Search

Ballistocardiography (BCG) and Seismocardiography (SCG) assess the vibrations produced by cardiac contraction and blood flow, respectively, by means of micro-accelerometers and micro-gyroscopes. From the BCG and SCG signals, maximal velocities (VMax), integral of kinetic energy (iK), and maximal power (PMax) can be computed as scalar parameters, both in linear and rotational dimensions. Standard echocardiography and 2-dimensional speckle tracking imaging echocardiography were performed on 34 healthy volunteers who were infused with increasing doses of dobutamine (5–10–20 μg/kg/min). Linear VMax of BCG predicts the rates of left ventricular (LV) twisting and untwisting (both p < 0.0001). The linear PMax of both SCG and BCG and the linear iK of BCG are the best predictors of the LV ejection fraction (LVEF) (p < 0.0001). This result is further confirmed by mathematical models combining the metrics from SCG and BCG signals with heart rate, in which both linear PMax and iK strongly correlate with LVEF (R = 0.7, p < 0.0001). In this setting of enhanced inotropism, the linear VMax of BCG, rather than the VMax of SCG, is the metric which best explains the LV twist mechanics, in particular the rates of twisting and untwisting. PMax and iK metrics are strongly associated with the LVEF and account for 50% of the variance of the LVEF., SCOPUS: ar.j, info:eu-repo/semantics/published

INTRODUCTION Cardiovascular autonomic nervous system (CV-ANS) function is negatively impacted after concussion. The arterial baroreflex buffers pressor and depressor challenges through efferent modulation of cardiac chronotropism and inotropism, and peripheral vascular tone. Baroreceptor sensitivity (BRS) reflects the capacity of the CV-ANS to accommodate dynamic metabolic demands in the periphery. The impact of concussion on BRS has yet to be defined. METHODS Cardiovascular autonomic nervous system assessment (e.g., electrocardiogram and beat-to-beat systolic blood pressure [SBP]) was performed the seated upright position at rest within 48 h (V1) of concussion and 1 wk later (V2) in 10 intercollegiate male athletes with concussion and 10 noninjured male athletes. Changes in HR, SBP, high- and low-frequency HR variabilities (HF-HRV and LF-HRV, respectively), LF-SBP variability and BRS for increasing (BRSn-Up) and decreasing (BRSn-Dn) SBP excursions, and overall BRS (BRSn-Avg) were assessed for differences at V1 and V2. RESULTS The concussion (age, 20 ± 1 yr; height, 1.79 ± 0.14 m; weight, 83 ± 10 kg) and control (age, 20 ± 1 yr; height, 1.78 ± 0.10 m; weight, 79 ± 13 kg) groups were matched for demographics. Concussed athletes had a significantly reduced BRSn-Up, BRSn-Dn, and BRSn-Avg compared with controls at V1 or V2; these changes occurred without differences in conventional markers of CV-ANS function (e.g., HF-HRV, LF-HRV, LF-SBP), HR, or SBP at either visit. CONCLUSIONS Reduced BRS is a postconcussive consequence of CV-ANS dysfunction during the first postinjury week. Because SBP was similar between groups, it may be speculated that reduced BRS was not afferent in origin, but represents a postinjury consequence of the central nervous system after injury.

Our aim was to evaluate whether endothelial overexpressing of the bradykinin B1 receptor could be associated with altered left ventricular and myocardial performance. Echocardiography and hemodynamic were employed to assess left ventricular morphology and function in Sprague Dawley transgenic rats overexpressing the endothelial bradykinin B1 receptor (Tie2B1 rats). The myocardial inotropism was evaluated on papillary muscles contracting in vitro. In Tie2B1 animals, an enlarged left ventricular cavity and lower fractional shortening coupled with a lower rate of pressure change values indicated depressed left ventricular performance. Papillary muscle mechanics revealed that both Tie2B1 and wild-type rat groups had the same contractile capacities under basal conditions; however, in transgenic animals, there was accentuated inotropism due to post-pause potentiation. Following treatment with the Arg9-BK agonist, Tie2B1 papillary muscles displayed a reduction in myocardial inotropism. Endothelial B1 receptor overexpression has expanded the LV cavity and worsened its function. There was an exacerbated response of papillary muscle in vitro to a prolonged resting pause, and the use of a B1 receptor agonist impairs myocardial inotropism.

Exercise training effects on the contractility of aged myocardium have been investigated for more than 20 years, but the data are still unclear. This study evaluated the hypothesis that a swimming training (ST) may improve myocardial inotropism in older rats. Male Wistar rats aged 4 (young)-and 21 (old)-months-old were divided into young untrained (YNT), old untrained (ONT), and old trained (OTR; 6 weeks of ST) groups. Echocardiography and hemodynamic were employed to assess left ventricular morphology and function. Myocardial mechanics was evaluated on papillary muscles. Histological and immunoblotting were carried out to evaluate fibrosis and proteins that modulate the myocardial function and calcium handling. We found that older rats did not show cardiac dysfunction, but ONT group showed lower physical performance during a swimming test (YNT: 5 ± 2; ONT: -16 ± 0.4; OTR: 51 ± 3; Δ%, sec). Moreover, ONT group showed worse myocardial inotropism, in which it was reversed by ST (Peak developed tension: YNT: 6.2 ± 0.7; ONT: 3.9 ± 0.3; OTR: 6.9 ± 0.9; g/mm2). The ST was associated with preserved collagen content (YNT: 0.38 ± 0.05; ONT: 0.78 ± 0.12; OTR: 0.34 ± 0.09; %). Exercise partially mitigated the effects of aging on intracellular Ca2+-regulating protein (eg, L-Ca2+ channel and phospholamban) and β-isoform of myosin. Thus, we propose that these molecular alterations together with inhibition of collagen increase contribute to improved myocardial performance in older rats.

Levodopa is the most effective medical treatment for Parkinson’s disease (PD) to date. As dopamine is known to increase cardiac inotropism and vasomotor tone, peripheral dopamine decarboxylase inhibitor is coadministered to suppress the peripheral conversion of levodopa to dopamine. Levodopa poses potential cardiovascular risks, thus its use in patients with existing coronary artery disease needs to be carefully monitored. We report a case of an elderly male with newly diagnosed PD who developed non-ST-elevation myocardial infarction following levodopa (Madopar) initiation.

The present study aimed to analyze the effects of reperfusion of a distant coronary artery on cardiac function, the ultrastructure, and the molecular environment of the remote myocardium immediately after the completion of myocardial regional necrosis: delayed reperfusion (DR). Additionally, the effects of prior exercise on the outcomes of DR were investigated. Female rats with permanent occlusion or delayed reperfusion were randomly assigned to an exercise (swimming, 1 h/day, 5 days/week for 8 weeks) or sedentary protocol. Thus, the study included the following four groups: sedentary permanent occlusion, exercise permanent occlusion, sedentary delayed reperfusion, and exercise delayed reperfusion. The descending coronary artery was occluded for 1 h. Reperfusion was confirmed by contrast echocardiography, and the rats were observed for 4 weeks. Permanent occlusion and DR caused similar myocardial infarction sizes among the four groups. Interestingly, exercise significantly decreased the mortality rate. Delayed reperfusion resulted in significant benefits, including enhanced hemodynamics and papillary muscle contraction, as well as reduced apoptosis and collagen content. Protein calcium kinetics did not change. Meanwhile, developed tension and the Frank-Starling mechanism were enhanced, suggesting that calcium sensitivity was intensified in myofilaments. Remarkable remote myocardial benefits occurred after distant DR, and prior exercise intensified cardiac recovery. Our findings provide valuable information about DR. Our data might explain the better clinical outcomes in recent studies showing that late reperfusion could improve heart failure in patients with myocardial infarction. In conclusion, DR has remote myocardial benefits, including inotropism enhancement, pulmonary congestion reduction, and collagen and apoptosis attenuation, which are enhanced by prior exercise.

Implantable accelerometers have been already proposed for the continuous monitoring of heart wall motion. Although a number of markers extracted from cardiac accelerometry have been associated with contractility, they are mainly based on uniaxial (1D) sensors, that not always reflect this relationship consistently. In this work, 3D-acceleration signals obtained from sensors located at the left ventricle (LV) of two anesthetized pigs were acquired at baseline and during dobutamine infusion, along with LV pressure. For each cardiac cycle, the reference contractility was estimated as the maximal LV pressure first derivative $(dP/dt_{max})$ . The peak of maximum energy (PE) and the peak of acceleration (PA) were computed for each accelerometry axis and for the acceleration modulus. Different polynomial curves were fitted to scatterplots representing $dP/dt_{max}$ vs. each extracted feature, in order to quantify fitting qualities. Three-dimensional features, and particularly PE, seemed to better represent contractility. Based on results, inotropism seems to be quadratically related to acceleration-based features, which may lead to more reliable LV contractility estimates when based on 3D data.

