Zacopride stimulates 5-HT4 serotonin receptors in the human atrium.

Zacopride (4-amino-5-chloro-2-methoxy-N-(quinuclidin-3-yl)-benzamide) is a potent agonist in human 5-HT4 serotonin receptors in vitro and in the gastrointestinal tract. Zacopride was studied as an antiemetic drug and was intended to treat gastric diseases. Zacopride has been speculated to be useful as an antiarrhythmic agent in the human ventricle by inhibiting cardiac potassium channels. It is unknown whether zacopride is an agonist in human cardiac 5-HT4 serotonin receptors. We tested the hypothesis that zacopride stimulates human cardiac atrial 5-HT4 serotonin receptors. Zacopride increased the force of contraction and beating rate in isolated atrial preparations from mice with cardiac-specific overexpression of human 5-HT4 serotonin receptors (5-HT4-TG). However, it was inactive in wild-type mouse hearts (WT). Zacopride was as effective as serotonin in raising the force of contraction and beating rate in atrial preparations of 5-HT4-TG. Zacopride raised the force of contraction in human right atrial preparations (HAP) in the absence and presence of the phosphodiesterase III inhibitor cilostamide (1 µM). The positive inotropic effect of zacopride in HAP was attenuated by either 10 µM tropisetron or 1 µM GR125487, both of which are antagonists at 5-HT4 serotonin receptors. These data suggest that zacopride is also an agonist at 5-HT4 serotonin receptors in the human atrium.

Mosapride stimulates human 5-HT4-serotonin receptors in the heart.

Mosapride (4-amino-5-chloro-2-ethoxy-N-[[4-[(4-fluorophenyl) methyl]-2-morpholinyl]-methyl] benzamide) is a potent agonist at gastrointestinal 5-HT4 receptors. Mosapride is an approved drug to treat several gastric diseases. We tested the hypothesis that mosapride also stimulates 5-HT4 receptors in the heart. Mosapride increased the force of contraction and beating rate in isolated atrial preparations from mice with cardiac overexpression of human 5-HT4-serotonin receptors (5-HT4-TG). However, it is inactive in wild-type mouse hearts (WT). Mosapride was less effective and potent than serotonin in raising the force of contraction or the beating rate in 5-HT4-TG. Only in the presence of cilostamide (1 µM), a phosphodiesterase III inhibitor, mosapride, and its primary metabolite time dependently raised the force of contraction under isometric conditions in isolated paced human right atrial preparations (HAP, obtained during open heart surgery). In HAP, mosapride (10 µM) reduced serotonin-induced increases in the force of contraction. Mosapride (10 µM) shifted the concentration-response curves to serotonin in HAP to the right. These data suggest that mosapride is a partial agonist at 5-HT4-serotonin receptors in HAP.

Initial characterization of a transgenic mouse with overexpression of the human D1-dopamine receptor in the heart.

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 ß-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.

Habitat and Season Effects on Small Mammal Bycatch in Live Trapping.

Trapping small mammals is frequently used to study the dynamics, demography, behavior and presence of pathogens. When only particular small mammal species are in the focus of interest, all other species are unnecessary bycatch. We analyzed data from extensive live trapping campaigns conducted over the last decade in Germany, following a consistent standard trapping protocol that resulted in about 18,500 captures of small mammals. Animals were trapped with Ugglan multiple capture traps in grassland, forest and margin habitat. Trap success and the proportion of bycatch were about 30% when target species were common voles (Microtus arvalis) in grassland and common voles and bank voles (Clethrionomys glareolus) in margins and forests. This was more pronounced in spring and along margins. Species mentioned in the early warning list according to the Red List Germany were higher in numbers and proportion in spring and in grassland. The results will help to avoid periods with enhanced presence of bycatch, including endangered species (if the purpose of the study allows) or to pay particular attention in certain seasons and habitats when the occurrence of bycatch is most likely.

No Evidence for the Presence of SARS-CoV-2 in Bank Voles and Other Rodents in Germany, 2020-2022.

Rodentia is the most speciose mammalian order, found across the globe, with some species occurring in close proximity to humans. Furthermore, rodents are known hosts for a variety of zoonotic pathogens. Among other animal species, rodents came into focus when the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) spread through human populations across the globe, initially as laboratory animals to study the viral pathogenesis and to test countermeasures. Under experimental conditions, some rodent species including several cricetid species are susceptible to SARS-CoV-2 infection and a few of them can transmit the virus to conspecifics. To investigate whether SARS-CoV-2 is also spreading in wild rodent populations in Germany, we serologically tested samples of free-ranging bank voles (Myodes glareolus, n = 694), common voles (Microtus arvalis, n = 2), house mice (Mus musculus, n = 27), brown or Norway rats (Rattus norvegicus, n = 97) and Apodemus species (n = 8) for antibodies against the virus. The samples were collected from 2020 to 2022 in seven German federal states. All but one sample tested negative by a multispecies ELISA based on the receptor-binding domain (RBD) of SARS-CoV-2. The remaining sample, from a common vole collected in 2021, was within the inconclusive range of the RBD-ELISA, but this result could not be confirmed by a surrogate virus neutralization test as the sample gave a negative result in this test. These results indicate that SARS-CoV-2 has not become highly prevalent in wild rodent populations in Germany.