Search

Abstract Cardioprotective Unani drug, Saad Kufi (Cyperus scariosus R.Br.), mentioned by the intellectual colossus Ibn Sina (Avicenna) a thousand years back in his book, “Kitab al-Adviya al-Qalbia” and still widely used by Unani physicians, was selected for experimental study. The main objective of the study was to explore the trial drug ex vivo for validation, hemodynamic elucidation, and molecular mechanism identification for the improvement of Unani therapeutics and to identify a safe and effective novel cardiovascular drug for mainstream medicine. Five doses of 50% ethanolic extract of the physiochemically standardized root were studied in a normal rat heart, on a semi-automated Langendorff apparatus supported with an advanced data acquisition system, perfused with carbogenated non-recirculating Kreb’s-Hensleit solution, at constant flow mode, by continuous recording. The effect of 6 repetitions (n = 6) of each dose was studied with the following parameters on the Lab chart pro version: heart rate, left ventricular developed pressure, cardiac work, and coronary pressure. The significance of the difference was determined by the student’s “t” test. Results of all doses of Saad Kufi showed a significant increase in the above parameters. The maximum increase was observed by Dose III. It could be concluded that Unani’s clinical use of Saad Kufi (C. scariosus R.Br) as cardioprotective was validated and higher doses were indicated to be clinically optimal. Hemodynamically and molecular mechanism-wise, it is indicated to be a sympathomimetic or inotropic-like agent and possibly a direct vasodilator. Since existing long-term treatment of heart failure is not done by cardiac stimulants or positive inotropic and chronotropic agents, the possible future clinical demonstration of therapeutic improvement in heart failure will bring Saad Kufi as a novel drug in mainstream medicine.

Cardioprotective Unani drug, Saad Kufi (Cyperus scariosus R.Br.), mentioned by the intellectual colossus Ibn Sina (Avicenna) a thousand years back in his book, "Kitab al-Adviya al-Qalbia" and still widely used by Unani physicians, was selected for experimental study. The main objective of the study was to explore the trial drug ex vivo for validation, hemodynamic elucidation, and molecular mechanism identification for the improvement of Unani therapeutics and to identify a safe and effective novel cardiovascular drug for mainstream medicine. Five doses of 50% ethanolic extract of the physiochemically standardized root were studied in a normal rat heart, on a semi-automated Langendorff apparatus supported with an advanced data acquisition system, perfused with carbogenated non-recirculating Kreb's-Hensleit solution, at constant flow mode, by continuous recording. The effect of 6 repetitions (n = 6) of each dose was studied with the following parameters on the Lab chart pro version: heart rate, left ventricular developed pressure, cardiac work, and coronary pressure. The significance of the difference was determined by the student's "t" test. Results of all doses of Saad Kufi showed a significant increase in the above parameters. The maximum increase was observed by Dose III. It could be concluded that Unani's clinical use of Saad Kufi (C. scariosus R.Br) as cardioprotective was validated and higher doses were indicated to be clinically optimal. Hemodynamically and molecular mechanism-wise, it is indicated to be a sympathomimetic or inotropic-like agent and possibly a direct vasodilator. Since existing long-term treatment of heart failure is not done by cardiac stimulants or positive inotropic and chronotropic agents, the possible future clinical demonstration of therapeutic improvement in heart failure will bring Saad Kufi as a novel drug in mainstream medicine. [ABSTRACT FROM AUTHOR]

