmHg under control conditions to 11.8 +/- 1.53 mmHg at 100 microM AlCl3 (P < 0.01) (diastolic pressure = 0 mmHg). The atrial and ventricular rates also decreased, but only with AlCl3 concentrations greater than 1 microM (from 180 +/- 5 to 94 +/- 11 bpm for atrial rate and from 180 +/- 5 to 78 +/- 7 bpm for ventricular rate). Reduction of coronary flow was also observed, reaching 60% at 100 microM Al3+. A delay in atrioventricular conduction occurred at 10 microM Al3+, increasing progressively up to 100 microM (62.3 +/- 4 ms in the Al(3+)-free solution to 143 +/- 34 ms in the presence of 100 microM Al3+, P < 0.01, ANOVA). QRS duration did not change as a function of increasing Al3+ concentrations (37.1 +/- 1.7 ms in the Al(3+)-free solution vs 32.1 +/- 1.6 ms in the presence of 100 microM Al3+). No qualitative changes in ECG were observed. These data show that the toxic effects of Al3+ on the myocardium are reflected in reduced systolic pressure development and coronary flow and increased PR interval. These effects are discussed in terms of the inhibition of nucleotide hydrolysis by Al3+.

Acute exposure to lead increases myocardial contractility independent of hypertension development.

We studied the effects of the acute administration of small doses of lead over time on hemodynamic parameters in anesthetized rats to determine if myocardial contractility changes are dependent or not on the development of hypertension. Male Wistar rats received 320 µg/kg lead acetate iv once, and their hemodynamic parameters were measured for 2 h. Cardiac contractility was evaluated in vitro using left ventricular papillary muscles as were Na+,K+-ATPase and myosin Ca2+-ATPase activities. Lead increased left- (control: 112 ± 3.7 vs lead: 129 ± 3.2 mmHg) and right-ventricular systolic pressures (control: 28 ± 1.2 vs lead: 34 ± 1.2 mmHg) significantly without modifying heart rate. Papillary muscles were exposed to 8 µM lead acetate and evaluated 60 min later. Isometric contractions increased (control: 0.546 ± 0.07 vs lead: 0.608 ± 0.06 g/mg) and time to peak tension decreased (control: 268 ± 13 vs lead: 227 ± 5.58 ms), but relaxation time was unchanged. Post-pause potentiation was similar between groups (n = 6 per group), suggesting no change in sarcoplasmic reticulum activity, evaluated indirectly by this protocol. After 1-h exposure to lead acetate, the papillary muscles became hyperactive in response to a ß-adrenergic agonist (10 µM isoproterenol). In addition, post-rest contractions decreased, suggesting a reduction in sarcolemmal calcium influx. The heart samples treated with 8 µM lead acetate presented increased Na+,K+-ATPase (approximately 140%, P < 0.05 for control vs lead) and myosin ATPase (approximately 30%, P < 0.05 for control vs lead) activity. Our results indicated that acute exposure to low lead concentrations produces direct positive inotropic and lusitropic effects on myocardial contractility and increases the right and left ventricular systolic pressure, thus potentially contributing to the early development of hypertension.

Deleterious effect of hypothermia in myocardial protection against cold ischemia: a comparative study in isolated rat hearts.

BACKGROUND: There is a growing need to improve heart preservation benefit the performance of cardiac operations, decrease morbidity, and more important, increase the donor pool. Therefore, the objective of this study was to evaluate the cardioprotective effects of Krebs-Henseleit buffer (KHB), Bretschneider-HTK (HTK), St. Thomas No. 1 (STH-1), and Celsior (CEL) solutions infused at 10°C and 20°C. METHODS: Hearts isolated from male albino Wistar rats and prepared according to Langendorff were randomly divided equally into 8 groups according to the temperature of infusion (10°C or 20°C) and cardioprotective solutions (KHB, HTK, STH-1, and CEL). After stabilization with KHB at 37°C, baseline values were collected (control) for heart rate (HR), left ventricle systolic pressure (LVSP), coronary flow (CF), maximum rate of rise of left ventricular pressure during ventricular contraction (+dP/dt) and maximum rate of fall of left ventricular pressure during left ventricular relaxation (-dP/dt). The hearts were then perfused with cardioprotective solutions for 5 minutes and kept for 2 hours in static ischemia at 20°C. Data evaluation used analysis of variance (ANOVA) in all together randomized 2-way ANOVA and Tukey's test for multiple comparisons. The level of significance chosen was P < .05. RESULTS: We observed that all 4 solutions were able to recover HR, independent of temperature. Interestingly, STH-1 solution at 20°C showed HR above baseline throughout the experiment. An evaluation of the corresponding hemodynamic values (LVSP, +dP/dt, and -dP/dt) indicated that treatment with CEL solution was superior at both temperatures compared with the other solutions, and had better performance at 20°C. When analyzing performance on CF maintenance, we observed that it was temperature dependent. However, when applying both HTK and CEL, at 10°C and 20°C respectively, indicated better protection against development of tissue edema. Multiple comparisons between treatments and hemodynamic variable outcomes showed that using CEL solution resulted in significant improvement compared with the other solutions at both temperatures. CONCLUSION: The solutions investigated were not able to fully suppress the deleterious effects of ischemia and reperfusion of the heart. However, these results allow us to conclude that temperature and the cardioprotective solution are interdependent as far as myocardial protection. Although CEL solution is the best for in myocardial protection, more studies are needed to understand the interaction between temperature and perfusion solution used. This will lead to development of better and more efficient cardioprotective methods.