The hypothalamic neuropeptide Nesfatin-1 is present in both mammals and teleosts in which it elicits anorexigenic effects. In mammals, Nesfatin-1 acts on the heart by inducing negative inotropism and lusitropism, and cardioprotection against ischemic damages. We evaluated whether in teleosts, Nesfatin-1 also influences cardiac performance. In the goldfish (Carassius auratus), mature, fully processed Nesfatin-1 was detected in brain, gills, intestine and skeletal muscle, but not in the cardiac ventricle. However, on the isolated and perfused working goldfish heart, exogenous Nesfatin-1 induced a positive inotropic effect, revealed by a dose-dependent increase of stroke volume (SV) and stroke work (SW). Positive inotropism was abolished by inhibition of adenylate cyclase (AC; MDL123330A) and cAMP-dependent kinase (PKA; KT5720), suggesting a cAMP/PKA-mediated pathway. This was confirmed by the increased cAMP concentrations revealed by ELISA on Nesfatin-1-treated hearts. Perfusion with Diltiazem, Thapsigargin and PD98059 showed the involvement of L-type calcium channels, SERCA2a pumps and ERK1/2, respectively. The role of ERK1/2 and phospholamban in Nesfatin-1-induced cardiostimulation was supported by Western blotting analysis. In conclusion, this is the first report showing that in teleosts, Nesfatin-1 potentiates mechanical cardiac performance, strongly supporting the evolutionary importance of the peptide in the control of the cardiac function of vertebrates.

Cyclic nucleotide phosphodiesterase (PDE)3 and PDE4 provide the major PDE activity in cardiac myocytes and shape β1-adrenoceptor-dependent cardiac cAMP signaling but their role in regulating β2-adrenoceptor-mediated responses is less well known. We investigated potential differences in PDE3 and PDE4 activities between right (RV) and left (LV) ventricular myocardium, and their role in regulating β2-adrenoceptor effects. PDE3 activity in the microsomal fraction was lower in RV than in LV but was the same in the cytosolic fraction. However, no significant difference between RV and LV was found when the PDE4 activity was studied. β2-adrenoceptor activation increased inotropism and lusitropism in LV when measured in the presence of either the PDE3 inhibitor cilostamide, the PDE4 inhibitor rolipram or a non-selective PDE inhibitor IBMX. However, the joint inhibition of both PDE3 and PDE4 was necessary in RV to uncover β2-adrenoceptor-induced inotropic and lusitropic effects. Our results indicate different regulation of β2-adrenoceptor-mediated contractility by PDE3 and PDE4 in RV and LV of the rat heart. In the case of PDE3 due to a different contribution of the enzyme in the microsomal fraction whereas in the case of PDE4 it can be attributed to differences in the intracellular distribution and coupling to β2-adrenoceptors.

Background: Hemodynamics during dynamic exercise is finely regulated by some neural mechanisms. One of these mechanisms is the metabolic part of the exercise pressor reflex, i.e. the muscle metaboreflex. Hemodynamic response during the metaboreflex is characterised by the re-cruitment of the reserves in cardiac inotropism, pre-load, after-load and chronotropism. If one of these reserves is exhausted, then the cardiovascular response is achieved by recruiting one of the other re-serves, thereby indicating a remarkable plasticity of the control of circulation. Conclusion: In this review, the effects of a number of cardiovascular diseases – such as heart failure, heart failure with preserved ejection fraction, hypertension, type 1 and type 2 diabetes mellitus, obesi-ty and metabolic syndrome - on hemodynamics during the metaboreflex are reviewed.

Transition from compensated to decompensated left ventricular hypertrophy (LVH) is accompanied by functional and structural changes. Here, the aim was to evaluate dystrophin expression in murine models and human subjects with LVH by transverse aortic constriction (TAC) and aortic stenosis (AS), respectively. We determined whether doxycycline (Doxy) prevented dystrophin expression and myocardial stiffness in mice. Additionally, ventricular function recovery was evaluated in patients 1 year after surgery. Mice were subjected to TAC and monitored for 3 weeks. A second group received Doxy treatment after TAC. Patients with AS were stratified by normal left ventricular end-diastolic wall stress (LVEDWS) and high LVEDWS, and groups were compared. In mice, LVH decreased inotropism and increased myocardial stiffness associated with a dystrophin breakdown and a decreased mitochondrial O2 uptake (MitoMVO2). These alterations were attenuated by Doxy. Patients with high LVEDWS showed similar results to those observed in mice. A correlation between dystrophin and myocardial stiffness was observed in both mice and humans. Systolic function at 1 year post-surgery was only recovered in the normal-LVEDWS group. In summary, mice and humans present diastolic dysfunction associated with dystrophin degradation. The recovery of ventricular function was observed only in patients with normal LVEDWS and without dystrophin degradation. In mice, Doxy improved MitoMVO2. Based on our results it is concluded that the LVH with high LVEDWS is associated to a degradation of dystrophin and increase of myocardial stiffness. At least in a murine model these alterations were attenuated after the administration of a matrix metalloprotease inhibitor. Fil: Donato, Pablo Martín. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Buchholz, Bruno. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Morales, Celina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina Fil: Valdez, Laura Batriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Zaobornyj, Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Baratta, Sergio. Hospital Austral; Argentina Fil: Paez, Diamela T.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina Fil: Matoso, Mirian. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina Fil: Vaccarino, Guillermo. Hospital Austral; Argentina Fil: Chejtman, Demian. Hospital Austral; Argentina Fil: Agüero, Oscar. Hospital Austral; Argentina Fil: Telayna, Juan. Hospital Austral; Argentina Fil: Navia, José. Hospital Austral; Argentina Fil: Hita, Alejandro. Hospital Austral; Argentina Fil: Boveris, Alberto Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Gelpi, Ricardo Jorge. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Hydrogen sulfide (H2S) has recently emerged as an important mediator of mammalian cardiovascular homeostasis. In nonmammalian vertebrates, little is known about the cardiac effects of H2S. This study aimed to evaluate, in the avascular heart of the frog, Rana esculenta, whether and to what extent H2S affects the cardiac performance, and what is the mechanism of action responsible for the observed effects. Results were analyzed in relation to those obtained in the rat heart, used as the mammalian model. Isolated and perfused (working and Langendorff) hearts, Western blot analysis, and modified biotin switch (S-sulfhydration) assay were used. In the frog heart, NaHS (used as H2S donor, 10−12/10−7M) dose-dependently decreased inotropism. This effect was reduced by glibenclamide (KATPchannels blocker), NG-monomethyl-l-arginine (NOS inhibitor), 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (guanylyl cyclase inhibitor), KT5823(PKG inhibitor), and it was blocked by Akt1/2 (Akt inhibitor) and by detergent Triton X-100. In the rat, in addition to the classic negative inotropic effect, NaHS (10−12/10−7M) exhibited negative lusitropism. In both frog and rat hearts, NaHS treatment induced Akt and eNOS phosphorylation and an increased cardiac protein S-sulfhydration that, in the rat heart, includes phospholamban. Our data suggest that H2S represents a phylogenetically conserved cardioactive molecule. Results obtained on the rat heart extend the role of H2S also to cardiac relaxation. H2S effects involve KATPchannels, the Akt/NOS-cGMP/PKG pathway, and S-sulfhydration of cardiac proteins.

This chapter is an overview of the cardiotropic actions of the Chromogranin A-derived peptides, vasostatins and catestatin on the isolated and perfused eel (Anguilla anguilla) and frog (Rana esculenta) hearts, used as paradigms of fish and amphibian hearts. Our studies highlight important cardiotropic features of the two peptides both at basal (negative inotropism) and stimulated (anti-adrenergic effect: eel and frog; anti-endothelin action: frog) conditions. In addition, catestatin positively modulates the Frank-Starling response both in eel and frog hearts. Overall, the comparison of vasostatins and catestatin-mediated role in cardiac homeostasis of fish and amphibians illustrates aspects of uniformity and species specific differences in the mechanism of action of the peptides.