Objective(s): Cardiac arrest is a crucial procedure in various cardiac surgeries, during which the heart is subjected to an ischemic state. The occurrence of ischemia/reperfusion (I/R) injury is inevitable due to aortic blockage and opening. The Histidine-tryptophan-ketoglutarate (HTK) solution is commonly used as an organ protection liquid to mitigate cardiac injury during cardiac surgery. Despite its widespread use, there is significant potential for improving its protective efficacy.Materials and Methods: The cardioprotective effect of HTK solution with and without melatonin was evaluated using the isolated Langendorff-perfused mouse heart model. The isolated C57bL/6 mouse hearts were randomly divided into four groups: control, I/R, HTK solution treatment before reperfusion (HTK+I/R), and HTK solution combined with melatonin before reperfusion (HTK+M+I/R). Cardiac function and myocardial injury markers were then measured. AMP-activated protein kinase α2 (AMPKα2) KO mice were used to investigate the underlying mechanism.Results: In our study, we found that melatonin significantly improved the protective effects of HTK solution in an isolated Langendorff-perfused mouse model, mechanistically by reducing mitochondrial damage, improving energy metabolism, inhibiting cardiomyocyte apoptosis, and reducing myocardial infarction size. We also observed that the HTK solution alone was ineffective in inhibiting ER stress, but when melatonin was added, there was a significant reduction in ER stress. Furthermore, melatonin was found to alleviate carbonyl stress during cardiac I/R. Interestingly, our results showed that the cardioprotective properties of melatonin were dependent on AMPKα2.Conclusion: The findings presented in this study offer a valuable empirical foundation for the development of perioperative cardioprotective strategies.

The isolated heart perfusion model, a fundamental tool in cardiovascular research, has evolved significantly since its inception in the late 19 th century. This review traces the development of the isolated heart model, from its early adaptations by pioneers such as Langendorff and Starling to modern advancements by researchers like Morgan and Neely. We discuss the various applications of the model in pharmacological testing, disease modeling, and educational settings, emphasizing its crucial role in understanding cardiac function and disease mechanisms. Recent technological enhancements, including high-resolution imaging, integration with bioengineering, and advanced genomic and proteomic analyses, have significantly broadened the capabilities of these models. Looking forward, we explore potential future developments such as the integration of precision medicine, stem cell research, and artificial intelligence, which promise to revolutionize the use of isolated heart perfusion models. This review highlights the model's crucial role in bridging experimental research and clinical applications., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 Termedia & Banach.)

Here we describe the acute myocardial effects of an elapid (red spitting cobra, Naja pallida) and a viper (western diamondback rattlesnake, Crotalus atrox) venom using an ex vivo heart model. Our results reveal two different pathophysiological trajectories that influence heart function and morphology. While cobra venom causes a drop in contractile force, rattlesnake venom causes enhanced contractility and frequency that coincides with differences in myocellular morphology. This highlights the medical complexity of snake venom-induced cardiotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Cardiac arrest is a crucial procedure in various cardiac surgeries, during which the heart is subjected to an ischemic state. The occurrence of ischemia/reperfusion (I/R) injury is inevitable due to aortic blockage and opening. The Histidine-tryptophan-ketoglutarate (HTK) solution is commonly used as an organ protection liquid to mitigate cardiac injury during cardiac surgery. Despite its widespread use, there is significant potential for improving its protective efficacy., Materials and Methods: The cardioprotective effect of HTK solution with and without melatonin was evaluated using the isolated Langendorff-perfused mouse heart model. The isolated C57bL/6 mouse hearts were randomly divided into four groups: control, I/R, HTK solution treatment before reperfusion (HTK+I/R), and HTK solution combined with melatonin before reperfusion (HTK+M+I/R). Cardiac function and myocardial injury markers were then measured. AMP-activated protein kinase α2 (AMPKα2) KO mice were used to investigate the underlying mechanism., Results: In our study, we found that melatonin significantly improved the protective effects of HTK solution in an isolated Langendorff-perfused mouse model, mechanistically by reducing mitochondrial damage, improving energy metabolism, inhibiting cardiomyocyte apoptosis, and reducing myocardial infarction size. We also observed that the HTK solution alone was ineffective in inhibiting ER stress, but when melatonin was added, there was a significant reduction in ER stress. Furthermore, melatonin was found to alleviate carbonyl stress during cardiac I/R. Interestingly, our results showed that the cardioprotective properties of melatonin were dependent on AMPKα2., Conclusion: The findings presented in this study offer a valuable empirical foundation for the development of perioperative cardioprotective strategies., Competing Interests: The authors declare no conflicts of interest.

