Heart Papillary Muscle Research Articles

Effects of Trimetazidine on Rat Heart Muscle during Hypoxia and Reperfusion

Objective: Trimetazidine (TMZ) is a cardioprotective drug with anti-ischemic and anti-hypoxic metabolic actions. This study aims to investigate the impact of TMZ on the contractile and recovery properties of isolated papillary heart muscle under normoxic and hypoxic conditions. Methods: Left ventricular papillary muscles were harvested from 40 Wistar rats. After a 10-minute equilibration period in a normoxic bath, contractile and relaxation responses were recorded in normoxic and hypoxic baths with varying concentrations of TMZ (0 M, 5 x 10–6 M, and 5 x 10-5 M). The specimens were then re-perfused with oxygenated Krebs-Henseleit solution (95% O2 and 5% CO2) and equilibrated for 10 minutes in a normoxic bath. Recovery contractile and relaxation responses were measured. Results: Both doses of TMZ had a negative inotropic effect on muscle (p < 0.001), resulting in a limited decline in biomechanical performance in the hypoxic bath (p < 0.001). However, both doses of TMZ also increased the recovery biomechanical performance compared to the control group (p < 0.001). Conclusions: Under normoxic conditions, TMZ pretreatment alone did not show any cardioprotective effect. However, adding TMZ at a concentration of 5 x 10-6 M, a therapeutic level in humans, reduced ischemic contracture and improved postischemic recovery of contraction forces in both pretreated and control groups. Despite trimetazidine’s negative inotropic effect under normoxic conditions, near-therapeutic doses of the drug have significant protective effects on isolated papillary heart muscle contractility, leading to improved contractile function under hypoxic conditions.

MyBP-C binds myosin S2 in mouse heart as revealed by super-resolution microscopy.

Supporting the hypothesis that myosin binding protein C (MyBP-C) binds to myosin subfragment-2 (S2) in the heart, a monoclonal antibody (MF30) to S2 was inhibited by the presence of MyBP-C in skinned mouse heart papillary muscle. Using a form of super-resolution microscopy called expansion microscopy, the relative positions of the fluorescent labels attached to a hydrogel could be expanded approximately four-fold in all three dimensions prior to imaging the sample with a Zeiss Airyscan super-resolution microscope. This muscle tissue was prepared for expansion microscopy by labeling with the fluorescently conjugated MF30 and embedding in a hydrogel, followed by crosslinking the fluorescent labels to the hydrogel and thoroughly digesting the proteins within the hydrogel. Images of these samples readily enable measurements of the relative fluorescent intensities of the P-, C-, and D-zones along thick filaments in the A-bands of the sarcomere. The A-bands from wild type mice showed low fluorescent intensities from MF30 in the C-zones relative to the P- and D-zones. Since MyBP-C resides in the C-zones of the thick filament, it was hypothesized that MyBP-C inhibited the MF30 binding in the C-zone. This hypothesis was tested by comparing tissues from MyBP-C knockout mice with the wild type mice using this super-resolution microscopy technique. The overall fluorescence intensity from MF30 was significantly greater in the tissue from MyBP-C knockout mice vs. wild type tissue. Furthermore, the MF30 fluorescence intensity in the C-zone was no longer inhibited in the MyBP-C knockout mice, relative to the D-zone in the wild type. These data support the hypothesis that MyBP-C binds myosin S2 and may compete with the MF30 binding to S2. (Supported by NIH/NHLBI R01HL149164.)

Mechanism of Positive Inotropic Effect of Vincanine on Cardiac Muscle Contraction Activity

In the present study, the dose-dependent effect of the alkaloid vincanine on the contractile activity of rat heart papillary muscle was investigated and it was found to increase the force of muscle contraction at all concentrations. The half-maximal inotropic effect concentration (ED50) of vincanine was 21.8 μM, respectively. Studies of the effect of this alkaloid on the cardiomyocyte Na+-channel in the presence of its blocker lidocaine showed that the positive inotropic effect of vincanine does not involve the Na+-channel. When studying the effect of vincanine on Сa2+L-channels in the presence of nifedipine (IC50=0.01 μM), the positive inotropic effect of vincanine (50 μM) alkaloid was partially reduced. In general, it was found that the positive inotropic effect of vincanine on the force of papillary muscle contraction is partially mediated by Сa2+L-channels and mainly Na+/Сa2+ exchange.