Introduction There was no data for cardiac repercussion of exercise training associated with tobacco smoking. This issue is interesting because some smoking people can be enrolled in an exercise-training program. Thus, we evaluated swimming training effects on the function and structural myocardial in rats exposed to tobacco smoking. Methods Male Wistar rats were assigned to one of four groups: C, untrained rats without exposure to tobacco smoking; E, exercised rats without exposure to tobacco smoking; CS, untrained rats exposed to tobacco smoking; ECS, exercised rats exposed to tobacco smoking. Rats swam five times a week twice daily (60min per session) for 8 weeks. Before each bout exercise, rats breathed smoke from 20 cigarettes for 60min. Twenty-four hours after the last day of the protocol, papillary muscles were isolated for in vitro analysis of myocardial mechanics. The myocardial mass and nuclear cardiomyocyte volume were used as hypertrophy markers, and collagen content was determined by picrosirius red staining. Results There was a well-pronounced myocardial hypertrophic effect for two interventions. The exercise blunted myocardial collagen increases induced by tobacco smoking. However, exercise and tobacco-smoking association was deleterious to myocardial performance. Thereby, in vitro experiments with papillary muscles contracting in isometric showed impairment myocardial inotropism in exercised rats exposed to tobacco smoking. Conclusions This work presents novel findings on the role of exercise training on cardiac remodeling induced by tobacco smoking. Although exercise has mitigated tissue fibrosis, their association with tobacco smoking exacerbated hypertrophy and in vitro myocardial dysfunction. Implications This is first study to show that the association of an aerobic exercise training with tobacco smoking intensifies the phenotype of pathological cardiac hypertrophy. Therefore, the combination of interventions resulted in exacerbated myocardial hypertrophy and contractility dysfunction. These findings have significant clinical implication because some smoking people can be enrolled in an exercise-training program.

The present study aimed to investigate the inotropic effects of R(+)-pulegone, a monoterpene found in plant species belonging to the genus Mentha, on the mammalian heart. In electrically stimulated guinea pig atria, R(+)-pulegone reduced the contractile force (~ 83%) and decreased the contraction time measured at 50% of the maximum force amplitude (CT50) from 45.8 ± 6.2 ms to 36.9 ± 6.2 ms, suggesting that R(+)-pulegone may have an effect on Ca2+ homeostasis. Nifedipine (40 μM), taken as a positive control, showed a very similar profile. To explore the hypothesis that R(+)-pulegone is somehow affecting Ca2+ handling, we determined concentration–response curves for both CaCl2 and BAY K8644. R(+)-pulegone shifted these curves rightward. Using isolated mouse ventricular cardiomyocytes, we measured whole-cell L-type Ca2+ current and observed an ICa,L peak reduction of 13.7 ± 2.5% and 40.2 ± 2.9% after a 3-min perfusion with 0.11 and 1.1 mM of R(+)-pulegone, respectively. In addition, the intracellular Ca2+ transient was decreased (72.9%) by 3.2 mM R(+)-pulegone, with no significant changes in [Ca2+]i transient decay kinetics. Moreover, R(+)-pulegone at 1.1 mM prolonged the action potential duration at 10, 50, and 90% of repolarisation. The lengthening of the action potential duration may be attributed to the substantial blockade of the outward K+ currents caused by 1.1 mM of R(+)-pulegone (90.5% at 60 mV). These findings suggest that R(+)-pulegone exerts its negative inotropic effect on mammalian heart mainly by decreasing the L-type Ca2+ current and the global intracellular Ca2+ transient.

SUMMARY Catestatin (CST), the 21-amino acid, cationic and hydrophobic peptide proteolytically derived from the ubiquitous chromogranin A (CgA), is an endogenous inhibitor of catecholamine release, a potent vasodilator in vivo and an anti-hypertensive agent in mammals, including humans. Recently, we discovered that CST also functions as an important negative modulator of heart performance in frog and rat. To gain an evolutionary perspective on CST cardiotropism in fish, we analysed the influence of bovine CST (CgA344-364) on the eel heart, as well as the eventual species-specific mechanisms of its myocardial action. Experiments were carried out on fresh-water eels (Anguilla anguilla L.) using an electrically paced isolated working heart preparation. Stroke volume and stroke work were used as measures of ventricular performance. Under basal conditions, CST (from 11 nmol l–1 to 165 nmol l–1) caused a concentration-dependent negative inotropism, which was abolished by inhibitors of either β1/β2 (propranolol) or β3 (SR59230) adrenergic receptors, or by Gi/o protein (PTx) or nitric oxide synthase (L-NMMA), or guanylate cyclase (ODQ) blockers. This suggests a β-adrenergic receptor-Gi/o protein-NO-cGMP-dependent mechanism. By contrast, the CST-induced cardio-suppression was not influenced by atropine, unspecific muscarinic antagonist, thus excluding cholinergic receptor involvement. CST also counteracted the adrenergic (isoproterenol)-mediated positive inotropism. Under increased preload (i.e. Frank–Starling response) conditions, CST induced a significant increase of the Frank–Starling response, which was blocked by L-NMMA and thapsigargin, but independent from guanylate cyclase. In conclusion, this is the first report in fish that CST modulates myocardial performance under basal, as well as under increased preload, conditions and counteracts the adrenergic-mediated positive inotropism, which strikingly supports the evolutionary significance and establishes the cardioactive role of this peptide.

Androgens produce acute vasodilation of systemic, pulmonary, and coronary arteries in several mammal preparations and increase cardiomyocyte contractility. A decrease of the spontaneous beating of sinoatrial cells has also been described. The aim of this study was to characterize the direct effect of 5alpha-dihydrotestosterone on the spontaneous chronotropism and inotropism in the same preparation as an approach to establish the effect on cardiac output and their mechanism of action. The effects were studied on isolated right atria of Wistar rats placed in an organ bath in Tyrode solution at 37 degrees C and bubbled with carbogen. In male rats, the acute administration of 5alpha-dihydrotestosterone, a nonaromatizable derivate of testosterone, elicited a positive inotropism, which was associated with a negative chronotropism. As reported in the left atria, polyamines and beta-adrenoceptors played a role in 5alpha-dihydrotestosterone-elicited positive inotropism because the effect was antagonized by alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, and atenolol, a beta1-adrenoceptor blocker, but not on the negative effect on chronotropism. The androgen increased the sinoatrial node recovery time, suggesting an effect on the mechanisms of spontaneous diastolic depolarization involved in atria pacemaking. These effects of 5alpha-dihydrotestosterone are not hormonally regulated because they are similarly produced in estrogenized females and gonadectomized male and female rats. These results suggest that the androgen could acutely improve cardiac performance.

Summary Several investigators have independently discovered that the calcium antagonist, verapamil, causes a 60–80% increase in plasma digoxin. Pharmacokinetic studies indicate, that the elevated plasma digoxin level is due to verapamil-induced inhibition of both renal and extrarenal digoxin clearance. No significant changes in single-dose digoxin pharmacokinetics were observed during nifedipine coadministration. To elucidate the clinical relevance of this interaction, we investigated the influence of verapamil on digoxin-induced inotropism as assessed from systolic time intervals. In single-dose trials, the verapamil-induced elevation of plasma digoxin was associated with a more sustained reduction in left ventricular ejection time as compared to control. Correspondingly, the concentration-response relationship of digoxin inotropism was unaffected by verapamil. In-vitro studies showed that verapamil had no influence on the number of digitalis receptors on human lymphocytes. In accordance, verapamil enhanced the digoxin-induced elevation of intracellular sodium concentration possibly reflecting an increased receptor effect. The plasma digoxin elevation resulting from verapamil coadministration seems cardioactive with regard to both inotropism and toxic effects.

The calcium sensitizer levosimendan has anti-ischaemic effects mediated via the opening of sarcolemmal and mitochondrial ATP-sensitive potassium channels. These properties suggest potential application in clinical situations where cardioprotection would be beneficial, such as cardiac surgery. We thus decided to investigate whether pharmacological pre-treatment with levosimendan reduces intensive care unit (ICU) length of stay in patients undergoing elective myocardial revascularization under cardiopulmonary bypass.One hundred and six patients undergoing elective coronary artery bypass grafting were randomly assigned in a double-blind manner to receive levosimendan or placebo. Levosimendan (24 microg kg(-1)) or placebo was administered as a slow i.v. bolus over a 10 min period before the initiation of bypass.Tracheal intubation time and the length of ICU stay were significantly reduced in the levosimendan group (P0.01). The number of patients needing inotropic support for12 h was significantly higher in the control group (18.0% vs 3.8%; P=0.021). Compared with control patients, levosimendan-treated patients had lower postoperative troponin I concentrations (P0.0001) and a higher cardiac power index (P0.0001).Pre-treatment with levosimendan in patients undergoing surgical myocardial revascularization resulted in less myocardial injury, a reduction in tracheal intubation time, less requirement for inotropic support, and a shorter length of ICU stay.