Our aim was to investigate if the cardioplegic solution HTK can be improved by the addition of the ROS scavenger melatonin. 158 guinea pig hearts without (UI80) or with HTK protection (HTK80) were investigated in ischemia/reperfusion experiments. Ischemia lasted 80 min at 30 °C. Melatonin was given before ischemia (UI80 + M1, HTK80 + M1) or before and after ischemia (UI80 + M2, HTK80 + M2). We measured the left ventricular developed pressure (LVDP), diastolic pressure (LVPmin), cardiac rhythm (VC-RR), time of electrical cell uncoupling (t-in) and recovery (t-ret), intracellular Ca++ [Ca++], and postischemic ROS. After 45 min reperfusion, LVDP in UI80 was significantly higher than in HTK80 (p <.01). Compared to UI80, the postischemic ROS burst was slightly smaller in HTK80 and significantly smaller in HTK80 + M1 and HTK80 + M2 (p <.05). Melatonin had no effect on LVPmin, t-in, t-ret, [Ca++], and on LVDP in groups UI80 + M1 and HTK80 + M1, improved slightly VC-RR (n. s.) but significantly decreased LVDP in the groups UI80 + M2 and HTK80 + M2 (p <.01). With melatonin we were able to attenuate the postischemic ROS burst, but the tissue damage by ROS seemed to be less important for the chosen ischemia condition because melatonin was unable to improve the functional recovery during reperfusion of HTK protected hearts. • Regardless of protection, melatonin attenuates the ROS burst during reperfusion. • The attenuation of the ROS burst was strongest after melatonin combined with HTK. • Even with HTK protection melatonin did not improve postischemic heart function. [ABSTRACT FROM AUTHOR]

Ag2S nanodots have already been demonstrated as promising near-infrared (NIR-II, 1.0–1.45 μm) emitting nanoprobes with low toxicity, high penetration and high resolution for in vivo imaging of, for example, tumors and vasculature. In this work, we have systematically investigated the potential application of functionalized Ag2S nanodots for accurate imaging of damaged myocardium tissues after a myocardial infarction induced by either partial or global ischemia. Ag2S nanodots surface-functionalized with the angiotensin II peptide (ATII) have shown over 10-fold enhanced binding efficiency to damaged tissues than non-specifically (PEG) functionalized Ag2S nanodots due to their interaction with the upregulated angiotensin II receptor type I (AT1R). It is demonstrated how the NIR-II images generated by ATII-functionalized Ag2S nanodots contain valuable information about the location and extension of damaged tissue in the myocardium allowing for a proper identification of the occluded artery as well as an indirect evaluation of the damage level. The potential application of Ag2S nanodots in the near future for in vivo imaging of myocardial infarction was also corroborated by performing proof of concept whole body imaging experiments. [ABSTRACT FROM AUTHOR]

Described here is a study of transesophageal thermal ablation of isolated and perfused beating hearts and non-human primates. An endoscope integrating a transesophageal echocardiography probe and a high-intensity focused ultrasound transducer was built and tested on five Langendorff-isolated hearts and three 30-kg baboons. B-Mode ultrasound, passive elastography and magnetic resonance imaging were performed to monitor thermal lesions. In isolated hearts, continuous and gated sonication parameters were evaluated with acoustic intensities of 9-12 W/cm2. Sonication parameters of gated exposures with 12 W/cm2 acoustic intensity for 5 min consistently produced visible lesions in the ventricles of isolated hearts. In animals, left atria and ventricles were exposed to repeated continuous sonications (4-15 times for 16 s) at an acoustic intensity at the surface of the transducer of 9 W/cm2. Clinical states of the baboons during and after the treatment were good. One suspected lesion in the left ventricle could be evidenced by elastography, but was not confirmed by magnetic resonance imaging. The transesophageal procedure therefore has the potential to create thermal lesions in beating hearts and its safety in clinical practice seems promising. However, further technical exploration of the energy deposition in the target would be necessary before the next pre-clinical experiments. [ABSTRACT FROM AUTHOR]