Abstract 15663: Trasapical Mitral Valve and Left Ventricular Reshaping to Repair Functional Mitral Regurgitation in a Dilated Ventricle

Background: The COAPT trial demonstrated that repair of functional mitral regurgitation (FMR) in heart failure (HF) improves prognosis, only when the LV end diastolic diameter is <65mm. A significant need exists for a new therapy that can address both FMR and the LV in patients with LV EDD>65mm. In this study, we report a novel beating heart transapical device that can address FMR by beating heart papillary muscle approximation (PMA), and reduces the LV size and sphericity as well. Preclinical efficacy of this novel device in a swine HF/FMR model is reported. Methods: The device was prototyped using biocompatible 3D printed parts (Fig A), and a delivery catheter was custom designed for beating heart deployment (Fig B). In 7 healthy pigs, and 4 pigs induced with chronic post-myocardial infarction HF, with moderate or greater FMR, the device was implanted via a transapical access. The device was adjusted in steps - (step 1) reduce the inter-PM distance to an extent that FMR is mild or less; and (step 2) reshape the LV to achieve a 30% reduction in LV EDV and 25% reduction in sphericity index (SI). Echocardiography was used to assess mitral valve function and LV geometry, and LV function was assessed with invasive hemodynamics. Pigs were survived thereafter. Results: With this new device, MR was consistently reduced from moderate levels to none/mild. Mitral valve coaptation length increased from 3.49 ± 0.42 to 6.45± 1.13 mm (p=.019) and tenting area decreased from 158.09± 33 to 116.4± 16.7mm 2 (p=.05). LV EDV was reduced from 142.8± 29.6 to 97.5± 19.6ml (p=.025), SI was decreased from 0.67± 0.04 to 0.49± 0.07 (p=.0497) and IPMD was reduced from 23.5± 5.7 to 12.76± 3.0mm (p=.032). The device did not adversely impact cardiac output (6.59± 1.3 to 4.83± 1.6 LPM, p=.067) or E/A wave ratio (1.40± 0.23 to 1.35±0.29, p=.60). Conclusion: This novel transapical beating heart MV and LV reshaping device, significantly reduced FMR and reshaped the LV in this swine model.

Cadaveric Study on the Morphology and Morphometry of Heart Papillary Muscles.

IntroductionA normal atrioventricular valve complex of the heart consists of the atrioventricular (A-V) ring, cusps, chordae tendineae, and papillary muscles. The right ventricle contains three while the left ventricle contains only two papillary muscles, which are named according to their location. A thorough understanding of the normal anatomy as well as possible variations can help surgeons in various corrective surgeries involving papillary muscles.Material & methodsThe study included 50 formalin-preserved hearts procured from human cadavers of unknown age and cause of death. The number of papillary muscles along with their shape, size, and pattern were noted separately for each ventricle. Data were analyzed using SPSS Version 21.0 (IBM Corp., Armonk, NY).ResultsThe left and right ventricles contained two and three papillary muscles, respectively, in all the hearts. In the right ventricles, conical shape and the single base and divided apex (SBDA) pattern were found to be most prevalent. Anterior papillary muscles exhibited the mean length of 12.71±3.81 and 16.41±4.33 in the right and left ventricles, respectively. Similarly, posterior papillary muscles exhibited a mean length of 12.40±3.03 and 14.64±3.92 in the right and left ventricles, respectively. Both differences were found to be statistically significantConclusionFor the appropriate functioning of valves, both anatomical and mechanical coherence of the papillary muscles is required. A very keen understanding of this valvular complex is thus essential for anatomists, physiologists, and cardiologists to deal with normal as well as pathological valvular conditions.

