Search Results (7)

Aim: Cardiac arrhythmias are among the most important pathologies that cause sudden death. The exploration of new therapeutic options against arrhythmias with low undesirable effects is of paramount importance. Methods: However, the convenient and typical animal model for screening the potential lead compound becomes a very critical modality, particularly in anti-arrhythmia. In this study, mice were intraperitoneally (i.p.) injected with BaCl₂, CaCl₂, and adrenaline to induce arrhythmia, and simultaneously compared with BaCl₂-induced rats. Results: Electrocardiogram (ECG) showed that the majority of mice repeatedly developed ventricular bigeminy, ventricular tachycardia (VT), and ventricular fibrillation (VF) after BaCl₂-injection as seen in rats. The ECG of mice developed ventricular bigeminy and VT after CaCl₂ and AT after adrenaline i.p. injection. Additionally, acute cardiac arrhythmia after BaCl₂ i.p. injection could be reverted by drugs (lidocaine and amiodarone) administration. Additionally, the different routes of administration for various chemical-induced arrhythmia in both mice and rats were also retrieved from PubMed and summarized. Comparing this approach with previous studies after the literature review reveals that arrhythmia of BaCl₂-induced i.p. mice is compatible with the induction of other routes. Conclusions: This study brings an alternative experimental model to investigate antiarrhythmic theories and provides a promising approach to discovering new interventions for acute arrhythmias. Full article

Cardiovascular diseases remain one of the leading causes of death worldwide. Unfortunately, the available pharmacotherapeutic options have limited effectiveness. Therefore, developing new drug candidates remains very important. We selected six novel arylpiperazine alkyl derivatives of salicylamide to investigate their cardiovascular effects. Having in mind the beneficial role of α₁-adrenergic receptors in restoring sinus rhythm and regulating blood pressure, first, using radioligand binding assays, we evaluated the affinity of the tested compounds for α-adrenergic receptors. Our experiments revealed their high to moderate affinity for α₁- but not α₂-adrenoceptors. Next, we aimed to determine the antiarrhythmic potential of novel derivatives in rat models of arrhythmia induced by adrenaline, calcium chloride, or aconitine. All compounds showed potent prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia model and no effects in calcium chloride- or aconitine-induced arrhythmias. Moreover, the tested compounds demonstrated therapeutic antiarrhythmic activity, restoring a normal sinus rhythm immediately after the administration of the arrhythmogen adrenaline. Notably, none of the tested derivatives affected the normal electrocardiogram (ECG) parameters in rodents, which excludes their proarrhythmic potential. Finally, all tested compounds decreased blood pressure in normotensive rats and reversed the pressor response to methoxamine, suggesting that their hypotensive mechanism of action is connected with the blockade of α₁-adrenoceptors. Our results confirm the antiarrhythmic and hypotensive activities of novel arylpiperazine derivatives and encourage their further investigation as model structures for potential drugs. Full article

Arrhythmia, an irregular heartbeat, might be a life-threatening condition but also a risk factor for stroke or worsen the prognosis after myocardial infarction. The limited efficacy and proarrhythmic potential of the available drugs require searching for new, more effective, and safer pharmacotherapies. Studies indicate that the blockade of α₁-adrenoceptors could be effective in treating heart rhythm abnormalities. In this study, we aimed to assess the antiarrhythmic and hypotensive potential of HBK-10, a novel 2-methoxyphenylpiperazine derivative, as well as its binding to the selected adrenergic receptors. Radioligand binding studies demonstrated that HBK-10 showed a high affinity for α₁ but not for α₂ or β₁ receptors. Next, we evaluated the ability of HBK-10 to protect against an adrenaline-induced arrhythmia in rats. The compound showed potent prophylactic antiarrhythmic properties in this arrhythmia model. Notably, the compound did not show proarrhythmic potential in normotensive rats since it did not influence the ECG parameters at antiarrhythmic doses. Finally, the compound showed hypotensive properties in rats, which were not observed after coadministration with adrenaline, noradrenaline, or methoxamine, which suggests α₁-adrenolytic properties of HBK-10. Our results confirm that compounds with a 2-methoxyphenylpiperazine group show a high affinity for α₁-adrenoceptors and a significant antiarrhythmic effect. Given the promising results of our study, further evaluation of HBK-10 is necessary to unravel the mechanisms behind its pharmacological effects and evaluate the safety profile. Full article

