Negative Lusitropic Effects Research Articles

The inversion of the inotropic effect of isoproterenol in the rat myocardium during deep hypothermia

The present study examined the effects of the в-adrenergic receptor agonist, isoproterenol, on contractile activity of right ventricle papillary muscles in the rat heart at near-physiological temperature (30°C) and under conditions of deep hypothermia (10°C). Isoproterenol exerts a pronounced positive inotropic effect at 30°C. After agonist addition, the force of contraction increases from 1.2 ± 0.1 mN in control to 2.4 ± 0.4 mN that leads to a reliable acceleration of time parameters of contraction. So, time-to-maximum contraction decreased from 101 ± 6 ms to 85 ± 4 ms; time-to-50% relaxation declined from 55 ± 3 ms to 36 ± 1 ms. Under hypothermic conditions, isoproterenol produced a powerful negative inotropic effect, reducing the force of contraction from 2.2 ± 0.4 mN to 1.2 ± 0.4 mN. Similarly as at 30°C, there was a tendency for increase in contraction speed, so time-to-maximum contraction decreased from 717 ± 52 ms to 624 ± 50 ms, and time-to-50% relaxation was shortened from 667 ± 86 ms to 450 ± 40 ms. Thus, under conditions of deep hypothermia at 10°C, the isoproterenol-induced inotropy changes from positive to negative, while negative lusitropic effect remains clear.

Chronic cannabidiol treatment reduces the carbachol-induced coronary constriction and left ventricular cardiomyocyte width of the isolated hypertensive rat heart

Cannabidiol (CBD) is suggested to possess cardioprotective properties. We examined the influence of chronic (10 mg/kg once daily for 2 weeks) CBD administration on heart structure (e.g. cardiomyocyte width) and function (e.g. stimulatory and inhibitory responses induced by β-adrenoceptor (isoprenaline) and muscarinic receptor (carbachol) activation, respectively). Experiments were performed on hearts and/or left atria isolated from spontaneously (SHR) and deoxycorticosterone (DOCA-salt) hypertensive rats; Wistar-Kyoto (WKY) and sham-operated rats (SHAM) served as the respective normotensive controls. CBD diminished the width of cardiomyocytes in left ventricle and reduced the carbachol-induced vasoconstriction of coronary arteries both in DOCA-salt and SHR. However, it failed to affect left ventricular hypertrophy and even aggravated the impaired positive and negative lusitropic effects elicited by isoprenaline and carbachol, respectively. In normotensive hearts CBD led to untoward structural and functional effects, which occurred only in WKY or SHAM or, like the decrease in β1-adrenoceptor density, in either control strain. In conclusion, due to its modest beneficial effect in hypertension and its adverse effects in normotensive hearts, caution should be taken when using CBD as a drug in therapy.

Trastuzumab-induced negative chronotropic and lusitropic effects in cynomolgus monkeys

Trastuzumab-induced negative chronotropic and lusitropic effects in cynomolgus monkeys

P561Acute effects of dronedarone and amiodarone on functional, morphological and oxidative stress parameters in isolated rat heart with hypertension