Anatomical variations of papillary muscles in human cadaveric hearts of Chhattisgarh, India

In both ventricles of the heart papillary muscles play important role for proper cardiac valvular function of heart. The present study was done to analyse the papillary muscles of heart with respect to the variations in their number, length, shape, position and pattern in both ventricles. Forty well preserved cadaveric human hearts were used for the study. The variations in the papillary muscles of both right and left ventricles were categorized, documented and photographed. In the right ventricle, authors observed 31.42% anterior, 34.3% posterior and 34.3% septal papillary muscles, and in the left ventricle, 41.7% anterior and 58.3% posterior papillary muscles. Classical papillary muscles were observed in 64.3% heart specimens in right ventricle and 55% in left ventricle. Authors found conical, pyramidal and broad apexed papillary muscles in 44.3%, 51.4% and 4.3% heart specimens respectively in right ventricle, whereas in left ventricle the corresponding values were 33.3%, 30% and 36.7%. Separate bases and fused apex pattern was observed in 24.3%, single base and divided apex in 55.7% heart specimens in right ventricle and in left ventricle in 45% and 43.3% heart specimens respectively. The length of anterior, posterior and septal papillary muscle in right ventricle was 1.27±0.45, 1.36±0.52, 0.92±0.54 cm respectively whereas in left ventricle, the mean length of anterior and posterior papillary muscles was 2.13±0.44 and 1.76±0.46 cm. In right ventricle mean thickness was 1.17±0.31cm whereas in left ventricle it was 2.16±0.32 cm. The papillary muscles has complex and variable anatomy. Knowledge of this variation to the cardiac surgeons during reparative surgical procedures conducted for mitral/ tricuspid valve replacement is of utmost importance to prevent untoward event.

The Force-Frequency Dependence in the Heart Papillary Muscle of Ground Squirrel as a Reflection of Changes in the Functional State of Animals during the Annual Cycle

Abstract—A study was conducted to explore the characteristics of the dependence of the contraction force (isometric mode at 30°C) on the frequency of stimulation (0.1–4.0 Hz) in the right ventricle papillary muscles of the heart of the ground squirrel Spermophilus undulatus in groups of animals in the summer (June–July) and autumn (October–November) periods and the period of hibernation, as well as of animals that were active in the interbout euthermic period, entering into torpor (Theart ~ 30°C), in torpor, and in interbout awakenings (Theart ~ 30°C). It has been shown that the dependence of the contraction force on the frequency of stimulation (rhythm–inotropic relationship) in papillary muscles of the ground squirrel heart is of the negative type in its major manifestations regardless of the functional state of the animals; that is, the force of contraction at high frequencies (from 1.0 to 4.0 Hz) is always less than at low frequencies (in the region close to 0.1 Hz). At the same time, two types of the rhythm–inotropic relationship could be distinguished in each group, namely, one with a relatively weak (type 1) and another with a pronounced (type 2) frequency dependence. A weak positive component may occur in both types of rhythm–inotropic relationship (due to increased force of contraction); it was observed at the frequency of stimulation from 0.2 to 0.5 Hz in type 1 (it occurred only in the animals at the period of hibernation, namely, when they are active between bouts, in torpid state or when they entered into a state of torpor, that is, tending to reduce activity); it was observed at a high frequency of stimulation (above 1.0 Hz) in type 2 and mostly expressed in animals at the periods of resumption of functional activity, that is, upon awakening in the period of hibernation and in the final spring awakening. These data indicate that the process of formation of a particular type of rhythm–inotropic relationship in the heart of hibernating animals occurs before changes in the functional state of animals during the annual cycle.

Benzolamide perpetuates acidic conditions during reperfusion and reduces myocardial ischemia-reperfusion injury.

