Search Results (10)

The developmental changes in the excitation–contraction mechanisms of the ventricular myocardium of small animals (guinea pig, rat, mouse) and their sympathetic regulation will be summarized. The action potential duration monotonically decreases during pre- and postnatal development in the rat and mouse, while in the guinea pig it decreases during the fetal stage but turns into an increase just before birth. Such changes can be attributed to changes in the repolarizing potassium currents. The T-tubule and the sarcoplasmic reticulum are scarcely present in the fetal cardiomyocyte, but increase during postnatal development. This causes a developmental shift in the Ca²⁺ handling from a sarcolemma-dependent mechanism to a sarcoplasmic reticulum-dependent mechanism. The sensitivity for beta-adrenoceptor-mediated positive inotropy decreases during early postnatal development, which parallels the increase in sympathetic nerve innervation. The alpha-adrenoceptor-mediated inotropy in the mouse changes from positive in the neonate to negative in the adult. This can be explained by the change in the excitation–contraction mechanism mentioned above. The shortening of the action potential duration enhances trans-sarcolemmal Ca²⁺ extrusion by the Na⁺-Ca²⁺ exchanger. The sarcoplasmic reticulum-dependent mechanism of contraction in the adult allows Na⁺-Ca²⁺ exchanger activity to cause negative inotropy, a mechanism not observed in neonatal myocardium. Such developmental studies would provide clues towards a more comprehensive understanding of cardiac function. Full article

Maternal nutritional status represents a pivotal predictor of pregnancy outcome. This prospective observational study investigates the associations between maternal characteristics and nutritional habits at term, hemodynamic parameters, and pregnancy outcomes. Healthy women with singleton uncomplicated pregnancies were enrolled at 36–41 gestational weeks. At enrollment, a nutritional score (0–10) was calculated in order to quantify maternal adherence to a healthy diet and lifestyle. Maternal hemodynamic parameters were assessed by using the Ultrasonic Cardiac Output Monitor (USCOM), including cardiac output (CO), systemic vascular resistance (SVR) and Smith–Madigan inotropy index (SMII). Pregnancy outcomes were recorded at delivery. Associations between maternal characteristics and nutritional score, hemodynamic parameters, and pregnancy outcomes were investigated by using multi-adjusted generalized linear models. In total, 143 pregnancies were enrolled. Pregestational body mass index (BMI) was positively associated with SVR, and negatively associated with CO and SMII. Additionally, a positive association was detected between the nutritional score and SMII. Finally, CO was positively associated with birth and placental weight, while RVS showed a negative association with birth and placental weight. This study shows that maternal derangements in nutritional status and habits are associated with a compromised hemodynamic profile at term, with additional impacts on intrauterine growth. Full article

Mechanisms for the α-adrenoceptor-mediated positive inotropy in neonatal mouse ventricular myocardium were studied with isolated myocardial preparations. The phenylephrine-induced positive inotropy was suppressed by prazosin, nifedipine, and chelerythrine, a protein kinase C inhibitor, but not by SEA0400, a selective Na⁺/Ca²⁺ exchanger inhibitor. Phenylephrine increased the L-type Ca²⁺ channel current and prolonged the action potential duration, while the voltage-dependent K⁺ channel current was not influenced. In the presence of cromakalim, an ATP-sensitive K⁺ channel opener, the phenylephrine-induced prolongation of action potential duration, as well as the positive inotropy, were smaller than in the absence of cromakalim. These results suggest that the α-adrenoceptor-mediated positive inotropy is mediated by an increase in Ca²⁺ influx through the L-type Ca²⁺ channel, and the concomitant increase in action potential duration acts as an enhancing factor. Full article

