Tyrosine kinases inhibitors (TKIs) may alter glycaemia and may be cardiotoxic with importance in the diabetic heart. We investigated the effect of multi-TKI crizotinib after short-term administration on metabolic modulators of the heart of diabetic rats. Experimental diabetes mellitus (DM) was induced by streptozotocin (STZ; 80 mg·kg^–1, i.p.), and controls (C) received vehicle. Three days after STZ, crizotinib (STZ+CRI; 25 mg·kg^–1 per day p.o.) or vehicle was administered for 7 days. Blood glucose, C-peptide, and glucagon were assessed in plasma samples. Receptor tyrosine kinases (RTKs), cardiac glucose transporters, and peroxisome proliferator-activated receptors (PPARs) were determined in rat left ventricle by RT-qPCR method. Crizotinib moderately reduced blood glucose (by 25%, P < 0.05) when compared to STZ rats. The drug did not affect levels of C-peptide, an indicator of insulin secretion, suggesting altered tissue glucose utilization. Crizotinib had no impact on cardiac RTKs. However, an mRNA downregulation of insulin-dependent glucose transporter Glut4 in the hearts of STZ rats was attenuated after crizotinib treatment. Moreover, crizotinib normalized Ppard and reduced Pparg mRNA expression in diabetic hearts. Crizotinib decreased blood glucose independently of insulin and glucagon. This could be related to changes in regulators of cardiac metabolism such as GLUT4 and PPARs.

Semaglutide is a glucagon-like peptide 1 receptor (GLP-1R) agonist. GLP-1R agonists are used to treat type 2 diabetes and obesity. It is currently unknown whether semaglutide can directly increase force of contraction (FOC) in the human heart. We tested the hypothesis that semaglutide might increase the FOC in the isolated human atrium. To this end, we conducted contraction experiments in isolated human right atrial muscle preparations (HAP). HAP were obtained during open-heart surgery. We detected a concentration- and time-dependent positive inotropic effect (PIE) of semaglutide in HAP. These PIEs were accompanied by increases in the rates of tension development and tension relaxation and a reduction in muscle relaxation time. The PIE of semaglutide in HAP was attenuated by H89, an inhibitor of the cyclic AMP-dependent protein kinase and by ryanodine, an inhibitor of sarcoplasmic Ca²⁺ release. Semaglutide up to 100 nM failed to exert a PIE in isolated electrically paced (1 Hz) wild-type mouse left atrial preparations studied for comparison. Our data suggest that semaglutide can increase the FOC in the atria of patients at therapeutic drug concentrations.

There is controversy whether H₁-histamine receptors increase or decrease contractility in the mammalian heart. Therefore, we have generated mice that overexpress the human H₁-histamine receptor in the heart (H₁-TG). We hypothesized that histamine would either increase or decrease force of contraction and beating rate compared to littermate wild type mice (WT). In H₁-TG mice, we ascertained the presence of H₁-histamine receptors by autoradiography of atrium and ventricle using [³H]mepyramine. The messenger RNA for human H₁-histamine-receptors was present in cardiac samples from H₁-TG and absent from WT. Using in-situ-hybridization, we noted mRNA for the human H₁-histamine receptor in cardiomyocytes from H₁-TG. We noted that histamine (1 nM - 10 µM cumulatively applied) in electrically stimulated (1 Hz) left atrial preparations from H₁-TG, exerted at each concentration studied a transient negative inotropic effect followed by a positive inotropic effect. Likewise, in spontaneously beating left atrial preparations from H₁-TG, we noted a transient negative chronotropic effect, followed by a positive chronotropic effect of histamine. The negative inotropic and chronotropic and the positive inotropic effects in atrial preparations from H₁-TG were attenuated by the H₁-histamine receptor antagonist mepyramine. Neither a positive inotropic effect nor a negative chronotropic effect to histamine was discernable in atrial preparations from WT. We conclude that stimulation of H₁-histamine-receptors can decrease and then increase force of contraction in the mammalian heart and stimulation of H₁-histamine-receptors exerts a negative chronotropic effect. Significance Statement We have generated transgenic mice with cardiomyocyte-specific overexpression of the human H₁-histamine receptor to contribute to the clarification of the controversy whether H₁-histamine receptors increase or decrease contractility and beating rate in the mammalian heart. From our data, we conclude that stimulation of H₁-histamine-receptors first decrease and then increase force of contraction in the mammalian heart, but exert only a negative chronotropic effect. .