During ischemia, increased anaerobic glycolysis results in intracellular acidosis. Activation of alkalinizing transport mechanisms associated with carbonic anhydrases (CAs) leads to myocardial intracellular Ca2+ increase. We characterize the effects of inhibition of CA with benzolamide (BZ) during cardiac ischemia-reperfusion (I/R). Langendorff-perfused isolated rat hearts were subjected to 30 min of global ischemia and 60 min of reperfusion. Other hearts were treated with BZ (5 μM) during the initial 10 min of reperfusion or perfused with acid solution (AR, pH 6.4) during the first 3 min of reperfusion. p38MAPK, a kinase linked to membrane transporters and involved in cardioprotection, was examined in hearts treated with BZ in presence of the p38MAPK inhibitor SB202190 (10 μM). Infarct size (IZ) and myocardial function were assessed, and phosphorylated forms of p38MAPK, Akt, and PKCε were evaluated by immunoblotting. We determined the rate of intracellular pH (pHi) normalization after transient acid loading in the absence and presence of BZ or BZ + SB202190 in heart papillary muscles (HPMs). Mitochondrial membrane potential (ΔΨm), Ca2+ retention capacity and Ca2+-mediated swelling after I/R were also measured. BZ, similarly to AR, reduced IZ, improved postischemic recovery of myocardial contractility, increased phosphorylation of Akt, PKCε, and p38MAPK, and normalized ΔΨm and Ca2+ homeostasis, effects abolished after p38MAPK inhibition. In HPMs, BZ slowed pHi recovery, an effect that was restored after p38MAPK inhibition. We conclude that prolongation of acidic conditions during reperfusion by BZ could be responsible for the cardioprotective benefits of reduced infarction and better myocontractile function, through p38MAPK-dependent pathways. NEW & NOTEWORTHY Carbonic anhydrase inhibition by benzolamide (BZ) maintains acidity, decreases infarct size, and improves postischemic myocardial dysfunction in ischemia-reperfusion (I/R) hearts. Protection afforded by BZ mimicked the beneficial effects elicited by an acidic solution (AR). Increased phosphorylation of p38MAPK occurs in I/R hearts reperfused with BZ or with AR. Mitochondria from I/R hearts possess abnormal Ca2+ handling and a more depolarized membrane potential compared with control hearts, and these changes were restored by treatment with BZ or AR.

GW28-e0616 Expression of connective tissue growth factor in papillary muscles of heart of patients with rheumatic heart disease

To investigate the expression and the effect of connective tissue growth factor (CTGF) on rheumatic myocardial fibrosis of rheumatic heart disease (RHD). The papillary muscles samples were obtained from patients with RHD during mitral valve replacement. The expression of CTGF mRNA and CTGF protein

Exercise Attenuates Renal Dysfunction with Preservation of Myocardial Function in Chronic Kidney Disease

Previous studies have suggested that exercise improves renal and cardiac functions in patients with chronic kidney disease. The aim of this study was to evaluate the effects of long-term aerobic swimming exercise with overload on renal and cardiac function in rats with 5/6 nefrectomy (5/6Nx). Eight Wistar rats were placed into 4 groups: Control (C), Control+Exercise (E), Sedentary 5/6Nx (NxS) and 5/6Nx+Exercise (NxE). The rats were subjected to swimming exercise sessions with overload for 30 min five days per week for five weeks. Exercise reduced the effect of 5/6Nx on creatinine clearance compared to the NxS group. In addition, exercise minimized the increase in mean proteinuria compared to the NxS group (96.9±10.0 vs. 51.4±9.9 mg/24 h; p<0.05). Blood pressure was higher in the NxS and NxE groups compared to the C and E groups (216±4 and 178±3 vs. 123±2 and 124±2 mm Hg, p<0.05). In the 200 glomeruli that were evaluated, the NxS group had a higher sclerosis index than did the NxE group (16% vs. 2%, p<0.05). Echocardiography demonstrated a higher anterior wall of the left ventricle (LV) in diastole in the NxS group compared with the C, E and NxE groups. The NxS group also had a higher LV posterior wall in diastole and systole compared with the E group. The developed isometric tension in Lmax of the heart papillary muscle was lower in the NxS group compared with the C, E and NxE groups. These results suggested that exercise in 5/6Nx animals might reduce the progression of renal disease and lessen the cardiovascular impact of a reduction in renal mass.