Absorbance spectroscopy of intrinsic cardiac chromophores provides nondestructive assessment of cytosolic oxygenation and mitochondria redox state. Isolated perfused heart spectroscopy is usually conducted by collecting reflected light from the heart surface, which represents a combination of surface scattering events and light that traversed portions of the myocardium. Reflectance spectroscopy with complex surface scattering effects in the beating heart leads to difficulty in quantitating chromophore absorbance. In this study, surface scattering was minimized and transmural path length optimized by placing a light source within the left ventricular chamber while monitoring transmurally transmitted light at the epicardial surface. The customdesigned intrachamber light catheter was a flexible coaxial cable (2.42-Fr) terminated with an encapsulated side-firing LED of 1.8 x 0.8 mm, altogether similar in size to a Millar pressure catheter. The LED catheter had minimal impact on aortic flow and heart rate in Langendorff perfusion and did not impact stability of the left ventricule of the working heart. Changes in transmural absorbance spectra were deconvoluted using a library of chromophore reference spectra to quantify the relative contribution of specific chromophores to the changes in measured absorbance. This broad-band spectral deconvolution approach eliminated errors that may result from simple dualwavelength absorbance intensity. The myoglobin oxygenation level was only 82.2 ± 3.0%, whereas cytochrome c and cytochrome a + a3 were 13.3 ± 1.4% and 12.6 ± 2.2% reduced, respectively, in the Langendorff-perfused heart. The intracardiac illumination strategy permits transmural optical absorbance spectroscopy in perfused hearts, which provides a noninvasive real-time monitor of cytosolic oxygenation and mitochondria redox state. [ABSTRACT FROM AUTHOR]

Purpose: Sodium thiosulfate (STS) has of late been proven efficacious in models of urolithiasis and vascular calcification. However, its cardiovascular effects on ischemia reperfusion injury (IR) have not been revealed. Being an antioxidant and calcium chelator, it is assumed to play a vital role in IR as ROS production and calcium overload are major perpetrators of IR injury. Methods: The cardioprotective effect of STS was evaluated in vitro using H9C2 cardiomyocytes and in vivo using both isolated rat heart and intact left anterior descending artery (LAD) occlusion models of ischemia reperfusion injury. Finally, in silico tools were utilized to establish its possible mode of action. Myocardial injury markers and expression of apoptotic proteins were studied along with myocardial histopathology. Results: STS of 1 mM recovered H9C2 cells from glucose oxidase/catalase-induced apoptosis. The isolated rat heart treated with STS prior to IR injury improved its hemodynamics and reduced the infarct size to 9%. This was supported by the absence of derangement of cardiac fibers from H&E stained section of LAD-occluded rats. Plasma troponin levels decreased by 15% compared to IR and the myocardium showed diminished apoptotic proteins. An in silico docking analysis revealed higher binding affinity of STS for caspase-3 with a binding energy of − 60.523 kcal/mol for the complex. Conclusion: The effectiveness of STS as a cardioprotective agent is attributed to the reduction of apoptosis by binding to the active site of caspase-3 in silico, which was substantiated by the reduced expression of caspase-3 and poly ADP ribose polymerase levels. [ABSTRACT FROM AUTHOR]