Abstract Introduction Amiodarone represents the most widely used antiarrhythmic drug, even though it has been shown that it has negative inotropic and lusitropic effect in healthy hears. On the other hand, dronedarone reduces the risk of recurrent atrial fibrillation, but with increased early mortality related to the worsening of heart failure. However, the mechanisms responsible for these fatal outcomes remain unclear and require further examinations. Purpose To investigate acute, direct effects of Dronedarone and Amiodarone on cardiac contractility, coronary flow and oxidative stress parameters in isolated rat heart with hypertension. Methods The present study was carried out on 18 isolated hearts of spontaneously hypertensive Wistar Kyoto male rats (6 weeks old, bodyweight 200 ± 10 g). After isolation, all hearts were retrogradely perfused according to Langendorff technique with a gradually increment of coronary perfusion pressure (CPP from 40 to 120 cm H2O) and randomly divided into 3 groups: Control (n = 6), Amiodarone (n = 6, isolated hearts perfused with Amiodarone in dose of 3 umol), Dronedarone (n = 6, isolated hearts perfused with Dronedarone in dose of 1.8 umol). During ex vivo protocol continuously were registered cardiac contractility parameters and coronary flow, while from collected coronary venous effluent markers of oxidative stress were measured. All hearts were then fixated and stained with Hematoxylin/eosin. Results Dronedarone severely depressed the function of all cardiodynamic parameters of the heart compared with Amiodarone or Control while Amiodarone intensified the function of the isolated rat heart with hypertension compared to Control (dp/dt max mmHg/s at coronary perfusion pressure 120cmH2O Dronedarone vs. Amiodarone vs. Control 579.733 ± 202.27 vs. 3063.65 ± 467.93 vs. 2682.88 ± 368.75; p < 0.001. dp/dt min mmHg/s 120cmH2O -352.13 ± 204.65 vs. 1960 ± 242.21 vs. -1858.83 ± 118.23; p < 0.001. SLVP mmHg at CPP 120cmH20 27.8 ± 3.46 vs. 98.95 ± 11.78 vs. 71.45 ± 7.56; p < 0.001. DLVP mmHg at CPP 120cmH2O 6.32 ± 0.49 vs. 4.83 ± 0.54 vs. 0.85 ± 0.35; p < 0.001). Acute administration of Dronedarone decreased the level of NO2- and increased the level of H2O2 , while Amiodarone heightens O2- levels (O2- nmol/min g wt at coronary perfusion pressure 120cmH2O Dronedarone vs. Amiodarone vs. Control 28.62 ± 2.54 vs. 77.3 ± 8.86 vs. 31.72 ± 4.56; p < 0.001. H2O2 nmol/min g wt at CPP 120cmH2O 92.56 ± 11.65 vs. 48.63 ± 10.11 vs. 42.84 ± 84; p < 0.001. NO2- nmol/min g wt at CPP 120cmH2O 38.61 ± 4.94 vs. 82.28 ± 5.76 vs. 64.71 ± 3.51; p < 0.001). Pathohistological, structural changes were observed in both, experimental groups. Conclusions Acute administration of Dronedarone depresses cardiac function in isolated, working rat heart with hypertension, with decreasing the NO2- levels, increasing the level of H2O2 and enhanced structural changes when compared to Amiodarone.

Negative lusitropic property of nifekalant identified using ventricular pressure-volume loop analyses in anesthetized monkeys.

The present study was conducted to clarify multiple cardiohemodynamic and electrophysiological properties including inotropic/lusitropic effects of nifekalant, a class III antiarrhythmic drug, in an isoflurane-anesthetized monkey. Nifekalant was administered intravenously at the therapeutic dose of 0.3 mg/kg over 10 min to male cynomolgus monkeys (n=4), followed by higher dose of 1 (n=3) or 3 mg/kg (n=1) that was limited due to arrythmogenicity. Left ventricular (LV) pressure-volume (PV) analysis revealed that the 0.3 mg/kg dose of nifekalant induced a negative lusitropic effect, recognized as a decrease in maximal rate of reduction in LV pressure and a prolonged isovolumic relaxation time. Nifekalant also decreased heart rate and increased LV end-diastolic pressure, but had no effects on the other cardiohemodynamic parameters examined. Electrophysiological analysis showed nifekalant at 0.3 mg/kg prolonged QT/QTc intervals with no evidence of arrhythmia. Higher doses of nifekalant induced ventricular arrhythmia in 3 out of 4 animals, in which both the short-term and long-term variability of the QT interval increased just before the occurrence of arrhythmia. In conclusion, a therapeutic dose of nifekalant had no effect on inotropic activity or cardiac compliance, whereas it showed negative lusitropic properties and QT/QTc prolongation in isoflurane-anesthetized monkeys. In addition, higher doses of nifekalant showed remarkable QT/QTc prolongation leading to arrhythmogenicity, which showed good accordance with clinical findings. Caution should be paid to negative lusitropic properties as well as arrhythmogenisity for the safe use of nifekalant.