Functional and biochemical studies were performed in isolated left atria of male Wistar rats to study whether endogenous polyamines may mediate androgen-elicited positive inotropism and their relationship with a rise in cAMP during the cardiotonic effect. 5 alpha-Dihydrotestosterone (100 microM) exposure increased intracellular putrescine as determined by HPLC, but it did not increase spermidine and spermine. This effect was antagonized by an inhibitor of ornithine decarboxylase, alpha-difluoromethylornithine (10 mM), suggesting enzyme activation. alpha-Difluoromethylornithine also antagonized androgens-elicited inotropism and the increase in intracellular cAMP. Putrescine (1 to 10 mM) elicited a concentration-dependent positive inotropism associated with the cAMP increase. The prior incubation with putrescine antagonized 5 alpha-dihydrotestosterone-elicited inotropism and did not produce sinergism on intracellular cAMP. Short-term incubation with 5 alpha-dihydrotestosterone or forskolin shifted to the left the cardiotonic effect of isoproterenol, an agonist of beta-adrenoceptors, without any increase in Emax, suggesting that a common mechanism was involved. Therefore, polyamines might modulate the cAMP production associated with the cardiotonic effect of androgens.

Summary Background The intensive physical activity is often associated with cardiac changes. Objectives (i) To evaluate the IGF-I system and myocardial structure and function by standard Doppler echocardiography and Tissue Doppler in athletes and sedentary controls; and (ii) to determine any relationship between IGF-I system and echocardiographic parameters. Methods Nineteen male top-level rowers and 19 age-matched healthy sedentary male controls underwent blood determination of fasting serum IGF-I, IGFBP-3 and acid-labile subunit levels and standard Doppler echocardiography combined with pulsed Tissue Doppler of posterior septal wall, left ventricular (LV) lateral mitral annulus and right ventricular (RV) tricuspid annulus. Myocardial presystolic (PSm), systolic (Sm), the ratio of early diastolic (Em) to atrial (Am) velocities as well as myocardial time intervals were calculated. Results Rowers had higher serum IGF-I levels (P = 0·04), higher biventricular cavity dimensions and wall thicknesses compared to controls. They also had better LV and RV myocardial function than controls. In the rowers, IGF-I was associated with LV ejection fraction (r = 0·50, P = 0·03), RV PSm velocity (r = 0·55, P = 0·01) and with RV myocardial precontraction time (r = −0·57, P = 0·01). These associations remained significant after adjusting for age and heart rate. Conclusions Top-level athletes showed higher IGF-I levels and a better myocardial performance than controls, particularly for the RV systolic activity. The independent correlations between IGF-I and systolic parameters of the left (ejection fraction) and right (PSm velocity and precontraction time) ventricles may possibly indicate a role of IGF-I system in the modulation of myocardial inotropism in athletes. Further studies are needed to confirm this hypothesis.

SUMMARY 1 Chronic ouabain administration increases blood pressure and produces a positive inotropic effect. However, the temporal changes capable of affecting both arterial and ventricular pressures and myosin ATPase activity during the induced hypertension have not been determined. 2 The aim of the present study was to investigate the time-course of the induction of hypertension to define when changes occur in Wistar rats treated with 25 mg/kg per day, s.c., ouabain for 3, 7, 15 or 30 days. 3 In anaesthetized rats, diastolic blood pressure increased after 7 days treatment with ouabain and after 15 and 30 days treatment, increases were observed in systolic blood pressure, left ventricular systolic pressure and myosin ATPase activity. After 15 days treatment, heart rate (HR) also increased, but after 30 days treatment HR returned to control levels. However, only after 30 days treatment did the left ventricular positive and negative first derivatives of intraventricular pressure (dP/dtmax and dP/dtmin, respectively) increase. Increased arterial and left ventricular systolic pressures and myosin ATPase activity observed after 15 days treatment maintained similar levels as those after 30 days treatment. 4 The results suggest that changes in arterial and left ventricular pressures, HR and myosin ATPase activity induced by chronic ouabain treatment are time dependent, increasing after 15 days treatment. After 30 days treatment, the increase in systolic and diastolic arterial and ventricular pressures remained stable, as did inotropism. Normalization of HR after 30 days treatment suggests that during the period from Day 16 to Day 30 ouabain-induced hypertension is dependent, at least in part, on increased sympathetic activity.

Circulating levels of catestatin (Cts; human chromogranin A352-372) decrease in the plasma of patients with essential hypertension. Genetic ablation of the chromogranin A (Chga) gene in mice increases blood pressure and pretreatment of Chga-null mice with Cts prevents blood pressure elevation, indicating a direct role of Cts in preventing hypertension. This notable vasoreactivity prompted us to test the direct cardiovascular effects and mechanisms of action of wild-type (WT) Cts and naturally occurring human variants (G364S-Cts and P370L-Cts) on myocardial and coronary functions. The direct cardiovascular actions of WT-Cts and human variants were determined using the Langendorff-perfused rat heart. WT-Cts dose-dependently increased heart rate and coronary pressure and decreased left ventricular pressure, rate pressure product and both positive and negative LVdP/dt. WT-Cts not only inhibited phospholamban phosphorylation, but also the inotropic and lusitropic effects of WT-Cts were abolished by chemical inhibition of beta2-adrenergic receptors, Gi/o protein, nitric oxide or cGMP, indicating involvement of beta2-adrenergic receptors-Gi/o protein-nitric oxide-cGMP signaling mechanisms. In contrast, G364S-Cts did not affect basal cardiac performance but abolished isoproterenol-induced positive inotropism and lusitropism. P370L-Cts decreased rate pressure product and inhibited only isoproterenol-induced positive inotropism and lusitropism by 70%. Cts also inhibited endothelin-1-induced positive inotropism and coronary constriction. Taken together, the cardioinhibitory influence exerted on basal mechanical performance and the counterregulatory action against beta-adrenergic and endothelin-1 stimulations point to Cts as a novel cardiac modulator, able to protect the heart against excessive sympathochromaffin overactivation, e.g. hypertensive cardiomyopathy.

Introduction: Apelin-APLNR system is a peptide system with a widerange of physiologic actions, which include inotropism and vasodilatation. It is thought to be dysregulated in various cardiovascular disorders. We have shown that apelin (A) levels increase with exercise in healthy volunteers and in this study wished to examine the effect of exogenous A supplementation on exercise performance. Methods: Normal healthy volunteers were recruited to undertake an incremental cardiopulmonary exercise test to establish max workload. Thereafter participants attended for 2 exercise tests at 80% of the max workload and were randomised in a double blinded cross-over design to either (Pyr1)apelin-13 or placebo. Endurance time, peak VO2 and kinetics of the VO2 response were analysed. Results: 11 males (30.18± 8.53 years)participated in the study. Infusion of A during exercise had no impact on endurance time but reduced peak VO2 from 52.4±9.7 to 50.3±10.1 ml/min/kg (A vs placebo; p=0.004) and increased heart rate at 1 min (146±14 vs 141±11; p=0.02) with a similar trend at peak (177±9 vs 171±18; p=0.28). Using the following function the resulting τ for each subject were obtained and compared: V·O2 =A*(1 - e^-T/τ) + b: Infusion of A showed a trend towards faster VO2 kinetics, with τ 104.5 ± 45.5 vs 125 ± 63.8 sec, p=0.06. No difference was seen in blood pressure response. Conclusion: Exogenous apelin in healthy volunteers reduced peak VO2 in an endurance test. We hypothesize that systemic vasodilation and a tachycardic response increased VO2 kinetics but this led to an overall worsening of performance. In a system where apelin is not dysregulated, exercise performance cannot be enhanced with further supplementation.