Abstract 19066: D-Dopachrome Tautomerase Provides a Novel Cardioprotective Mechanism Through its Modulation on AMPK Activation in Heart During Ischemia-reperfusion

Endogenously released cardiac proteins or cardiokines regulate intracelluar signaling pathway and cardiac injury in response to stress. Macrophage migration inhibitory factor (MIF) modulates AMP-activated protein kinase (AMPK) activation and limits cardiac injury during ischemia-reperfusion. Genetic deletion of the MIF receptor, CD74, has more profound effects on ischemic tolerance and AMPK activation, than deletion of MIF alone, suggesting the possibility of a second receptor ligand. We recently identified D-dopachrome tautomerase (DDT) as a homolog of MIF, and the purpose of this study was to determine the actions of DDT in the heart. DDT perfusion in mouse heart increased AMPK in a dose-dependent manner (from 10 to 50ng/ml) without alterations in LV contractile function. Immunohistochemistry showed that DDT was highly expressed in cardiomyocytes in the mouse heart. DDT release from perfused mouse hearts (baseline: 2 ± 0.5 ng/min; post-ischemia: 4.5 ± 0.7 ng/min, p&lt;0.05) was triggered by brief episodes (15 min) of ischemia and the inhibition of DDT actions by perfusion with neutralizing antibody (anti-DDT vs. non-immune IgG) significantly attenuated AMPK activation during ischemia. Anti-DDT (100µg/ml) also resulted in more pronounced cardiac injury following ischemia-reperfusion. Parallel effects were observed in isolated rat heart papillary muscles: recombinant DDT treatment had a similar pharmacologic effect to induce AMPK activation in a dose-dependent manner. Hypoxia (15 min) also stimulated DDT release from rat papillary muscles and inhibition of extracellular DDT by DDT neutralizing antibodies impaired AMPK activation. These pharmacologic and physiologic effects of DDT were also observed in isolated rat cardiomyocytes, indicating that DDT has specific autocrine effects. DDT treatment (400ng/ml) increased intracellular calcium in cardiomyocytes and STO-609 (2µM), a calmodulin-dependent protein kinase kinase (CaMKK) inhibitor attenuated DDT induced AMPK phosphorylation, suggesting that DDT induced AMPK activation is mediated by calcium-CaMKK pathway. Thus, DDT is a novel endogenous cardiac protein that modulates cardiac stress response pathways and protects against injury during ischemia.

Effect of 1-Acyl-5,6-dialkoxy-2-alkylthiobenzo[d]imidazoles on the Action Potential Duration and Isometric Contraction in Guinea Pig Atrium Activated by Carbachol and in Guinea Pig Heart Papillary Muscles