Endothelins as mediators in the modulation of cardiac performance

The role of endothelin in cardiovascular physiology and pathophysiology has been undeniable ever since its discovery. Endothelins in the heart are important for the development, growth and remodeling, as well as for the control of contractility and rhythm. Cardiac endothelial cells in the endocardium and myocardial capillaries represent the main source of endothelin, and cardiomyocytes are their primary targets. Endothelin-1 is one of the most potent substances with a positive inotropic effect known to man; subsequently endothelin plays a key role in the cardiac endothelial-myocardial interaction. The endothelins are a family of 21 amino acid peptidesof which there are three distinct isoforms endothelin-1, endothelin-2 and endothelin-3. Their effects are achieved by the activation of endothelin receptors, ETA and ETB, which belonging to the family of G protein-linked receptors. ETA and ETB receptors are densely distributed in cardiomyocytes, the cells of the cardiovascular system, coronary vascular and endocardial endothelial cells. Under physiological conditions, endothelin is synthesized in endothelial cells, while under pathophysiological conditions in the large number of non-endothelial cells of the heart as well. Endothelin-1 has positively inotropic and chronotropic effects. The administration of ET-1 causes coronary vasoconstriction, leads to myocardial ischemia and a lethal ventricular arrhythmia. In the acute myocardial infarction, ET-1 increases myocardial necrosis and arrhythmia but has a favorable effect on heart recovery after a myocardial infarction at an early stage of cardiac remodeling. ET-1 reverses acidosis-induced negative lusitropic and inotropic effects without the increase of intracellular calcium. Endothelin can resist the arrhythmogenic effects of catecholamines. Thus, low concentrations of endothelin have a protective effect on the heart. Primary indications for the administration of endothelin antagonists are heart failure, pulmonary hypertension and resistant arterial hypertension. Careful and well-designed clinical studies are needed to verify the therapeutic potential of new types of drugs in cardiovascular medicine.

Malvidin, a red wine polyphenol, modulates mammalian myocardial and coronary performance and protects the heart against ischemia/reperfusion injury

A moderate red wine consumption and a colored fruit-rich diet protect the cardiovascular system, thanks to the presence of several polyphenols. Malvidin-3-0-glucoside (malvidin), an anthocyanidine belonging to polyphenols, is highly present in red grape skin and red wine. Its biological activity is poorly characterized, although a role in tumor cell inhibition has been found. To analyze whether and to which extent, like other food-derived polyphenols, malvidin affects the cardiovascular function, in this study, we have performed a quantitative analysis by high-performance liquid chromatography of polyphenolic content of red grape skins extract, showing that it contains a high malvidin amount (63.93±12.50 mg/g of fresh grape skin). By using the isolated and Langendorff perfused rat heart, we found that the increasing doses (1–1000 ng/ml) of the extract induced positive inotropic and negative lusitropic effects associated with coronary dilation. On the same cardiac preparations, we observed that malvidin (10−10–10−6 mol/L) elicited negative inotropism and lusitropism and coronary dilation. Analysis of mechanism of action revealed that malvidin-dependent cardiac effects require the activation of the phosphatidylinositol 3-kinase (PI3K)/nitric oxide (NO)/cGMP/PKG pathway and are associated with increased intracellular cGMP and the phosphorylation of endothelial NO synthase (eNOS), PI3K–AKT, ERK1/2, and GSK-3β. AKT and eNOS phosphorylation was confirmed in human umbilical vein endothelial cell. We also found that malvidin act as a postconditioning agent, being able to elicit cardioprotection against ischemia/reperfusion damages. Our results show the cardioactivity of polyphenols-rich red grape extracts and indicate malvidin as a new cardioprotective principle. This is of relevance not only for a better clarification of the beneficial cardiovascular effects of food-derived polyphenols but also for nutraceutical research.