There is a controversy whether histamine H₁-receptor activation raises or lowers or does not affect contractility in the human heart. Therefore, we studied stimulation of H₁-receptors in isolated electrically stimulated (one beat per second) human atrial preparations (HAP). For comparison, we measured force of contraction in left atrial preparations (LA) from mice with overexpression of the histamine H₁-receptor in the heart (H₁-TG). We detected the messenger ribonucleic acid (mRNA) expression of human histamine H₁-receptors in HAP. In LA from H₁-TG, each cumulatively applied concentration of histamine and a dual H₁/H₂-agonist called 2-(2-thiazolyl)-ethylamine (ThEA) caused a time-dependent initial negative inotropic effect followed over time by a lasting positive inotropic effect. Both effects were concentration-dependent in LA from H₁-TG. After 100 µM cimetidine, 10 µM histamine exercised a positive inotropic effect in HAP that was diminished by 10 µM mepyramine, an H₁-receptor antagonist. The concentrations of mepyramine and cimetidine used here are based on the work of others and our own work (e.g., Guo et al. J Cardiovasc Pharmacol. 6:1210-5 1984, Rayo Abella et al. J Pharmacol Exp Ther. 389:174-185 2024). Similarly, we observed that ThEA (10 µM, 30 µM, 100 µM cumulatively applied) induced a concentration- and time-dependent positive inotropic effect in HAP. In HAP, we detected never negative inotropic effects to either histamine or ThEA. The positive inotropic effects to ThEA in HAP were reduced by mepyramine. The positive inotropic effects of ThEA in LA from H₁-TG and in HAP were not accompanied by reductions in the time of tension relaxation. We conclude that stimulation of histamine H₁-receptors only increases and does not decrease force of contraction in the HAP in our patients.

Dopamine can exert effects in the mammalian heart via five different dopamine receptors. There is controversy whether dopamine receptors increase contractility in the human heart. Therefore, we have generated mice that overexpress the human D₁-dopamine receptor in the heart (D₁-TG) and hypothesized that dopamine increases force of contraction and beating rate compared to wild-type mice (WT). In D₁-TG hearts, we ascertained the presence of D₁-dopamine receptors by autoradiography using [³H]SKF 38393. The mRNA for human D₁-dopamine receptors was present in D₁-TG hearts and absent in WT. We detected by in-situ-hybridization mRNA for D₁-dopamine receptors in atrial and ventricular D₁-TG cardiomyocytes compared to WT but also in human atrial preparations. We noted that in the presence of 10 µM propranolol (to antagonize β-adrenoceptors), dopamine alone and the D₁- and D₅-dopamine receptor agonist SKF 38393 (0.1–10 µM cumulatively applied) exerted concentration- and time-dependent positive inotropic effects and positive chronotropic effects in left or right atrial preparations from D₁-TG. The positive inotropic effects of SKF 38393 in left atrial preparations from D₁-TG led to an increased rate of relaxation and accompanied by and probably caused by an augmented phosphorylation state of the inhibitory subunit of troponin. In the presence of 0.4 µM propranolol, 1 µM dopamine could increase left ventricular force of contraction in isolated perfused hearts from D₁-TG. In this model, we have demonstrated a positive inotropic and chronotropic effect of dopamine. Thus, in principle, the human D₁-dopamine receptor can couple to contractility in the mammalian heart.

Drug‐induced long QT syndrome (LQTS) and Torsades de Pointes (TdP) are serious concerns in drug development. Although rats are a useful scientific tool, their hearts, unlike larger species, usually do not respond to torsadogenic drugs. Consequently, their resistance to drug‐induced arrhythmias is poorly understood. Here, we challenged rats with rapid delayed rectifier current (Ikr)‐inhibiting antibiotic clarithromycin (CLA), loop diuretic furosemide (FUR) or their combination (CLA + FUR), and examined functional and molecular abnormalities after stimulation with isoproterenol. Clarithromycin and furosemide were administered orally at 12‐h intervals for 7 days. To evaluate electrical instability, electrocardiography (ECG) was recorded either in vivo or ex vivo using the Langendorff‐perfused heart method under basal conditions and subsequently under beta‐adrenergic stimulation. Gene expression was measured using real‐time quantitative PCR in left ventricular tissue. Indeed, FUR and CLA + FUR rats exhibited hypokalemia. CLA and CLA + FUR treatment resulted in drug‐induced LQTS and even an episode of TdP in one CLA + FUR rat. The combined treatment dysregulated gene expression of several ion channels subunits, including KCNQ1, calcium channels and Na+/K + ‐ATPase subunits, while both monotherapies had no impact. The rat with recorded TdP exhibited differences in the expression of ion channel genes compared to the rest of rats within the CLA + FUR group. The ECG changes were not detected in isolated perfused hearts. Hence, we report rapid orchestration of ion channel reprogramming of hearts with QT prolongation induced by simultaneous administration of clarithromycin and furosemide in rats, which may account for their ability to avoid arrhythmias triggered by beta‐adrenergic stimulation.