Background: Reactive oxygen species, such as superoxide, are being increasingly recognized as key components of a vast array of signaling pathways. Angiotensin II is a well-recognized stimulus for superoxide production through NADPH oxidase activation and opening of the mitochondrial ATP-sensitive potassium channels (mKATP). A role for this mechanism has been proposed to explain several physiological effects of the peptide. The aim of this study was to evaluate the involvement of this mechanism in the inotropic response to 100 nmol/L angiotensin II. Methods: Sarcomere shortening and intracellular pH (BCECF-epifluorescence technique) were evaluated in isolated cat ventricular myocytes placed in a perfusion chamber on the stage of an inverted microscope. Myocardial superoxide production was evaluated by the lucigenin quimioluminiscence method. Results: Angiotensin II (100 nmol/L) increased~70% sarcomere shortening, effect that was only partially prevented by NADPH oxidase inhibition,mKATP channel blockade or inhibition of the cardiac Na+/H+ exchanger (NHE-1). Moreover, angiotensin II stimulates NHE-1 activity by a NADPH oxidase-dependent mechanism. Myocardial superoxide production was also increased by angiotensin II, and this action was completely prevented either by NADPH oxidase inhibition or mKATP channel blockade. Conclusions: The positive inotropic response to 100 nmol/L angiotensin II is due to both ROS/NHE-1 dependent and independent pathways, this being a point of divergence with the signaling previously described to be triggered by lower concentrations of angiotensin II (i.e.: 1 nmol/L)., Centro de Investigaciones Cardiovasculares

Neuroendocrine regulation of cardiac function involves a population of three types of beta-adrenoceptors (ARs). In various mammalian species, beta1- and beta2-AR stimulation produces an increase in contractility; whereas beta3-AR activation mediates negative inotropic effects. At the moment, nothing is known about the physiological role of beta3-AR in fish. Using an isolated working heart preparation, we show that a beta3-AR selective agonist BRL(37344) (0.1-100 nmol l(-1)) elicits a dose-dependent negative inotropism in the freshwater eel Anguilla anguilla. This effect was insensitive to the beta1/beta2-AR inhibitor nadolol (10 mumol l(-1)), but was blocked by the beta3-AR-specific antagonist SR(59230) (10 nmol l(-1)). The analysis of the percentage of stroke work (SW) variations, in terms of EC(50) values, induced by BRL(37344) alone (10 nmol l(-1)), and in presence of SR(59230) (10 nmol l(-1)), indicated a competitive antagonism of SR(59230). In addition to the classic positive inotropism, the non-specific beta agonist isoproterenol (100 nmol l(-1)) induced, in 30% of the preparations, a negative inotropic effect that was abrogated by pre-treatment with SR(59230), pointing to a beta3-mediated pathway. The BRL(37344)-induced negative inotropic effect was abolished by exposure to a G(i/o) proteins inhibitor pertussis toxin (PTx; 0.01 nmol l(-1)), suggesting a G(i/o)-dependent mechanism. Using L-N5(l-imino-ethyl)ornithine (L-NIO; 10 mumol l(-1)), as a nitric oxide (NO) synthase (NOS) blocker and haemoglobin (Hb; 1 mumol l(-1)), as a NO scavenger, we demonstrated that NO signalling is involved in the BRL(37344)-induced response. Pre-treatment with either an inhibitor of soluble guanylate cyclase (GC) 1H-(1,2,4) oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ; 10 mumol l(-1)), or an inhibitor of the cGMP-activated protein kinase (PKG) KT(5823) (100 nmol l(-1)), abolished the beta3-dependent negative inotropism, indicating the cGMP-PKG component as a crucial target of NO signalling. Taken together, our findings provide functional evidence for the presence of beta3-like adrenoceptors in the eel Anguilla anguilla heart identifying, for the first time in a working fish heart, the beta3-AR-dependent negative inotropy discovered in mammals.

The spontaneous activity of pacemaker cells in the sino-atrial node controls the heart rhythm and rate under physiological conditions. Compared to working myocardial cells, pacemaker cells express a specific array of ionic channels. The functional importance of different ionic channels in the generation and regulation of cardiac automaticity is currently subject of an extensive research effort and has long been controversial. Among families of ionic channels, Ca(2+) channels have been proposed to substantially contribute to pacemaking. Indeed, Ca(2+) channels are robustly expressed in pacemaker cells, and influence the cell beating rate. Furthermore, they are regulated by the activity of the autonomic nervous system in both a positive and negative way. In this manuscript, we will first discuss how the concept of the involvement of Ca(2+) channels in cardiac pacemaking has been proposed and then subsequently developed by the recent advent in the domain of cardiac physiology of gene-targeting techniques. Secondly, we will indicate how the specific profile of Ca(2+) channels expression in pacemaker tissue can help design drugs which selectively regulate the heart rhythm in the absence of concomitant negative inotropism. Finally, we will indicate how the new possibility to assign a specific gene activity to a given ionic channel involved in cardiac pacemaking could implement the current postgenomic research effort in the construction of the cardiac Physiome.

The mechanical properties of ventricular myocardium of the South American lungfish, Lepidosiren paradoxa , acclimated to 25 °C, were evaluated in vitro at 15, 25 and 35 °C. The inotropism (Fc—% of initial values) of ventricle strips was examined in response to adrenaline (from 10 −8 to 10 −5 M) and extracellular calcium (from 2.5 to 14.5 mM) in all experimental temperatures. At 15 and 25 °C, Fc rose when extracellular Ca 2+ or adrenaline were increased, while Fc remained unchanged at 35 °C. These results suggest that at lower temperatures Ca 2+ availability is a limiting step to cardiac performance and can be ameliorated by adrenergic stimulation. In contrast, since inotropic agents failed to increase cardiac inotropism at 35 °C, lungfish myocytes seem to show a high temperature sensitivity, which increases Ca 2+ -buffering capacity and/or Ca 2+ transportation from and to cytosol as well as myofilaments Ca 2+ sensitivity.

The effects of the chronic administration of cholesterol on the stunned myocardium have not been studied. The objective was to determine the effect of a cholesterol enriched diet on postischemic ventricular dysfunction. In group 1 (G1, n = 7) isolated rabbit hearts underwent a follow up of ventricular function during 30 min in aerobic conditions. In group 2 (G2, n = 6) G1 was repeated but the animals were subjected to a 1% cholesterol enriched diet during 4 weeks (hypercholesterolemic animals). In group 3 (G3, n = 8) hearts underwent 15 min of global ischemia followed by 30 min of reperfusion. In Group 4 (G4, n = 11) G3 was repeated, but in hypercholesterolemic animals. Since cholesterol decreased the inotropism in basal situation, and this makes the comparison between groups difficult, we performed a Group 5 (G5, n = 7), in which G4 protocol was repeated but isoproterenol (8 microg/kg/min) was administered 10 min before ischemia, in order to match the preischemic inotropic state with respect to the normocholesterolemic ones. G1 and G2 maintained a stable inotropism during the 30 min of perfusion. The preischemic left ventricular developed pressure (LVDP) in G3 and G4 was 91.4 +/- 4.3 and 70.8 +/- 3.4 mmHg (p0.05), respectively, and after 30 min of reperfusion differences were not observed between G3 and G4. Nevertheless, when LVDP is expressed as a percentage, we detected an attenuation of postischemic systolic alterations in hypercholesterolemic animals (67.3 +/- 3.6 in G4 vs. 90.8 +/- 3.1% in G3, p0.05). When LVDP in G5 was increased until matching the one of G3, there were no differences after 30 min of reperfusion. Left ventricular end diastolic pressure increased 285 +/- 46%, 61 +/- 25% (p0.05 vs. G3 and G5) and 216 +/- 25% in G3, G4 and G5 at 30 min of reperfusion. There were no differences either in the values of tau or infarct size between groups. Thus, in hypercholesterolemic animals, a decrease of the preischemic inotropism exists and there is an attenuation of the stunned myocardium. When contractility of the normo and hypercholesterolemic animals is matched, the beneficial effect disappears.

Chromogranin A (CGA) N-terminal fragments corresponding to residues 1-76 and 1-113, named vasostatins for their inhibitory effects on vascular tension, have been postulated as important homeostatic regulators of the cardiovascular system. We have used an in vitro isolated working frog (Rana esculenta) heart as a bioassay to study the effects of exogenous human recombinant CGA 1-76 (VS-1) and human CGA 7-57 synthetic peptide on cardiac performance. Under basal conditions, the concentration-response curves of the two peptides exhibited a significant negative inotropism. This vasostatin response was unaffected by pretreatment with either Triton X-100 or two nitric oxide synthase inhibitors, i.e., N(G)-monornethyl-L-arginme and L-N(5)(1-iminoethyl) ornithine or the soluble guanylate cyclase inhibitor 1H-(1,2,4) oxadiazolo-(4,3-a) quinoxalin-1-one, indicating an endocardial endothelium-nitric oxide-cGMP-independent mechanism. The negative inotropism was also unaffected by either adrenergic (i.e., phentolamine and propranolol) or muscarinic (atropine) receptor or G proteins (pertussis toxin) inhibition. On the contrary, it was dependent from both extracellular Ca(2+) and K(+) channels, since it was abolished by pretreatment to either the Ca(2+) channel inhibitors lanthanum and diltiazem or the K(+) channel inhibitors Ba(2+), 4-aminopyridine, tetraethylammonium chloride, and glibenclamide. In conclusion, the findings that vasostatins exert an inhibitory modulation on basal cardiac performance and counteract, as previously reported, the adrenergic-mediated positive inotropism, strongly support a cardio-regulatory role for these peptides. (C) 2004 Elsevier Inc. All rights reserved.