Safety and Efficacy of Ivabradine in the Management of Stable Angina Pectoris

The first selective If current inhibitor, ivabradine, lowers heart rate (HR) at rest and during exercise with no vasomotor, negative inotropic, or negative lusitropic effects. Given that elevated resting HR is a key factor in the onset of myocardial ischemia and a strong independent predictor of cardiovascular outcomes, ivabradine provides new therapeutic prospects in coronary artery disease (CAD). Its selective HR-lowering action has proven anti-ischemic and anti-anginal efficacy, and ivabradine is currently indicated for the symptomatic treatment of stable angina pectoris. Ivabradine can also be safely combined with other anti-anginal agents, and addition of ivabradine to beta-blocker therapy further improves anti-ischemic efficacy and exercise capacity of patients with stable angina. The recent BEAUTIFUL trial demonstrated that although the primary endpoint was not met in the overall population, addition of ivabradine on top of standard preventive treatments significantly reduced the risk of coronary events in stable CAD patients with left ventricular systolic dysfunction among the subgroup of patients with a resting HR ≥ 70 bpm. This is in accordance with pre-clinical data showing that long-term HR reduction improves endothelial function and reduces the progression of atherosclerosis. A significant proportion of patients with stable angina have elevated resting HR and ivabradine should therefore be considered as an important therapy in these cases. In combination with other standard treatments, ivabradine can improve angina and could potentially improve coronary outcomes. Ongoing and future clinical studies will evaluate the presence and magnitude of the cardioprotective benefits of HR lowering with ivabradine in patients with cardiovascular diseases.

Abstract 1499: Angiotensin And Endothelin Systems - Important Players In Urotensin II Induced Myocardial Distensibility

Objective: Urotensin II (U-II) is a vasoactive peptide with important actions in the cardiovascular system. It was recently shown that it acutely decreases myocardial stiffness. Although angiotensin II (AngII) and endothelin-1 (ET-1) also modulate myocardial diastolic properties, their interaction with U-II at this level has not yet been investigated. Methods: Effects of increasing concentrations of U-II (10 – 8–10 – 6M) were studied in rabbit papillary muscles immersed in a modified Krebs solution (0.6Hz;1.8mM Ca2+;35°C) in the absence (n=12) and in presence of losartan, a selective competitive antagonist of AngII receptor type 1 (10 – 6M;n=8) or PD-145065, a nonselective endothelin receptor antagonist (10 – 6M;n=6). Calculated parameters: passive tension (PT), active tension (AT), maximum velocity of tension rise and decline (dT/dtmax and dT/dtmin, respectively) and muscle length. Results presented as mean±SEM (p<0.05). Results: U-II induced a concentration dependent negative inotropic and lusitropic effects, decreasing at 10 – 6M 15.8±5.6%AT, 13.5±5.4%dT/dtmax and 18.1±4.5%%dT/dtmin. This effect was inhibited by losartan or PD-145065. Additionally, U-II induced a concentration dependent increase in passive muscle length of 1.0081±0.002L/ Lmax. Restoring muscle length to Lmax decreased 19.5±3.5%PT, indicating increased myocardial distensibility. In the presence of PD-145065, the maximal concentration of U-II only increased muscle length to 1.004±0.002%L/Lmax, which corresponded to a decrease of PT of just 11.6±2.7%. With losartan these effects of U-II were abolished. Conclusion: The acute increase in myocardial distensibility induced by U-II is attenuated by ET-1 receptor blockade and completely abolished in the presence of an AT1 antagonist. This interaction between U-II, AngII and ET-1 is a novel finding with potential pathophysiologic and therapeutic implications in heart failure that deserves further investigation.