Heart rhythm abnormalities are a cause of many deaths worldwide. Unfortunately, the available antiarrhythmic drugs show limited efficacy and proarrhythmic potential. Thus, efforts should be made to search for new, more effective, and safer pharmacotherapies. Several studies suggested that blocking the α₁-adrenoceptors could restore normal heart rhythm in arrhythmia. In this study, we aimed to assess the antiarrhythmic potential of S-61 and S-73, two novel pyrrolidin-2-one derivatives with high affinity for α₁-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with β₁-adrenoceptors. Next, we assessed whether S-61 and S-73 could protect rats against arrhythmia in adrenaline-, calcium chloride- and aconitine-induced arrhythmia models. Both compounds showed potent prophylactic antiarrhythmic properties in the adrenaline-induced arrhythmia model, but the effect of S-61 was more pronounced. None of the compounds displayed antiarrhythmic effects in calcium chloride- or aconitine-induced arrhythmia models. Interestingly, both derivatives revealed therapeutic antiarrhythmic activity in the adrenaline-induced arrhythmia, diminishing heart rhythm irregularities. Neither S-61 nor S-73 showed proarrhythmic potential in rats. Finally, the compounds decreased blood pressure in rodents. The hypotensive effects were not observed after coadministration with methoxamine, which suggests the α₁-adrenolytic properties of both compounds. Our results confirm that pyrrolidin-2-one derivatives possess potent antiarrhythmic properties. Given the promising results of our experiments, further studies on pyrrolidin-2-one derivatives might result in the development of a new class of antiarrhythmic drugs. Full article

Arrhythmia is a quivering or irregular heartbeat that can often lead to blood clots, stroke, heart failure, and other heart-related complications. The limited efficacy and safety of antiarrhythmic drugs require the design of new compounds. Previous research indicated that pyrrolidin-2-one derivatives possess an affinity for α₁-adrenergic receptors. The blockade of α₁-adrenoceptor may play a role in restoring normal sinus rhythm; therefore, we aimed to verify the antiarrhythmic activity of novel pyrrolidin-2-one derivative S-75. In this study, we assessed the influence on sodium, calcium, potassium channels, and β₁-adrenergic receptors to investigate the mechanism of action of S-75. Lack of affinity for β₁-adrenoceptors and weak effects on ion channels decreased the role of these adrenoceptors and channels in the pharmacological activity of S-75. Next, we evaluated the influence of S-75 on normal ECG in rats and isolated rat hearts, and the tested derivative did not prolong the QT_c interval, which may confirm the lack of the proarrhythmic potential. We tested antiarrhythmic activity in adrenaline-, aconitine- and calcium chloride-induced arrhythmia models in rats. The studied compound showed prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia, but no significant activity in the model of aconitine- or calcium chloride-induced arrhythmia. In addition, S-75 was not active in the model of post-reperfusion arrhythmias of the isolated rat hearts. Conversely, the compound showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia, reducing post-arrhythmogen heart rhythm disorders, and decreasing animal mortality. Thus, we suggest that the blockade of α₁-adrenoceptor might be beneficial in restoring normal heart rhythm in adrenaline-induced arrhythmia. Full article

Mutations in the HERG gene encoding the potassium ion channel HERG, represent one of the most frequent causes of long QT syndrome type-2 (LQT2). The same genetic mutation frequently presents different clinical phenotypes in the family. Our study aimed to model LQT2 and study functional differences between the mutation carriers of variable clinical phenotypes. We derived human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from asymptomatic and symptomatic HERG mutation carriers from the same family. When comparing asymptomatic and symptomatic single LQT2 hiPSC-CMs, results from allelic imbalance, potassium current density, and arrhythmicity on adrenaline exposure were similar, but a difference in Ca²⁺ transients was observed. The major differences were, however, observed at aggregate level with increased susceptibility to arrhythmias on exposure to adrenaline or potassium channel blockers on CM aggregates derived from the symptomatic individual. The effect of this mutation was modeled in-silico which indicated the reactivation of an inward calcium current as one of the main causes of arrhythmia. Our in-vitro hiPSC-CM model recapitulated major phenotype characteristics observed in LQT2 mutation carriers and strong phenotype differences between LQT2 asymptomatic vs. symptomatic were revealed at CM-aggregate level. Full article

Torsades de pointes is a life-threatening cardiac arrhythmia. Occurrence of this arrhythmia as a result of hypoglycemia has not been reported in the literature. We describe an interesting case of an insulindependent diabetic patient presenting with torsades de pointes resulting from hypoglycemia. A 62-year-old male was admitted to the hospital following an episode of severe insulin-induced hypoglycemia and a cardiac arrest. He was found to unresponsive at home after taking insulin. His serum glucose was found to be 18. He was given juice initially to normalize his glucose and was then transferred by EMS to ER where he was given 5% dextrose infusion. Analysis of the LifeVest rhythm recording showed torsades de pointes that was terminated by defibrillation of the LifeVest. Several mechanisms are responsible for torsade, including QT interval prolongation, adrenalin secretion and calcium overload leading to intracellular calcium oscillations. These mechanisms are a trigger to torsade de pointes. Predisposing factors were present leading torsade to occur. Full article