Studies have shown that some benzo[d]imidazole derivatives (1-(5,6-dimethoxy-2-methylthio-1H-benzo[d]imidazol-1-yl)-1-ethanone (1), 1-(6-ethylthio-5H[1,31dioxolo[4',5':4,5] benzo[d]imidazol-5-yl)-1-propanone (2), 1-(2-ethylthio-6,7-dihydro-1H[1,4]dioxino [2:3':4,5]benzo[d]imidazol-1-yl)-1-pro-panone (3) and 2,3,9,10-tetrahydro-8H [1,4]dioxino[2' 3":4',5']benzo[4,5]imid-azo[2,1-b][1,3]thiazin-10-one (4)) possess strong cardiotonic activity. The goal of this study was to investigate the effect of compounds 1-4 on the action potential (AP) duration and contractile force in guinea pig atrium activated by carbachol and in guinea pig heart papillary muscles. The experiments were carried out on the guinea pig papillary muscles and atrium. Isometric contraction and transmembrane potential were recorded using a force transducer and standard microelectrode technique. Compounds 1-4 exerted a positive inotropic effect in a dose-dependent manner on the electrically driven left atrium and papillary muscles, more pronounced in atrium. In response to 1 micromol/L carbachol the AP duration at a 90 % repolarization in atrium shortened more than 70 %, the isometric contraction decreased to the similar level as well. Compounds 1 and 4 significantly antagonized the shortening of the AP duration induced by carbachol and increased it. Compound 1 abolished the reduction of isometric contraction as well. Derivative 3 significantly lengthened (31 ms) the AP duration at a 90 % repolarization in papillary muscles, while 1 and 4 failed to affect this index. The selective blockade of the rapid component of the delayed rectifier potassium current (Ikr) by dl-sotalol (1 micromol/L) did not show the substantial influence on benzimidazole effects. These findings support the hypothesis that the tested benzo[d] imidazole derivatives abolish the influence of carbachol on AP and the isometric contraction by inhibition of acetylcholine-activated potassium current (KACh) in guinea pig atrial myocytes and therefore may be beneficial for the prognosis of patients with advanced heart failure and atrial fibrillation.

Cystic Tumor of Papillary Muscle of Heart

Primary cystic tumors of papillary muscles of the heart are extremely rare. Here, one case of unusual cystic tumor in papillary muscle of the heart in a 37-year-old Myanmar migrant worker has been reported. He came to Malaysia 2 weeks before and one morning was found dead in sleep. Autopsy revealed cystic lesion in the papillary muscle of the mitral valve of heart, which was prolapsing into ventricular cavity. The cyst had white-jelly like sticky mucus material. The cyst was present in papillary muscle with slight invasion in septum area; it was lined by cuboidal-columnar epithelium and contained mucinous contents. There was no evidence of an inflammatory reaction in the cyst and in cardiac muscles. In addition to cystic neoplasm, the deceased also had histoplasmosis of the lungs. The case is presented with macroscopic and microscopic photographs of the cyst and histoplasmosis of the lungs. This case is reported because of its rarity, unique position, and unusual appearance.

Sustained anti-β-adrenergic effect of melatonin in guinea pig heart papillary muscle

Objective. Anti-β-adrenergic actions of several substances influence heart function significantly. The anti-β-adrenergic effect of melatonin was investigated, with special attention to protein kinase C (PKC) and nitric oxide (NO). Design. Guinea pig papillary muscles were exposed to melatonin (500 pM) for 15 min and 20 min washout. Contractile force was measured during a bolus of isoproterenol (300 nM) given before melatonin, at the end of melatonin-exposure and after washout. In separate experiments blockers of PKC, NO-synthase (NOS) and melatonin receptors were added, or forskolin (10 µM) substituted for isoproterenol. Results. Melatonin significantly reduced the increase in contractile force in response to isoproterenol, both when present and after melatonin-washout. The reduction was unaffected by inhibition of PKC, while inhibition of melatonin receptors or NOS seemed to abolish the effect. Melatonin induced a sustained but not acute reduction of contractile force response with forskolin stimulation. This was abolished by NOS-inhibition. Conclusion. Receptor-mediated immediate and sustained anti-β-adrenergic effects of melatonin were demonstrated in contractile function. A role for NO in the response was indicated, while a role for PKC was not verified.

Real-Time Four-dimensional Imaging of the Heart with Multi–Detector Row CT

An interactive four-dimensional (4D) visualizing system for the heart was developed by the authors. The system realizes high-resolution three-dimensional (3D) imaging with temporal resolution in a beating heart by using eight or more data sets reconstructed from multi-detector row computed tomography (MDCT) with a retrospective electrocardiograph-gated reconstruction algorithm. The motion of heart walls, papillary muscles, septa, and valves can now be observed in 4D multiplanar reformations (MPRs), as with sonography, while coronary arteries, coronary sinuses, and cardiac veins can be analyzed during the optimal phase in 4D volume-rendering images, as with angiography. All parameters such as window width, window level, field of view, panning, tilt, thresholds, opacity, color, and segmentation function are completely interactive in 4D imaging. Two longitudinal views and one latitudinal view of a heart can be simultaneously visualized in the three relative 4D MPR views. These newly developed capabilities in viewing both 3D volume and temporal resolution data, functional data, and even multiphase data with registration add considerable diagnostic potential. The advent of this real-time 4D visualizing system has enhanced the capabilities of MDCT.