Diabetic Cardiomyopathy and Anesthesia

Diabetic Cardiomyopathy and Anesthesia

Effects of bupivacaine, levobupivacaine and ropivacaine on myocardial relaxation

Ropivacaine and levobupivacaine were developed to reduce the risk of occasional toxicity reported with bupivacaine. While the effects of long-acting local anesthetics (LAAs) on myocardial contractility (inotropy) are well described, their effects on relaxation (lusitropy) remain largely unknown. The present study aimed to compare the effects of LAAs on rat myocardium. Left ventricular papillary muscles of male Wistar rats were used to compare the inotropic and lusitropic responses of increasing concentrations of LAAs (10(-8) to 10(-3) M) under isometric and isotonic conditions. Data are mean % (SD) of baseline value. Long-acting local anesthetics induced a significant impairment of relaxation in isotonic and isometric conditions. As compared to ropivacaine, bupivacaine and levobupivacaine induced greater negative lusitropic effects in isotony [at 10(-3) M, maximum unloaded shortening velocity ((max)Vr) = 27 +/- 11 vs 13 +/- 6 and 8 +/- 5%] and isometry (at 10(-3) M, time-to-half-relaxation: 106 +/- 10 vs 127 +/- 17 and 133 +/- 17%). When the comparison was made with equipotent concentrations, the negative lusitropic effects induced with levobupivacaine were significantly greater than those of bupivacaine and ropivacaine in isometric and isotonic conditions (at 10(-3) M, (max)Vr = 7 +/- 4 vs 13 +/- 6 and 17 +/- 4 %). As previously described, LAAs also induced concentration-dependent negative inotropic effects that were greater for levobupivacaine compared to equivalent or equipotent concentrations of bupivacaine and ropivacaine. Long-acting local anesthetics induce marked negative inotropic and lusitropic effects. Among LAAs, levobupivacaine exerts the greater depressant effects. Impairment of calcium handling and sarcoplasmic reticulum could explain the differential responses to local anesthetics.

The utility of levosimendan in the treatment of heart failure

Calcium sensitizers are a new group of inotropic drugs. Levosimendan is the only calcium sensitizer in clinical use in Europe. Its mechanism of action includes both calcium sensitization of contractile proteins and the opening of adenosine triphosphate (ATP)‐dependent potassium channels as mechanism of vasodilation. The combination of K‐channel opening with positive inotropy offers potential benefits in comparison to currently available intravenous inotropes, since K‐channel opening protects myocardium during ischemia. Due to the calcium‐dependent binding of levosimendan to troponin C, the drug increases contractility without negative lusitropic effects. In patients with heart failure levosimendan dose‐dependently increases cardiac output and reduces pulmonary capillary wedge pressure. Since levosimendan has an active metabolite OR‐1896 with a half‐life of some 80 hours, the duration of the hemodynamic effects significantly exceeds the 1‐hour half‐life of the parent compound.The hemodynamic effects of the levosimendan support its use in acute and postoperative heart failure. Several moderate‐size trials (LIDO, RUSSLAN, CASINO) have previously suggested that the drug might even improve the prognosis of patients with decompensated heart failure. These trials were carried out in patients with high filling pressures. Recently two larger trials (SURVIVE and REVIVE) in patients who were hospitalized because of worsening heart failure have been finalized. These trials did not require filling pressures to be measured. The two trials showed that levosimendan improves the symptoms of heart failure, but does not improve survival. The results raise the question whether a 24‐hour levosimendan infusion can be used without invasive hemodynamic monitoring.