Aim We studied whether available oxygen without induced mechanical stretch regulates the release of the biologically active B-type natriuretic peptide ( BNP) from Langendorff heart. Methods Rat hearts were isolated and perfused with a physiological Krebs-Henseleit solution at a constant hydrostatic pressure in Langendorff set-up. The basal O2 level of perfusate (24.4 ± 0.04 mg L−1) was gradually lowered to 3.0 ± 0.01 mg L−1 over 20 min using N2 gas ( n = 7). BNP and O2 level were measured from coronary flow. During control perfusions ( n = 5), the O2 concentration was kept at 26.6 ± 0.3 mg L−1. Results A low oxygen concentration in the perfusate was associated with a significant increase in BNP release ( F = 40.4, P < 0.001). Heart rate decreased when the oxygen concentration in the perfusate reached 9.1 ± 0.02 mg L−1 and continued to fall in lower oxygen concentrations ( F = 14.8 , P < 0.001). There was also a significant but inverse correlation between BNP and oxygen in the coronary flow ( R2 = 0.27, P < 0.001). Conclusion In the spontaneously beating Langendorff rat heart, a decreasing concentration of oxygen in the ingoing perfusion increased the secretion of BNP. The effect of oxygen was independent of mechanical stretch of the heart as it occurred even when the heart rate decreased but the pressure conditions remained constant. The difference in the oxygen capacitance of blood and Krebs-Henseleit solution appears to be a major factor affecting secretion of BNP, which is correlated with the oxygen tension of myocardial cells and affected both by the oxygen concentration and capacitance of solution perfusing the heart and by the coronary flow. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Tare M, Miller S, Wallace E, Sutherland A, Yawno T, Coleman H, Jenkin G, Parkington H. Glucocorticoid treatment does not alter early cardiac adaptations to growth restriction in preterm sheep fetuses. BJOG 2012;119:906-914. Objective To study the consequences of glucocorticoid treatment in fetal growth restriction (FGR) on cardiac function. Setting Laboratory. Sample Sheep. Methods Growth restriction was induced in sheep fetuses using single umbilical artery ligation (SUAL) on days 105-110 of gestation (term 147). Control fetuses were not ligated. Betamethasone (BM) (11.4 mg intramuscularly) or saline was administered to ewes on days 5 and 6 after surgery. Ewes were anaesthetised on day 7, the fetuses were removed, and their hearts were mounted on a Langendorff apparatus. Balloon catheters were inserted into the right and left ventricles. Outcome measures Ventricular contractile function and infarct area following ischaemia/reperfusion. Results The SUAL resulted in FGR (body weight 77% of control). The FGR was associated with increases in basal left ventricular pressure development and rates of contraction and relaxation. Right ventricular contraction was unaffected. Following brief ischaemia/reperfusion, the infarct area in FGR hearts was increased four-fold compared with controls. Antenatal BM resulted in a proportional increase in heart size and coronary flow, especially in FGR fetuses, and left ventricular pressure and heart rate responses to β-adrenoceptor activation were increased. Conclusions Fetal hearts rapidly adapt to FGR to maintain substrate delivery to the brain and heart. The FGR greatly enhanced the area of ischaemia, with implications for susceptibility in postnatal life. Antenatal BM treatment does not interfere with these cardiac changes but appears to increase left ventricle β-adrenoceptor responsiveness, which may render the offspring vulnerable to subsequent cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: The heart receives both a left and right sympathetic innervation. Currently there is no description of an in vitro whole heart preparation for comparing the influence of each sympathetic supply on cardiac function. The aim was to establish the viability of using an in vitro model to investigate the effects of left and right sympathetic chain stimulation (LSS/RSS). For this purpose the upper sympathetic chain on each side was isolated and bipolar stimulating electrodes were attached between T2–T3 and electrically insulated from surrounding tissue in a Langendorff innervated rabbit heart preparation (n=8). Heart rate (HR) was investigated during sinus rhythm, whilst dromotropic, inotropic and ventricular electrophysiological effects were measured during constant pacing (250bpm). All responses exhibited linear increases with increases in stimulation frequency (2–10Hz). The change in HR was larger during RSS than LSS (P<0.01), increasing by 78±9bpm and 49±8bpm respectively (10Hz, baseline; 145±7bpm). Left ventricular pressure was increased from a baseline of 50±4mmHg, by 22±5mmHg (LSS, 10Hz) and 4±1mmHg (RSS, 10Hz) respectively (P<0.001). LSS, but not RSS, caused a shortening of basal and apical monophasic action potential duration (MAPD90). We demonstrate that RSS exerts a greater effect at the sinoatrial node and LSS at the left ventricle. The study confirms previous experiments on dogs and cats, provides quantitative data on the comparative influence of right and left sympathetic nerves and demonstrates the feasibility of isolating and stimulating the ipsilateral cardiac sympathetic supply in an in vitro innervated rabbit heart preparation. [Copyright &y& Elsevier]