Recent cardiotropic drug developments have focused on cardiac myofilaments. Danicamtiv, the second direct myosin activator, has achieved encouraging results in preclinical and clinical studies, thus implicating its potential applicability in the treatment of heart failure with reduced ejection fraction (HFrEF). Here, we analyzed the inotropic effects of danicamtiv in detail. To this end, changes in sarcomere length and intracellular Ca²⁺ levels were monitored in parallel, in enzymatically isolated canine cardiomyocytes, and detailed echocardiographic examinations were performed in anesthetized rats in the absence or presence of danicamtiv. The systolic and diastolic sarcomere lengths decreased; contraction and relaxation kinetics slowed down with increasing danicamtiv concentrations without changes in intracellular Ca²⁺ transients in vitro. Danicamtiv evoked remarkable increases in left ventricular ejection fraction and fractional shortening, also reflected by changes in systolic strain. Nevertheless, the systolic ejection time was significantly prolonged, the ratio of diastolic to systolic duration was reduced, and signs of diastolic dysfunction were also observed upon danicamtiv treatment in vivo. Taken together, danicamtiv improves cardiac systolic function, but it can also limit diastolic performance, especially at high drug concentrations. Full article

Heart failure (HF) carries the highest mortality in the western world and β-blockers [β-adrenergic receptor (AR) antagonists] are part of the cornerstone pharmacotherapy for post-myocardial infarction (MI) chronic HF. Cardiac β₁AR-activated βarrestin2, a G protein-coupled receptor (GPCR) adapter protein, promotes Sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA)2a SUMO (small ubiquitin-like modifier)-ylation and activity, thereby directly increasing cardiac contractility. Given that certain β-blockers, such as carvedilol and metoprolol, can activate βarrestins and/or SERCA2a in the heart, we investigated the effects of these two agents on cardiac βarrestin2-dependent SERCA2a SUMOylation and activity. We found that carvedilol, but not metoprolol, acutely induces βarrestin2 interaction with SERCA2a in H9c2 cardiomyocytes and in neonatal rat ventricular myocytes (NRVMs), resulting in enhanced SERCA2a SUMOylation. However, this translates into enhanced SERCA2a activity only in the presence of the β₂AR-selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of carvedilol-occupied β₂AR subtype on carvedilol-occupied β₁AR-stimulated, βarrestin2-dependent SERCA2a activation. In addition, the amplitude of fractional shortening of NRVMs, transfected to overexpress βarrestin2, is acutely enhanced by carvedilol, again in the presence of ICI only. In contrast, metoprolol was without effect on NRVMs’ shortening amplitude irrespective of ICI co-treatment. Importantly, the pro-contractile effect of carvedilol was also observed in human induced pluripotent stem cell (hIPSC)-derived cardiac myocytes (CMs) overexpressing βarrestin2, and, in fact, it was present even without concomitant ICI treatment of human CMs. Metoprolol with or without concomitant ICI did not affect contractility of human CMs, either. In conclusion, carvedilol, but not metoprolol, stimulates βarrestin2-mediated SERCA2a SUMOylation and activity through the β₁AR in cardiac myocytes, translating into direct positive inotropy. However, this unique βarrestin2-dependent pro-contractile effect of carvedilol may be opposed or masked by carvedilol-bound β₂AR subtype signaling. Full article

Bufalin and other cardiac steroids (CS) have been used for centuries for the treatment of congestive heart failure, arrhythmias, and other maladies. However, toxicity and the small therapeutic window of this family of steroids limit their use. Therefore, attempts to synthesize a potent, but less toxic, CS are of major importance. In the present study, two novel bufalin derivatives were synthesized and some of their pharmacological properties were characterized. The reaction of bufalin with Ishikawa’s reagent resulted in the production of two novel bufalin derivatives: bufalin 2,3-ene and bufalin 3,4-ene. The compounds were purified with TLC and HPLC and their structure was verified with UV, NMR, and MS analyses. The biological activities of these compounds were evaluated by testing their ability to inhibit the Na⁺, K⁺-ATPase activity of the brain microsomal fraction to induce cytotoxic activity against the NCI-60 human tumor cell line panel and non-cancer human cells, and to increase the force of contraction of quail embryonic heart muscle cells in culture. The two steroids exhibited biological activities similar to those of other CS in the tested experimental systems, but with reduced cytotoxicity, advocating their development as drugs for the treatment of heart failure and arrhythmias. Full article