Alterations of β3-adrenoceptors expression and their myocardial functional effects in physiological model of chronic exercise-induced cardiac hypertrophy

Physical training induces cardiovascular autonomic nervous system regulation adaptations, which could result from beta adrenergic receptor (AR) modifications. Among them, beta(3 )AR alterations have been recently reported but their functional effect remained to discuss. To explain the beta(3) AR gene expression in relation to function, we simultaneously studied the left ventricle (LV) beta(3) AR mRNA and protein levels and the myocardial functional effects of a beta(3) AR agonist following physical training. Forty rats were assigned to either a control (C; N = 20) or a trained (T; N = 20) group. The treadmill running protocol was performed for 8 weeks. Histological measurements on LV slices were quantified. The beta(3) AR mRNA abundance was studied with RT-PCR and beta(3) AR protein density with Western-Blot analysis. Myocardial functional effects of a beta(3) AR agonist, BRL37344 (10(-8) M), were studied in Langendorff-perfused hearts. Histological data confirmed the adapted patterns of the physiological cardiac hypertrophy observed in T (P < 0.01), with a significant increase in arteries density (P < 0.01) and an unchanged collagen concentration. The beta(3) AR protein density was increased in T (154 +/- 38% in T vs. 100 +/- 24% in C; P < 0.05), but no change was noted concerning the beta(3) AR mRNA level. After BRL37344 perfusion LVDP, +dP/dT and -dP/dT, in C (P < 0.01), and only +dP/dT in T (P < 0.05) were decreased. Moreover, all LV hemodynamic parameters were more altered after BRL37344 in C than in T (P < 0.01).Thus, in this physiological model of cardiac hypertrophy, an increase of beta(3) AR density without beta(3) AR mRNA alteration was observed. Classical negative myocardial lusitropic and inotropic effects induced by a specific agonist of beta(3) AR were diminished in trained rats.

Comparison of the effects of mepivacaine and lidocaine on rat myocardium

To compare the inotropic and lusitropic effect of lidocaine and mepivacaine on rat papillary muscle. Effects of lidocaine and mepivacaine (10-8-10-3 M) were studied in rat left ventricular papillary muscles in vitro at a calcium concentration of 1 mmol, under low (isotony) and high (isometric) loads. Lidocaine induced a significant negative inotropic effect in isotonic and isometric conditions whereas mepivacaine did not. Mepivacaine only induced a negative inotropic effect when added as a bolus for the highest concentration and this effect was significantly more pronounced with lidocaine than with mepivacaine (active force at 10-3 M: 63 +/- 10 vs. 84 +/- 10% of baseline, P < 0.05). Increasing calcium concentration resulted in a greater positive inotropic effect in the control (199 +/- 11% of baseline) and mepivacaine groups (197 +/- 22% of baseline) when compared to the lidocaine group (163 +/- 19% of baseline, P < 0.05 vs. lidocaine and control groups), suggesting an impairment on intracellular Ca2+ handling by lidocaine. A negative lusitropic effect under low load was observed only for mepivacaine and suggested an impairment of sarcoplasmic reticulum function. Lidocaine and mepivacaine did not modify post-rest potentiation but significantly depressed the force-frequency relationship. The negative inotropic and lusitropic effects induced by lidocaine were more important than that of mepivacaine and may involve an impairment of intracellular Ca2+ handling.

In vivo versus in vitro comparison of swine cardiac performance: Induction of cardiodepression with halothane

An in situ versus in vitro comparison of relative dose-dependent effects of halothane on cardiac performance was investigated, including ventricular systolic/diastolic function. Such comparative studies may be of interest to individuals working on heart failure models, cardiac device testing, or xenotransplantation. Normal swine ( n = 9) received halothane at levels of 0.25, 0.5 and 1 MAC (minimum alveolar concentration) for 30 min each. Parameters assessed included: 1) heart rate; 2) arterial blood pressure; 3) pulmonary artery, central venous, left and right ventricular pressures; 4) cardiac output; 5) end-expiratory CO 2 and halothane levels; 6) cardiac temperature; and 7) arterial blood gases. Hearts were removed using standard cardioplegic procedures and reperfused in four-chamber working mode ( n = 8); again the effects of increasing halothane concentrations on cardiac performance were analyzed. When comparing biventricular depressive effects (negative inotropic, negative lusitropic) of halothane in vivo and in vitro, there were distinct quantitative differences. The negative lusitropic effects were less pronounced in vitro; this was especially true for the right ventricle . Yet, in vitro, halothane at all doses induced more pronounced decreases in left heart output compared to the right. The large mammalian isolated four-chamber working heart model allows for novel assessment of pharmacodynamics and/or evaluation of cardiac devices under a range of hemodynamic performances. Halothane, a cardiodepressive agent, induced direct myocardial depressive effects in vitro similar to those recorded in vivo; hence additional systemic effects are considered to play a minor role in ultimate performances, e.g., compensatory responses due to autonomic controls.