Comparison of calcium-sensitivity between physiological preparations of canine heart and ferret papillary muscle

Comparison of calcium-sensitivity between physiological preparations of canine heart and ferret papillary muscle

The influence of the neuropeptide galanin on the contractility and the effective refractory period of guinea-pig heart papillary muscle under normoxic and hypoxic conditions.

The aim of this study was to discover the effects of galanin, a neuropeptide comprising 29 amino acids capable of activating inward-rectifier K+ channels (IK1) in cardiomyocytes, on the force of contraction (Fc), velocity of contraction (+dF/dt), velocity of relaxation (-dF/dt) and effective refractory period (ERP) of guinea-pig heart. The influence of galanin on the time-course of hypoxia-induced disturbances in contractility and ERP was also examined. Experiments were performed on the isolated right ventricle papillary muscle of guinea-pig heart. In the concentration range 0.001-0.01 microM, galanin had no significant effect on the measured parameters. At 0.03 and 0.1 microM, galanin exerted a positive inotropic action and prolonged ERP. Further increasing the concentration led to a negative inotropic action and significant shortening of ERP. Although simulated hypoxia induced a significant drop in Fc, +dF/dt and -dF/dt, and a significant shortening of ERP, recovery of all the measured parameters was complete after 10 min reperfusion. In the presence of 0.03 and 0.1 microM galanin the effect of hypoxia on the contractility of papillary muscle was more profound and reperfusion did not result in complete recovery. In contrast, addition of 1 microM galanin to the hypoxic solution significantly protected the muscle and recovery of the tissues during reperfusion was rapid and complete (in 5 min). One can conclude that galanin at lower concentrations induced a positive inotropic action and a prolongation of ERP, but increased the sensitivity of heart muscle to hypoxia. At higher concentrations however, galanin exerted a negative inotropic action but protected the muscle against hypoxia-induced disturbances in contractility.

THE EFFECTS OF POTASSIUM CHANNEL MODULATORS ON THE SIMULATED ISCHAEMIA-INDUCED CHANGES IN CONTRACTILITY AND RESPONSIVENESS TO PHENYLEPHRINE OF RAT-ISOLATED PAPILLARY MUSCLE

The aim of the present study was to compare the influence of terikalant, a blocker of inwardly rectifying K+channels, galanin, a neuropeptide of 29 aminoacids with a complex mechanism of action including an activation of inwardly rectifying K+channels and glibenclamide, a blocker of ATP-sensitive K+channels, on simulated ischaemia-induced changes in contractility and response to phenylephrine of rat-isolated heart muscle. Experiments were performed on isolated rat heart papillary muscles. The following parameters were measured: force of contraction (Fc), velocity of contraction (+dF/dt) and velocity of relaxation (−dF/dt), time to peak contraction (ttp) and relaxation time at 10% of total amplitude of contraction (tt10). In the presence of 1 μmof galanin, as well as terikalant, simulated ischaemia caused a decrease inFc, +dF/dtand −dF/dt, however, it significantly increased a drop inFc and −dF/dt. After 60 min of reperfusion, all the measured parameters recovered completely exceptFc in the galanin group. Terikalant, but not galanin, prevents the negative inotropic action of phenylephrine observed in the control group. On the other hand, addition of 1 μmof glibenclamide to the no-substrate solution prevented the simulated ischaemia-induced decrease inFc, +dF/dtand −dF/dt. In this group phenylephrine did not cause the negative inotropic action. The above mentioned data reveal that pretreatment with the inhibitors of ATP-sensitive and inwardly rectifying K+channels protect rat-isolated papillary muscle against ischaemia-induced disturbances in contractility.