Although angiotensin II (Ang II) plays an important role in heart disease associated with pump dysfunction, its direct effects on cardiac pump function remain controversial. We found that after Ang II infusion, the developed pressure and +dP/dt(max) in isolated Langendorff-perfused mouse hearts showed a complex temporal response, with a rapid transient decrease followed by an increase above baseline. Similar time-dependent changes in cell shortening and L-type Ca(2+) currents were observed in isolated ventricular myocytes. Previous studies have established that Ang II signaling involves phosphoinositide 3-kinases (PI3K). Dominant-negative inhibition of PI3Kalpha in the myocardium selectively eliminated the rapid negative inotropic action of Ang II (inhibited by approximately 90%), whereas the loss of PI3Kgamma had no effect on the response to Ang II. Consistent with a link between PI3Kalpha and protein kinase C (PKC), PKC inhibition (with GF 109203X) reduced the negative inotropic effects of Ang II by approximately 50%. Although PI3Kalpha and PKC activities are associated with glycogen synthase kinase-3beta and NADPH oxidase, genetic ablation of either glycogen synthase kinase-3beta or p47(phox) (an essential subunit of NOX2-NADPH oxidase) had no effect on the inotropic actions of Ang II. Our results establish that Ang II has complex temporal effects on contractility and L-type Ca(2+) channels in normal mouse myocardium, with the negative inotropic effects requiring PI3Kalpha and PKC activities. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Cardiac liabilities represent a major cause of recent withdrawal of marketed drugs and also for the high attrition rate evidenced during late stage drug development. To identify molecules with potential cardiovascular risks early in drug development, a screening model of ex vivo Langendorff hearts has been validated with 26 reference compounds of various chemical and therapeutic classes. Methods: The hearts of adult guinea pigs were maintained by retrograde perfusion in Langendorff mode, beating spontaneously at sinus rhythm or paced via the right atrium at 200 and 300 beats per minute. Multiple parameters consisting of hemodynamic function (coronary and left ventricle pressure), cardiac electrophysiology (electrocardiogram and monophasic action potential) and indices of arrhythmogenesis (triangulation, reverse-use dependence, repolarization dispersion and beat-to-beat instability), together with overt arrhythmia were evaluated simultaneously. Ascending concentrations up to either 100-fold of the determined hERG IC50 or nominally 100 µM were routinely tested utilizing 4–6 hearts per compound. Results: Each compound exhibited a unique cardiovascular profile: (i) the majority displayed concentration and heart rate-dependent mixed-ion channel or multiple-target effects that frequently resulted in bradycardia, atrioventricular block, negative inotropy, coronary vasodilatation, and QRS widening. (ii) Compounds associated with high arrhythmogenic risk in the clinic exhibited more “positive signals” at concentrations within 30-fold of their maximal therapeutic free plasma concentration than those with less arrhythmogenic potential. (iii) For several potent torsadogens, proarrhythmic indices other than the prolongation of QT/QTc and MAP duration appeared more sensitive in representing proarrhythmic liability. (iv) A scoring system was developed to assist in the rank-ordering of potential cardiotoxicants. Discussion: The cardiovascular action of reference compounds profiled by this isolated heart model was generally consistent with their known mechanisms and, except for the sinus heart rate, correlated well with that observed in the clinic. Further, the overall cardiac liability estimated by the scoring system matched the clinical documentation, suggesting this model could serve as a valuable tool in early cardiovascular drug safety assessment. [Copyright &y& Elsevier]