This study analyzed the effects of temperature on cardiac function of Piaractus mesopotamicus . The data suggest that the heart performance during temperature elevations is regulated mainly by chronotropic adjustments and that increased extracellular Ca 2+ concentrations and high adrenaline can improve inotropism at high temperatures. When stimulation frequency was increased, a negative force–frequency relationship was observed at both 25°C and 35°C concomitant with increases in resting tension, indicating that relaxation is a limiting step. The post-rest potentiation was strongly inhibited by ryanodine, suggesting that, irrespective of temperature, the sarcoplasmic reticulum may contribute to excitation–contraction coupling.

To elucidate the role of atrial natriuretic peptides (NPs) in the amphibian heart, the myotropic effects and the cardiac distribution of frog atrial natriuretic factor (fANF) have been studied in Rana esculenta . Spontaneously, beating in vitro isolated working heart preparations were treated with increased concentrations (10 −11 –10 −8 M) of fANF-(1–24). The peptide at 10 −9 and 10 −8 M significantly reduced heart rate (HR) and, on the electrically paced preparations, decreased cardiac output (CO), stroke volume (SV) and work. Such negative inotropism was abolished by pretreatment with the pertussis toxin or by blocking the particulate guanylate cyclase (GC) with anantin while it was independent both from the functional impairment of the endocardium–endothelium by Triton X-100 and the inhibition of the soluble guanylate cyclase by 1 H -(1,2,4,) oxadiazolo-(4,3-a) quinoxalin-1-one (ODQ). By autoradiography, two classes of high and low affinity NPs binding sites were detected in the ventricular endocardium and myocardium and in the bulbus arteriosus. The analysis of displacement binding data using the radioligand [ 125 I]-rat atrial natriuretic peptide [ 125 I-rANP-(1–28)], its cold counterpart and the fANF-(1–24) showed that in the ventricular myocardium, the low affinity NPs sites bound both the heterologous and the homologous ligands at a concentration close to that responsible for the negative inotropism and chronotropism.

In isolated perfused guinea pig hearts, coronary flow causes a positive inotropic effect [positive coronary flow-induced effect (+CFIE)] that could be altered by dextrans (Dx) in the coronary perfusion solution. To test this possibility, Dx of 20, 40, 70, and 500 kDa were infused and found to modulate +CFIE; however, when Dx infusion was terminated, the effect persisted, i.e., was irreversible/nonwashable, suggesting that Dx may bind to luminal endothelial lectinic structures. This hypothesis was tested when Dx [with fluorescent traces (D*)] bound to the vessel wall was hydrolyzed by dextranase infusion and washout of D* fragments completely reverted the +CFIE, and it was found that bound D* to be displaced by free Dx required concentrations 50–100 times that used during binding. In addition, dose-response curves for Dx on +CFIE show that the higher the Dx molecular mass, the lesser the concentration required to have an effect. Because a large Dx molecule has a greater number polymeric glucose branches, it can bind to a larger number of endothelial lectinic sites, requiring a lower concentration to affect +CFIE. Our results suggest that luminal endothelial lectinic structures are part of the flow-sensing assembly.

This study investigated, in rabbit papillary muscles ( n = 61) and human auricular strips ( n = 7), effects of endothelin-1 (ET-1; 0.1–10 nM) on diastolic myocardial properties. ET-1 (1 nM) was also given in the presence of selective ETAor ETBantagonism, nonselective ETA/ETBantagonism, and Na+/H+exchanger inhibition. Effects of 6.3 mM Ca2+were also studied. ET-1 dose dependently increased inotropism. In contrast to baseline, in the presence of ET-1, resting tension (RT) decreased, after an isometric twitch, 3.4 ± 1.4, 6.9 ± 1.5, and 12.5 ± 3.1% with 0.1, 1, and 10 nM, respectively, reflecting an increase in myocardial distensibility. ET-1 effects were abolished with selective ETAas well as with nonselective ETA/ETBantagonism, whereas they were still present with ETBantagonism. Na+/H+exchanger inhibition abolished ET-1 effects on distensibility, whereas it only partially inhibited positive inotropic effect. Ca2+increased inotropism to a similar extent to ET-1 (1 nM) but did not affect distensibility. ET-1 therefore increased diastolic distensibility of acutely loaded human and nonhuman myocardium. This effect is mediated by ETAreceptors, requires Na+/H+exchanger activation, and cannot be elicited by Ca2+.

Vagus Nerve Stimulation (VNS) has been shown to be useful in heart failure patients, including antiarrhythmic effects, improvement of cardiac function and reduction of the mortality. However, the optimal configuration of VNS can be a difficult task, since there are several adjustable parameters, such as current amplitude (mA), pulse width (ms), burst frequency (Hz), number of pulses and, in the case of cardiac-triggered VNS, the delay (ms) between the R-wave and the beginning of the stimulation. The objective of this paper is to analyse the effect of these parameters, and their interaction, on the chronotropic and inotropic responses to vagal stimulation. 306 VNS sequences were tested on 12 sheep with induced heart failure. Autonomic markers of the chronotropic (changes in RR interval) and inotropic (changes in dP/dtmax) effects were extracted from the observed data. In order to analyse the influence of stimulation parameters on these markers, a sensitivity analysis method was applied. Results illustrate the strong interaction between the delay and the others parameters. The number of pulses, the current and the frequency seem to be particularly influent on chronotropism and inotropism although the effect of the frequency is highly non-linear or it depends on other parameters.

Coronary by-pass on a beating heart may provide a safer form of surgical revascularization by avoiding the well-documented side effects of cardiopulmonary by-pass. In addition, off-pump bypass is suggested to be a good alternative to on-pump especially in high risk patients. This study reviews the feasibility of coronary by-pass on the beating heart in all patients referred to surgery. Two hundred and ninety-four patients operated on the beating heart were prospectively followed and compared to the control group of 100 consecutive patients operated with the conventional method. There were no significant differences between the groups with respect to risk factors, except the incidence of chronic obstructive pulmonary disease and ejection fraction which were higher in the conventional group, whereas peripheral vascular disease was higher in the beating heart group. There was more distal anastomosis in the conventional group. Postoperative inotrope requirement, peak creatine phosphokinase—MB, ventilation time, blood loss in the first 24 h, transfusion needs, new atrial fibrillation and length of hospital stay were significantly lower in the beating heart operations. However, there were no significant differences between the groups in terms of neurological complications, chest infection, intraaortic balloon pump usage and mortality. In conclusion, multivessel off pump coronary by-pass is feasible with the same or better results as it is observed in the conventional technique when postoperative bleeding, neurogenic complications, arrythmias. hospital stay, overall morbidity and mortality are compared.

β1- and β2-adrenoceptors (AR) are polymorphic. β1-AR: There is a Gly389Arg polymorphism of the β1-AR with the Gly389 exhibiting reduced in vitro responsiveness upon agonist-induced stimulation. To study this in vivo we assessed exercise-induced increase in heart rate and shortening of heart rate-corrected duration of electromechanical systole (QS2c—a measure of inotropism) in 12 volunteers homozygous for Gly389 and 12 volunteers homozygous for Arg389. In both groups, exercise caused nearly identical increases in heart rate and shortening of QS2c, indicating that the differential responsiveness observed in vitro is not of major functional importance in vivo. β2-AR: There are at least three polymorphisms of the β2-AR: the Arg16Gly and the Gln27Glu polymorphisms differ from the wild-type (WT, Arg16, Gln27) β2-AR in vitro in their susceptibility to agonist-induced downregulation. We studied in 16 WT-volunteers, 6 volunteers homozygous for Glu27 and 6 volunteers homozygous for Gly16, the effects of 2-week treatment with 3×5 mg/day p.o. terbutaline on terbutaline infusion-induced increases in heart rate and shortening of QS2c. In all three groups, oral terbutaline treatment reduced terbutaline infusion-induced increases in heart rate and shortening of QS2c to a similar extent, indicating that the differential susceptibility to agonist-induced downregulation of the Gly16 and Glu27 polymorphism of the β2-AR observed in vitro is not of major functional importance in vivo. Finally, there is a Thr164Ile polymorphism of the β2-AR with Ile164 exhibiting reduced in vitro responsiveness upon agonist-induced stimulation. We studied in 12 WT-volunteers and in 6 volunteers heterozygous for the Ile164 polymorphism the effects of terbutaline infusion on heart rate and QS2c. In the Ile164 volunteers increases in heart rate and shortening of QS2c induced by the terbutaline infusion were significantly (p

The in vivo and in vitro cardiac responses of Lepidosiren paradoxa were analyzed during temperature variations from 25°C (acclimation temperature) to 15°C and 35°C, and subsequent return to 25°C. Chronotropic (heart frequency) and inotropic (twitch force) responses varied directly with temperature, decreasing from 25°C to 15°C and increasing from 25°C to 35°C. However, time to peak tension (TPT) and time to half relaxation (THR) showed an inverse tendency. The results indicate that the myocardium of L. paradoxa responds more appropriately to acute elevations in temperature, which results in an increased cardiac performance due to both positive chronotropism and inotropism, in spite of the temperature-induced curtailment of TPT and THR.