Pretreatment with rimalkalim changes the adrenergic responsiveness of isolated guinea pig papillary muscle

It has been proposed that the positive inotropic action of different drugs is influenced by the activation of ATP-sensitive K + channels (K ATP). This hypothesis was tested by investigating the effects of rimalkalim ((3 S,4 R)-3-hydroxy-2,2-dimethyl-4-(oxo-1 pyrrolidinyl)-6-phenyl-sulfonylchroman hemihydrate (formerly HOE-234)) as activator of K ATP channels on the positive inotropic action of forskolin, l-phenylephrine hydrochloride and dibutyryl cyclic AMP ( N 6,2′- O-dibutyryladenosine 3′:5′-cyclic monophosphate). Experiments were performed with the isolated guinea-pig heart papillary muscle. The force of contraction ( F c), velocity of contraction (+d F/d t) and relaxation (−d F/d t), time to peak contraction ( t tp) and duration of contractions at the level of 10% or more of their total amplitude ( t t 10 ) were measured. Pretreatment with 1 μM rimalkalim had no significant influence on the positive inotropic effects of dibutyryl cyclic AMP and l-phenylephrine in the presence of 1 μM metoprolol. However, the positive inotropic effects of l-phenylephrine in the absence of metoprolol were significantly attenuated after pretreatment with rimalkalim. The increase in force and velocity of contraction induced by forskolin was strongly enhanced under these conditions. Addition of 1 μM glibenclamide, an inhibitor of K ATP channels, to rimalkalim, prevented the above-mentioned changes in the positive inotropic effects of phenylephrine and forskolin obtained after pretreatment with rimalkalim. What is more, addition of 0.2 μM thapsigargin, a selective blocker of Ca 2+-adenosinetriphosphatase of sarcoplasmic reticulum (Ca 2+ ATP-ase), abolished the potentiation of the positive inotropic action of forskolin induced by pretreatment with rimalkalim. These results demonstrate that activation of K ATP channels by rimalkalim alters β-adrenoceptors, but has no effect on α-adrenoceptor signalling pathways and enhances forskolin inotropic effects by a mechanism which probably involves Ca 2+ ATP-ase.

Inotropic Response of Rat Heart Papillary Muscle to α1‐and β‐Adrenoceptor Stimulation in Relation to Dietary n‐6 and n‐3 Polyunsaturated Fatty Acids (PUFA) and Age

The effect of dietary n-6 and n-3 polyunsaturated fatty acids (PUFA) and age on inotropic responses of heart papillary muscle to alpha 1-or beta-adrenoceptor stimulation was examined in young (4 months), middle-aged (12 months) and senescent (27 months) male Wistar rats. From the age of two months the rats were fed a diet containing 2% or 12% of fat by weight varying in PUFA type: a) standard low-fat n-6 PUFA diet, b) high-fat n-6 PUFA diet or c) high-fat n-3 PUFA diet. The inotropic responses to alpha 1-adrenoceptor stimulation with phenylephrine were triphasic (positive, negative, then positive). Young, high-fat n-3 PUFA-fed rats exhibited significantly lower negative and higher positive responses to phenylephrine stimulation, and higher positive responses to isoprenaline stimulation than young, high-fat n-6 PUFA-fed rats. On the other hand, no such dietary-related difference was found between young rats fed a high-fat n-3 PUFA diet and a standard low-fat n-6 PUFA diet. The young high-fat n-6 PUFA-fed rats exhibited inotropic responses similar to those of the middle-aged and senescent rats within the three dietary groups. The time to peak force and the time of half relaxation did not differ within dietary and age groups. The findings indicate that dietary n-6 PUFA-rich supplementation at a young age induces changes resembling the effects of age, as evidenced by decreasing cardiac responses to adrenoceptor agonists, such as phenylephrine or isoprenaline.