Elke Hartmann

Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.

Abstract: Pharmacological blockade of the mineralocorticoid receptor (MR) ameliorates end-organ damage in chronic heart failure. However, the clinical use of available steroidal MR antagonists is restricted because of concomitant hyperkalemia especially in patients with diminished kidney function. We have recently identified a novel nonsteroidal MR antagonist, finerenone, which uniquely combines potency and selectivity toward MR. Here, we investigated the tissue distribution and chronic cardiorenal end-organ protection of finerenone in comparison to the steroidal MR antagonist, eplerenone, in 2 different preclinical rat disease models. Quantitative whole-body autoradiography revealed that [14C]-labeled finerenone equally distributes into rat cardiac and renal tissues. Finerenone treatment prevented deoxycorticosterone acetate-/salt-challenged rats from functional as well as structural heart and kidney damage at dosages not reducing systemic blood pressure. Finerenone reduced cardiac hypertrophy, plasma prohormone of brain natriuretic peptide, and proteinuria more efficiently than eplerenone when comparing equinatriuretic doses. In rats that developed chronic heart failure after coronary artery ligation, finerenone (1 mg·kg−1·d−1), but not eplerenone (100 mg·kg−1·d−1) improved systolic and diastolic left ventricular function and reduced plasma prohormone of brain natriuretic peptide levels. We conclude that finerenone may offer end-organ protection with a reduced risk of electrolyte disturbances.

Testing of endocrine active substances using an enhanced OECD test guideline 407: Experiences from studies on flutamide and ethinylestradiol

Groups of five male and five female Wistar rats were treated by gavage with 0, 1, 10, and 100 mg/kg body weight (b.w.) flutamide (FLU) or 0.01, 0.05, and 0.2 mg/kg b.w. of ethinylestradiol (EE2) for at least 28 days according to an enhanced Organization for Economic Cooperation and Development (OECD) test guideline (TG) 407 to investigate which of the current and/or additional parameters would detect effects on the endocrine system and to provide data on intralaboratory variability. Two identical studies were performed in parallel on each compound. Common enhancements were determination of thyroid hormones (T3, T4) and thyroid stimulating hormone (TSH), of the stage of the estric cycle to ensure necropsy of females in diestrus, of the number and morphology of epididymal sperm, and of additional organ weights (e.g., male accessory sex organs, MASO) and histopathology of additional organs (e.g., pituitary, vagina). Endocrine-mediated findings consistently observed in these studies were decreased relative weights of MASO at 100 mg/kg FLU and at 0.2 mg/kg EE2, histological changes in pituitary and testes at > or = 10 mg/kg and in MASO, epididymis and adrenals at 100 mg/kg in FLU-treated males, histological changes in the mammary gland at > or = 0.05 mg/kg and in testes, MASO and adrenals at 0.2 mg/kg in EE2-treated males, estrogenization of uterus and vagina (despite necropsy in diestrus) at > or = 0.01 mg/kg EE2, and changes in the ovary at 0.2 mg/kg EE2. Spermatology was insensitive (EE2) or revealed changes only at the maximum tolerated dose (MTD). Determination of T3, T4, and TSH did not contribute to the detection of the endocrine effects (FLU) or provided equivocal results. Doubling the group size to 10 animals by combining the studies run in parallel did not increase the sensitivity of detection of endocrine-mediated effects above the level obtained by histopathological examination of groups of five animals. Only some of the proposed enhancements evaluated were helpful in detecting the endocrine-mediated effects of FLU and EE2. Evaluation of studies according to an enhanced TG 407 on 10 compounds with different endocrine activities will identify the most appropriate enhancements.

Bilateral noncystic renal dysplasia in a Wistar-rat

In a young Wistar rat a bilateral renal malformation was observed microscopically. Clinical chemistry gave no evidence of impaired kidney function. The kidney weight was slightly elevated and the kidneys showed no gross pathological changes. The lesion was located in the inner cortex of both kidneys and consisted of multiple foci of abnormal renal parenchyma similar to fetal kidney. Three components could be distinguished in the foci: primitive glomerular/tubular structures, tubules resembling collecting ducts and mesenchyme. For further characterisation, histological stains (H&E, PAS, Novotny) and immunohistochemistry (vimentin, pan-cytokeratin, S 100, proliferating cell nuclear antigen, and terminal desoxyribosyl-transferase mediated dUTP nick end labelling) were applied. The glomerular and tubular structures were hyperplastic and positive for proliferating cell nuclear antigen and vimentin. The collecting duct-like tubules were positive for pan-cytokeratin and gave no evidence of proliferation. The two epithelial components of the foci were surrounded by mesenchymal cells which extended also between the normal cortical tubules so that no clear demarcation was discernible. The mesenchymal cells were uniformly spindle-shaped and associated with reticulin fibers. Immunohistochemically they were vimentin-positive and non-proliferative. With terminal desoxyribosyl-transferase mediated dUTP nick end labelling (TUNEL) and S 100 all components were nearly negative. Based on morphology and immunohistochemistry this malformation containing structures derived from the ureteric bud and from the metanephric blastema associated with oligonephronia probably represents a noncystic renal dysplasia. Transition to neoplasia was not observed. A specific cause of this unusual developmental anomaly which was not previously reported in rats could not be determined.