In the present work the effect of dioclein, a new flavonoid from Dioclea grandiflora, was investigated in rat hearts. The experiments were performed using the classic method of Langendorff, where flow, inotropic, chronotropic and electric parameters were analyzed. Bolus administration of Dioclein (1-100 microg) induced a sustained and dose-dependent increase in coronary flow with no modification in inotropic, chronotropic and electrical parameters. The duration of increase in coronary flow induced by dioclein (10 microg) was approximately 4-fold higher than that observed in the presence of sodium nitroprusside (NPS; 10 microg). Besides, the effect of dioclein measured as the area-under-the-curve was approximately 4.5-folds higher than that observed with NPS. Pre-treatment with L-NAME (100 microM) and indomethacin (10 microM) alone did not modify the effect of dioclein (10 microg), suggesting that nitric oxide (NO) and cyclooxygenase-derived factors were not involved. However, association of L-NAME plus indomethacin inhibited the duration of the effect of dioclein (10 microg) without changing its increase in the coronary flow. Furthermore, the absence of alteration in inotropism and chronotropism of the heart associated with its coronary effect suggest that dioclein could be an interesting lead compound for the development of drugs for the treatment coronary heart diseases.

International audience; RATIONALE: TRPM4 is a non-selective Ca2+-activated cation channel expressed in the heart, particularly in the atria or conduction tissue. Mutations in the Trpm4 gene were recently associated with several human conduction disorders such as Brugada syndrome. TRPM4 channel has also been implicated at the ventricular level, in inotropism or in arrhythmia genesis due to stresses such as ß-adrenergic stimulation, ischemia-reperfusion, and hypoxia re-oxygenation. However, the physiological role of the TRPM4 channel in the healthy heart remains unclear.OBJECTIVES: We aimed to investigate the role of the TRPM4 channel on whole cardiac function with a Trpm4 gene knock-out mouse (Trpm4-/-) model.METHODS AND RESULTS: Morpho-functional analysis revealed left ventricular (LV) eccentric hypertrophy in Trpm4-/- mice, with an increase in both wall thickness and chamber size in the adult mouse (aged 32 weeks) when compared to Trpm4+/+ littermate controls. Immunofluorescence on frozen heart cryosections and qPCR analysis showed no fibrosis or cellular hypertrophy. Instead, cardiomyocytes in Trpm4-/- mice were smaller than Trpm4+/+with a higher density. Immunofluorescent labeling for phospho-histone H3, a mitosis marker, showed that the number of mitotic myocytes was increased 3-fold in the Trpm4-/-neonatal stage, suggesting hyperplasia. Adult Trpm4-/- mice presented multilevel conduction blocks, as attested by PR and QRS lengthening in surface ECGs and confirmed by intracardiac exploration. Trpm4-/-mice also exhibited Luciani-Wenckebach atrioventricular blocks, which were reduced following atropine infusion, suggesting paroxysmal parasympathetic overdrive. In addition, Trpm4-/- mice exhibited shorter action potentials in atrial cells. This shortening was unrelated to modifications of the voltage-gated Ca2+ or K+ currents involved in the repolarizing phase.CONCLUSIONS: TRPM4 has pleiotropic roles in the heart, including the regulation of conduction and cellular electrical activity which impact heart development.

M. I. Tejero-Taldo ,J . L. Caffrey ,J . Sun and R. T. Mallet. Antioxidant Properties of Pyruvate Mediate its Potentiation of b-Adrenergic Inotropism in Stunned Myocardium. Journal of Molecular and Cellular Cardiology (1999) 31, 1863‐1872. This study tested the hypothesis that pyruvate’s antioxidant actions, particularly its enhancement of the endogenous glutathione system, mediate its potentiation of b-adrenergic inotropism in stunned myocardium. Isolated working guinea pig hearts, metabolizing 10 mm glucose and stunned by 45 min of low flow ischemia, were treated with 5 mm pyruvate, 5 mm N-acetylcysteine (NAC) and/or 2 nm isoproterenol beginning 15 min after reperfusion. The antioxidant NAC alone did not increase cardiac power (mJ/min/g wet: 11‐1 in untreated and 15‐2 in NAC treated stunned hearts), but NAC potentiated the increase in power produced by 2 nm isoproterenol (isoproterenol alone: 50‐10; NAC plus isoproterenol: 133‐24). Addition of NAC doubled cyclic AMP content but lowered cytosolic phosphorylation potential by 32% in isoproterenolstimulated hearts. Stunning decreased the glutathione antioxidant ratio (GSH/GSSG) by 68%. The antioxidant ratio was completely restored by pyruvate alone or in combination with isoproterenol, but only partially restored by isoproterenol alone. Combining isoproterenol and NAC increased the GSH/GSSG ratio by an additional 36%. The combined treatment of pyruvate and isoproterenol increased the NADPH/NADP + ratio almost three-fold, and produced the greatest accumulation of glucose-6-phosphate of any treatment. Conclusions: like pyruvate, the antioxidant NAC potentiated b-adrenergic inotropism of stunned myocardium. Unlike pyruvate, NAC did not increase cellular energy reserves, thus effectively limiting its potentiation of b-adrenergic stimulation. Thus, pyruvate’s potentiation of b-adrenergic stimulation in stunned myocardium is most likely the result of the combined effects of its antioxidant and energetic properties. ” 1999 Academic Press

S1319 (4-hydroxy-7-[1-(1-hydroxy-2-methylamino)ethyl]-1,3-benzothiazol-2(3H)-one acetate), a novel non-catecholamine β-adrenoceptor agonist, has been compared with isoprenaline, salbutamol and formoterol for activity in vitro on a range of β-adrenoceptor containing preparations from guinea-pig. S1319, like isoprenaline, salbutamol and formoterol, relaxed preparations of guinea-pig trachea (contracted by histamine) in a concentration-dependent manner. The relaxing activity of S1319 appeared to be more potent than that of isoprenaline and salbutamol, and similar to that of formoterol (pD2 values of 10.58±0.03 vs 7.60±0.01, 7.50±0.01 and 10.52±0.04, respectively), and was blocked by the β2-adrenoceptor selective antagonist (ICI 118,551). The intrinsic activity of S1319 was close to 1.0. In the β1-adrenoceptor containing preparations, guinea-pig right and left atria, a monophasic inotropic response of S1319 was observed. The pD2 value of S1319 for left atrial and right atrial inotropism was 6.70±0.15 and 7.81±0.01, respectively. The selectivity ratio (trachea/left atrial inotropism) of S1319, formoterol, salbutamol and isoprenaline was 8523, 284, 4.8 and 0.45, respectively. The relative selectivity ratio of S1319 was 18743, 1858 and 30 times greater than that of isoprenaline, salbutamol and formoterol, respectively. Relaxant responses of guinea-pig trachea to S1319 declined rapidly when the agonist was washed from the tissues, with complete recovery within 30 min. The duration of action of S1319 was similar to that of isoprenaline and less than that of salbutamol and formoterol. In summary, S1319, a sponge-derived β-adrenoceptor agonist, is a potent and selective β2-adrenoceptor agonist with a short-duration of action in isolated guinea-pig tracheas. British Journal of Pharmacology (1999) 128, 716–720; doi:10.1038/sj.bjp.0702839

We investigated whether the adenosine triphosphate (ATP)-sensitive K + (K ATP ) channel activation by bimakalim, at concentrations devoid of both negative inotropic and action-potential duration (APD) shortening effects, might exhibit myocardial protection after hypoxia and reoxygenation in human atrial myocardium by using 112 preparations. The recovery of contractility of human atrial trabeculae, subjected either to short-duration (5 min) or to long-duration (60 min) and severe (high pacing rate) hypoxia followed by reoxygenation, was assessed by challenging with dobutamine. Treated preparations were exposed to 10 or 100 nM bimakalim, I μM glibenclamide, or both before hypoxia. Variations of isometric developed tension (%DT) or APD 90 were studied. At concentrations