Inotropic and lusitropic effects of ghrelin and their modulation by the endocardial endothelium, NO, prostaglandins, GHS-R1a and K Ca channels

Contractile effects of ghrelin (10 −9 to 10 −6 M) were tested in rat papillary muscles of normal ( n = 50) and hypertrophic ( n = 16) right ventricles (RV). RV hypertrophy was induced by pulmonary hypertension using monocrotaline. In normal muscles, ghrelin was added either alone ( n = 9) or after pre-treatment with indomethacin (cycloxygenase inhibitor, 10 −5 M; n = 10), l-nitro- l-arginin (NO synthase inhibitor, 10 −4 M; n = 9), d-Lys(3)-GHRP-6 (GHS-R1a antagonist; 10 −4 M; n = 8) or apamin + charybdotoxin (K Ca channels blockers; 10 −6 M, n = 7), as well as after damaging the endocardial endothelium ( n = 7). In hypertrophic muscles, ghrelin was added either alone ( n = 9) or after pre-treatment with apamin + charybdotoxin (10 −6 M, n = 7). Ghrelin concentration-dependently decreased active tension (AT) and maximal velocity of tension rise (negative inotropic effect), as well as, maximal velocity of tension decay (negative lusitropic effect) and time to AT (onset of relaxation). These effects were maximal at 10 −6 M, similar in normal and hypertrophic muscles and were significantly altered only by apamin + charybdotoxin, indomethacin and l-nitro- l-arginin. Apamin + charybdotoxin attenuated the negative inotropic effect, while indomethacin and l-nitro- l-arginin, respectively, blunted and exacerbated the premature onset of relaxation. In conclusion, ghrelin induces negative inotropic and lusitropic effects and an earlier onset of relaxation in normal and hypertrophic myocardium, which are independent of GHS-R1a, since they were not affected by d-Lys(3)-GHRP-6. The negative inotropic effect is partly mediated by K Ca channels, while the earlier onset of relaxation is modulated by prostaglandins and NO.

717 Chromogranin A is produced by human ventricular myocardium in systolic and diastolic heart failure and exerts negative inotropic and lusitropic effects on mammalian heart

717 Chromogranin A is produced by human ventricular myocardium in systolic and diastolic heart failure and exerts negative inotropic and lusitropic effects on mammalian heart

Endothelin-1 and isoprenaline co-stimulation causes contractile failure which is partially reversed by MEK inhibition

The mitogen-activated kinase kinases (MEK)-extracellular signal-regulated kinases (ERK) signaling pathway is activated by agonists like catecholamines or endothelin-1 (ET-1) and has been implicated in cardiac pathology, such as the progression from cardiac hypertrophy to failure. The purpose of the present study, performed in an in vitro model of contractile failure, was to evaluate whether MEK inhibition prevents functional deterioration. Contractile dysfunction was induced in reconstituted rat heart tissue by concomitant treatment with ET-1 (10 nmol/l) and isoprenaline (ISO, 10 nmol/l) for 5 days. While basal force of contraction was unchanged, contractile responsiveness to beta-adrenoceptor agonists was markedly impaired (active force declined to 51% of controls) and was associated with decreased lusitropy. Moreover, in ET-1+ISO-treated heart tissues, reprogramming of gene expression was observed with an increased ratio of beta-myosin heavy chain (MHC) to alpha-MHC mRNA and increased transcript levels of ANF and skeletal/smooth muscle alpha-actin isoforms. The MEK inhibitor U0126 (10 micromol/l) almost completely prevented the reduction in beta-adrenergic responsiveness and the negative lusitropic effect of ET-1+ISO co-stimulation. In addition, U0126 completely normalized ANF gene expression, but did not affect or only marginally affected expression of MHC and alpha-actin isoforms. These results suggest that interruption of the MEK-ERK signaling pathway with a specific MEK inhibitor prevents, in part, the occurrence of a pathologic phenotype secondary to excessive stimulation with neurohumoral factors. The MEK-ERK pathway seems to be an important but not exclusive regulatory pathway responsible for the development of contractile dysfunction.

Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo

The endothelin (ET) system is involved in the regulation of myocardial function in health as well as in several diseases, such as congestive heart failure, myocardial infarction, and septic myocardial depression. Conflicting results have been reported regarding the acute contractile properties of ET-1. We therefore investigated the effects of intracoronary infusions of ET-1 and of the selective ET(B) receptor-selective agonist sarafotoxin 6c with increasing doses in anesthetized pigs. Myocardial effects were measured through analysis of the left ventricular pressure-volume relationship. ET-1 elicited increases in the myocardial contractile status (end-systolic elastance value of 0.94 +/- 0.11 to 1.48 +/- 0.23 and preload recruitable stroke work value of 68.7 +/- 4.7 to 83.4 +/- 7.2) that appear to be mediated through ET(A) receptors, whereas impairment in left ventricular isovolumic relaxation (tau = 41.5 +/- 1.4 to 58.1 +/- 5.0 and t(1/2) = 23.0 +/- 0.7 to 30.9 +/- 2.6, where tau is the time constant for pressure decay and t(1/2) is the half-time for pressure decay) was ET(B) receptor dependent. In addition, intravenous administration of ET-1 impaired ventricular relaxation but had no effect on contractility. Intracoronary sarafotoxin 6c administration caused impairments in left ventricular relaxation (tau from 43.3 +/- 1.8 to 54.4 +/- 3.4) as well as coronary vasoconstriction. In conclusion, ET-1 elicits positive inotropic and negative lusitropic myocardial effects in a pig model, possibly resulting from ET(A) and ET(B) receptor activation, respectively.

Polyphenolic compounds from Cognac induce vasorelaxation in vitro and decrease post-ischaemic cardiac infarction after an oral administration.

The effects of Cognac polyphenolic compounds (CPC) on aorta and isolated heart, the consequences of oral administration on haemodynamic parameters, vascular reactivity and cardiac recovery after ischaemia were investigated. CPC induced an endothelium-dependent vasorelaxation on rat-isolated aorta. This effect was prevented by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine-methyl ester, but not by the cyclo-oxygenase inhibitor, indomethacin, suggesting the implication of NO pathway. On isolated rat hearts, CPC induced positive inotropic, chronotropic, and lusitropic effect at 10(-4)-10(-2) g/L while at 10(-1) g/L, it had negative lusitropic effect and other parameters returned to baseline values. Oral administration of 40 mg/kg of CPC for 2 weeks did not modify systolic blood pressure and heart rate of rats throughout the treatment. CPC treatment did not affect ex vivo response of isolated thoracic aorta either to the contractile agent noradrenaline or to the endothelial-relaxant agent, acetylcholine. Isolated hearts from treated rats were submitted to 30-min global ischaemia followed by 120 min of reperfusion. Post-ischaemic recovery of functional cardiac parameters was not modified by treatment with CPC. Infarct size measured after the reperfusion in heart from CPC-treated rats was significantly decreased in comparison with hearts from control group. We conclude that in vitro, CPC had NO-dependent vasorelaxant effects and stimulated cardiac function. Oral treatment with CPC appeared to have no impact in vivo on blood pressure, heart rate of the rats or on cardiac contractility ex vivo; however, it could decrease the infarct size after an ischaemia-reperfusion.