Abstract: Objective: Due to limited resources, improvement of preservation solutions is still of great importance in cardiac transplant surgery. New additives with antioxidant properties were tested with respect to coronary function of isolated rat hearts. Methods: Bretschneider HTK solution containing none or an antioxidant additive (deferoxamine, trolox or LK 616) was used for 8h cold cardioplegia. After reperfusion with Krebs-Henseleit buffer (KHB), we assessed vascular dilator capacity (bradykinin, adenosine triphosphate, reactive hyperemia), myocardial function (left ventricular developed pressure, heart rate, oxygen consumption) and release of biochemical markers (aspartate aminotransferase, creatine kinase, lactate dehydrogenase, troponin, adenosine). Results: Bradykinin- and adenosine triphosphate-induced vasodilations were largely reduced in hearts stored 8h in traditional HTK as compared to unstored controls. Storage in HTK+LK 616 significantly improved bradykinin-induced vasodilation. Vasodilation toward ATP was best preserved in hearts stored in HTK+deferoxamine. Deferoxamine and trolox, both improved reactive hyperaemic response during reperfusion. Left ventricular pressure development was significantly reduced after 8h cardioplegia, but no difference existed between different cardioplegia groups. Release of biochemical markers of tissue injury was similar in all cardioplegia groups. After storage in HTK+LK 616 (100μM), however, heart marker release was slightly augmented as compared to HTK. Conclusions: Despite similar myocardial function and marker release, coronary vascular function after cardioplegic storage may profit by addition of iron chelators (or antioxidants) to traditional HTK solution. [Copyright &y& Elsevier]

Abstract: The recovery (%) of the left ventricular developed pressure by (S)-(−)-pyrapyridolol (5×10−8 M) (90.7%), an optical isomer of a new 5-HT1A receptor antagonist, was greater than that by (R)-(+)-pyrapyridolol (66.2%, control: 34.4%) against ischemia–reperfusion injury in perfused Langendorff guinea-pig hearts. In the perfused mitochondrial preparation, (S)-(−)-pyrapyridolol inhibited the mitochondrial Ca2+ (Cam) elevation that was brought about by the change of Ca2+ content or pH of perfusate, similar to findings with cyclosporin A, well known to be an inhibitor of the mitochondrial permeability transition pore (MPTP). The mitochondrial KATP channel opener, diazoxide, also inhibited the Cam elevation, but the mitochondrial KATP channel antagonist, 5-hydroxydecanoic acid, attenuated it. There were significantly fewer numbers of TUNEL-positive cells in these (S)-(−)-pyrapyridolol-treated hearts than the control or (R)-(+)-pyrapyridolol, with decreases of the caspase-3 activity. Therefore, these results suggest that (S)-(−)-pyrapyridolol likely inhibits the opening of the MPTP by preventing the Cam overload induced apoptosis related to endogenous 5-HT accumulation in ischemia–reperfusion hearts. [Copyright &y& Elsevier]

Abstract: Both mechanical induction and mechanical termination of arrhythmias have been reported in man. Examples include pre-cordial impacts by sports implements (baseballs, pucks) that can trigger arrhythmias, including ventricular fibrillation, or via the so-called pre-cordial thump, used as an emergency resuscitation measure to convert arrhythmias to normal sinus node rhythm. These interventions have been partially reproduced in experimental studies on whole animals. Relating observations at the system''s level to underlying mechanisms has been difficult, however, largely because of: (i) a deficit in efficient and affordable pharmacological agents to selectively target (sub-)cellular responses in whole animal studies, and (ii) the lack of suitable experimental models to study the above responses at intermediate levels of functional and structural integration, such as the isolated heart or cardiac tissue. This paper presents a soft tissue impact characterisation kit (STICK), suitable for quantitative investigations into the effects of acute mechanical stimulation on cardiac electro-mechanical function in rodent isolated heart or tissue preparations. The STICK offers independent control over a range of relevant biophysical parameters, such as impact location and energy, pre-impact projectile speed and contact area, as well as over the timing of a mechanical stimulus relative to the cardiac cycle (monitored via electrocardiogram, ECG, here recorded directly from the cardiac surface). Projectile deceleration upon interaction with the tissue is monitored, contact-free, with a resolution of 175μm, providing information on tissue deformation dynamics, force, pressure and work of the mechanical intervention. In order to study functional effects of cardiac mechanical stimulation in the absence of tissue damage, impacts must be limited (for juvenile Guinea pig heart) to 2–2.5mJ in the slack left ventricle (diastolic impact) and 5–10mJ in contracture (systolic impact), as confirmed by enzyme assay and histological investigation. Impacts, timed to coincide with the early T-wave of the ECG, are capable of triggering short runs of ventricular fibrillation. Thus, the STICK is a suitable tool for the study of acute cardiac mechano-electric feedback effects, caused by short impulse-like mechanical stimulation, at the level of the isolated organ or tissue. [Copyright &y& Elsevier]