Steroid hormones exert their biological actions via intracellular receptors modulation of transcription. In addition, a number of molecular interactions, and the existence of membrane receptors in several tissues, support the hypothesis of nongenomic action of steroids. The androgens, 5alpha- and 5beta-dihydrotestosterone (0.1 to 100 microM), induce a rapid positive inotropism in the isolated left atrium of male Wistar rats whose time course of response might suggest that it is a non-genomic effect. However, the fact that the facilitation of contractility was inhibited by actinomycin D (5 microg/ml) and cycloheximide (10 microg/ml) indicates that a transcriptional component might play a role. The existence of a rapid functional genomic role would be somewhat surprising. However, rapid transcriptional mechanisms were also observed in certain cAMP-dependent responses. In the left atrium of rat, Rp-cAMPS (10 microM), a cAMP-dependent protein kinase inhibitor, antagonized 5alpha- but not 5beta-dihydrotestosterone-induced positive inotropism. The inhibition by Rp-cAMPS of isoproterenol- and forskolin-induced positive inotropism, and the fact that these cAMP-dependent effects were also inhibited by actinomycin D and cycloheximide, suggest that a cAMP-dependent transcriptional component may be partly involved in the positive inotropism induced by 5alpha-dihydrotestosterone. In addition, 5alpha-dihydrotestosterone might increase the basal adenylyl cyclase activity by acting on unoccupied beta-adrenoceptor-G-protein-adenylyl cyclase complexes, since the elicited inotropism was inhibited by a beta-blocker, atenolol (1 microM), a G-protein inhibitor, pertussis toxin (2 microg/ml, 3 h), and an adenylyl cyclase inhibitor, dideoxy-adenosine (10 microM).

It is well known that beta-adrenoceptor stimulation induces positive inotropism by cAMP-dependent phosphorylation of cardiac calcium channels. Furthermore, hypertrophy of different tissues including the heart have been related to the stimulation of these adrenoceptors via mechanisms coupled to activation of transcription and protein synthesis. Early effects of isoproterenol mediated via this pathway has also been associated to the stimulation of beta-adrenoceptors. However, the effects on the inotropism through genomic mechanisms have not yet been described. Isoproterenol (3 nM to 3 microM) induced a concentration-dependent positive inotropism, in isolated left atrium of male Wistar rats electrically stimulated (0.5 Hz, 5 ms, 30-50% above the threshold voltage), which was antagonized by atenolol (1 microM) and inhibited by a protein kinase A inhibitor, (R)p-cAMPS (10 microM). The inhibitor of transcription, actinomycin D (4 microM), and the protein synthesis inhibitor, cycloheximide (35.5 microM), significantly decreased the positive inotropism induced by isoproterenol. Forskolin (0.1 to 3 microM), an activator of adenylyl cyclase, induced a concentration-dependent positive inotropism which was also inhibited by (R)p-cAMPS, actinomycin D and cycloheximide. In the left atrium of rat, isoproterenol induced a positive inotropism which seems, at least in part, dependent upon intact transcription and protein synthesis, as suggested by the fact that the response was inhibited by the incubation with actinomycin D and cycloheximide. In addition, this genomic effect seems to be mediated by a cAMP-dependent mechanism. As it was inhibited by a protein kinase A inhibitor ((R)p-cAMPS) and similarly to isoproterenol, the positive inotropism induced by forskolin, which increases cytosolic cAMP, was also inhibited by actinomycin D and cycloheximide.

The effects of arachidonic acid (AA) and indomethacin (IM) on performance, oxygen consumption and lactate release of the trout heart were studied in vitro TPa s m−3 using a perfusion system, which allowed the evaluation of the integrated function of ventricle and coronary system by continuously setting the input coronary flow and pressure proportional to the pressure and flow output of the heart. The heart was working against a fixed resistance. A reduction of input oxygen partial pressure (PO2) from 175 torr (high PO2) to 76 torr (low PO2) increased the coronary flow (from 0.51 ml min−1 kg−1 to 1.21 ml min−1 kg−1, respectively) due to a strong reduction in coronary resistance (from 0.60 TPa s m−3 to 0.19 TPa s m−3, respectively). Oxygen consumption by the heart was significantly reduced from 20.7 ml min−1 g−1 at high PO2 to 4.6 ml min−1 g−1 at low PO2, while lactate production was increased from 24 μmol h−1 g−1 to 42 μmol h−1 g−1, indicating a higher contribution of anaerobic respiration to mechanical work. Mechanical efficiency was significantly higher at low than at high PO2. Exogenous AA caused a depression of inotropism and a reduction in the aerobic metabolic rate (by 25–35%), which was not accompanied by increased lactate production. IM enhanced the depression of both inotropism and aerobic metabolism. The effect of AA and IM on the heart were amplified at low PO2.

We have reported that, in canine hearts, cardiac cooling to 29°C enhanced left ventricular contractility but changed neither the contractile efficiency of cross-bridge (CB) cycling nor the excitation-contraction coupling energy. The mechanism of this intriguing energetics remained unknown. To get insights into this mechanism, we simulated myocardial cooling mechanoenergetics using basic Ca2+and CB kinetics. We assumed that both adenosinetriphosphatase (ATPase)-dependent sarcoplasmic reticulum (SR) Ca2+uptake and CB detachment decelerated with cooling. We also assumed that all the ATPase-independent SR Ca2+release, Ca2+binding to and dissociation from troponin, and CB attachment remained unchanged. The simulated cooling shifted the CB force-free Ca2+concentration curve to a lower Ca2+concentration, increasing the Ca2+responsiveness of CB force generation, and increased the maximum Ca2+-activated force. The simulation most importantly showed that these cooling effects combined led to a constant contractile efficiency when Ca2+uptake and CB detachment rate constants changed appropriately. This result seems to account for our experimentally observed constant contractile efficiency under cooling inotropy.

Background The mechanisms underlying the negative inotropic effects of isoflurane are incompletely understood. One suggested mechanism is that isoflurane may decrease Ca2+ sensitivity of contractile proteins. If so, more free calcium would be needed to activate contractile proteins to the same degree, which would impose a greater requirement for myocardial oxygen consumption used in the cycling of calcium. In this study, the authors use the excised, cross-circulated, canine heart model and the volume servopump technique to measure the effects of isoflurane on Emax (a contractile index) and on the relationship between pressure-volume area (PVA, a measure of total mechanical energy) and myocardial oxygen consumption per beat (VO2). Methods Effects of intracoronary isoflurane infused via a precoronary oxygenator on myocardial mechanoenergetics were studied during isovolumic contractions. The authors measured left ventricular (LV) pressure, LV volume, coronary flow, and arteriovenous oxygen content difference and computed Emax, VO2 and PVA at 0, 1.0, 1.5, and 2.0% isoflurane. From these data, the authors obtained oxygen costs of PVA and Emax in control subjects and in those receiving 2.0% isoflurane. Results Emax, PVA, and VO2 dose-dependently decreased by similar degrees (P < 0.05). Isoflurane did not change the oxygen costs at 1.5% and 2.0% concentration (P < 0.05). Conclusions These mechanoenergetic findings suggest that the primary method by which isoflurane decreases contractility is not by decreasing Ca2+ sensitivity of contractile proteins but mainly by decreasing Ca2+ handling in the excitation-contraction coupling without myocardial oxygen wasting effect.

The negative inotropism of 2,3-butanedione monoxime (BDM) < or = 5 mmol/l has been attributed primarily to directly suppressed crossbridge force development without much suppressed intracellular Ca2+ handling. However, there is evidence that BDM simultaneously or even primarily suppresses myocardial excitation-contraction (E-C) coupling. We therefore studied the mechanoenergetic effects of intracoronary BDM in the left ventricle (LV) of 11 canine excised cross-circulated hearts. We fully utilized the VO2-PVA-Emax framework that we have developed, where VO2 is myocardial O2 consumption, PVA is the systolic pressure-volume area as a measure of the total mechanical energy, and Emax is a contractility index. We gradually depressed Emax from 5.9 to 3.4 mmHg/(ml/100 g) on average by increasing intracoronary BDM to 2.6 +/- 2.1 mmol/l, and then gradually restored Emax to the pre-BDM level by increasing intracoronary CaCl2. We compared the O2 cost of Emax between BDM and Ca2+. We found that BDM and Ca2+ had a similar O2 cost of Emax. BDM did not affect the concentrations of blood-borne catecholamines. We therefore conclude that the negative inotropism of BDM is primarily due to suppressed E-C coupling in canine blood-perfused hearts.