Angiotensin II (Ang II) has various cardiac effects and causes vasoconstriction. Ang II activates the type-1 angiotensin receptor—G_q/11 signaling pathway resulting in the release of 2-arachidonoylglycerol (2-AG). We aimed to investigate whether cardiac Ang II effects are modulated by 2-AG-release and to identify the role of type-1 cannabinoid receptors (CB₁R) in these effects. Expression of CB₁R in rat cardiac tissue was confirmed by immunohistochemistry. To characterize short-term Ang II effects, increasing concentrations of Ang II (10⁻⁹–10⁻⁷ M); whereas to assess tachyphylaxis, repeated infusions of Ang II (10⁻⁷ M) were administered to isolated Langendorff-perfused rat hearts. Ang II infusions caused a decrease in coronary flow and ventricular inotropy, which was more pronounced during the first administration. CB agonist 2-AG and WIN55,212-2 administration to the perfusate enhanced coronary flow. The flow-reducing effect of Ang II was moderated in the presence of CB₁R blocker O2050 and diacylglycerol-lipase inhibitor Orlistat. Our findings indicate that Ang II-induced cardiac effects are modulated by simultaneous CB₁R-activation, most likely due to 2-AG-release during Ang II signalling. In this combined effect, the response to 2-AG via cardiac CB₁R may counteract the positive inotropic effect of Ang II, which may decrease metabolic demand and augment Ang II-induced coronary vasoconstriction. Full article

Diabetes is a chronic, endocrine disorder that effects millions of people worldwide. Cardiovascular complications are the major cause of diabetes-related morbidity and mortality. Cardiac β₁- and β₂-adrenoceptor (AR) stimulation mediates positive inotropy and chronotropy, whereas β₃-AR mediates negative inotropic effect. Changes in β-AR responsiveness are thought to be an important factor that contributes to the diabetic cardiac dysfunction. Diabetes related changes in β-AR expression, signaling, and β-AR mediated cardiac function have been studied by several investigators for many years. In the present review, we have screened PubMed database to obtain relevant articles on this topic. Our search has ended up with wide range of different findings about the effect of diabetes on β-AR mediated changes both in molecular and functional level. Considering these inconsistent findings, the effect of diabetes on cardiac β-AR still remains to be clarified. Full article

As a follow-up to our previous studies on differently substituted 1,4-dihydropyridines endowed with a peculiar cardiac selectivity, in this paper, a small series of hybrid compounds bearing the pharmacophore fragment of lidoflazine in position 2 or 3 on a 4-(xanthen-9-one)-dihydropyridine core was reported. Lidoflazine was selected due to our promising previously reported data, and the xanthen-9-one substituent was introduced in position 4 of the dihydropyridine scaffold based on the cardiac selectivity observed in several of our studies. The new hybrid compounds were tested to assess cardiac and vascular activities, and the data were evaluated in comparison with those previously obtained for 4-(xanthen-9-one)-dihydropyridines and lidoflazine–nifedipine hybrid compounds. The functional studies indicated an interesting peculiar selectivity for the cardiac parameter inotropy, in particular when the lidoflazine fragment was introduced in position 2 of the dihydropyridine scaffold (4a–e), and thus a possible preferential binding with the Ca_v 1.2 isoform of l-type calcium channels, which are mainly involved in cardiac contractility. Full article

As a result of the ring-into-ring conversion of nitrosoimidazole derivatives, we obtained a molecular scaffold that, when properly decorated, is able to decrease inotropy by blocking L-type calcium channels. Previously, we used this scaffold to develop a quantitative structure-activity relationship (QSAR) model, and we used the most potent oxadiazolothiazinone as a template for ligand-based virtual screening. Here, we enlarge the diversity of chemical decorations, present the synthesis and in vitro data for 11 new derivatives, and develop a new 3D-QSAR model with recent in silico techniques. We observed a key role played by the oxadiazolone moiety: given the presence of positively charged calcium ions in the transmembrane channel protein, we hypothesize the formation of a ternary complex between the oxadiazolothiazinone, the Ca²⁺ ion and the protein. We have supported this hypothesis by means of pharmacophore generation and through the docking of the pharmacophore into a homology model of the protein. We also studied with docking experiments the interaction with a homology model of P-glycoprotein, which is inhibited by this series of molecules, and provided further evidence toward the relevance of this scaffold in biological interactions. Full article