Mineralocorticoid receptor (MR) antagonism with spironolactone reduces mortality in heart failure on top of ACE inhibition. To investigate the underlying mechanism, we compared the actions of both aldosterone and spironolactone to those of angiotensin (Ang) II in the rat heart.Hearts of male Wistar rats were perfused according to Langendorff. Ang II and aldosterone increased left ventricular pressure (LVP) by maximally 11±4 and 9±2%, and decreased coronary flow (CF) by maximally 36±7 and 20±4%, respectively. Spironolactone did not significantly affect LVP or CF.In hearts that were exposed to a 45-min coronary artery occlusion and 3 h of reperfusion, a 15-min exposure to spironolactone prior to occlusion reduced infarct size (% of risk area) from 68±2 to 45±3%, similar to the reduction (34±2%) observed following ‘preconditioning’ (15 min occlusion followed by 10 min reperfusion) prior to the 45-min occlusion. Aldosterone exposure did not affect infarct size (71±5%).In cardiomyocytes, aldosterone decreased [3H]thymidine incorporation maximally by 73±3%, whereas in cardiac fibroblasts it decreased [3H]proline incorporation by 33±7%. Spironolactone inhibited both effects. Ang II increased DNA and collagen synthesis, and these effects were reversed by aldosterone.In conclusion, aldosterone induces positive inotropic and vasoconstrictor effects in a nongenomic manner, and these effects are comparable to those of Ang II. Aldosterone reduces DNA and collagen synthesis via MR activation, and counteracts the Ang II-induced increases in these parameters. MR blockade reduces infarct size and increases LVP recovery following coronary artery occlusion. The MR-related phenomena may underlie, at least in part, the beneficial actions of spironolactone in heart failure.British Journal of Pharmacology (2005) 145, 664–671. doi:10.1038/sj.bjp.0706220 Published online 18 April 2005 [ABSTRACT FROM AUTHOR]

Given the importance of lipoprotein lipase (LPL) in cardiac and vascular pathology, the objective of the present study was to investigate whether the β-agonist isoproterenol (Iso) influences cardiac LPL. Incubation of quiescent cardiomyocytes with Iso for 60 mm had no effect on basal, intracellular, or heparin-releasable (HR)-LPL activity. Similarly, iso did not change HR-LPL in Langendorff isolated hearts that do not beat against an afterload. in the intact animal, LPL activity at the vascular lumen increased significantly in the Iso- treated group, together with a substantial increase in rate-pressure product. This LPL increase was likely via mechanisms regulated by activation of AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase (ACC280). In glucose-perfused hearts, simply switching from Langendorff to the isolated working heart (that beats against an afterload) induced increases in AMPK and ACC280 phosphorylation and enhanced HR-LPL activity. Pro- vision of insulin and albumin-bound palmitic acid to the working heart was able to reverse these effects. In these hearts, introduction of Iso to the buffer perfusate duplicated the effects seen when this β-agonist was given in vivo. Our data suggest that Iso can influence HR-LPL only during conditions of increased workload, mechanical performance and excessive energy expenditure, and likely in an AMPK-dependent manner. [ABSTRACT FROM AUTHOR]