title: Stress-induced cardiac insufficiency relating to abnormal leptin and FKBP12.6 is ameliorated by CPU0213, an endothelin receptor antagonist, which is not affected by the CYP3A suppressing effect of erythromycin.
abstract: OBJECTIVE
  Cardiac injury induced by isoprenaline produces stress. This stress can be mediated by the activated endothelin and leptin pathway; thus, the endothelin receptor antagonist CPU0213 may reverse these changes. CPU0213 is metabolized mainly by cytochrome P450 (CYP)3A, thus, erythromycin, an inhibitor of CYP3A, could affect its effects by raising its plasma levels.
  
  
  METHODS
  Forty rats were divided into five groups. Group 1 rats were normal. Group 2 rats were administered isoprenaline (1 mg/kg, s.c.) for 10 days. Groups 3, 4 and 5 were administered isoprenaline, but group 3 was given erythromycin (100 mg/kg, p.o.) alone on days six to ten, group 4 was given CPU0213 20 mg/kg (s.c.) on days six to ten, whilst group 5 received erythromycin plus CPU0213 on days six to ten. Measurements were conducted to observe changes in the haemodynamics, cardiac weight index, serum lactate dehydrogenase and creatine kinase levels, and expression of endothelin receptor A (ETA), leptin and its OBRb receptor.
  
  
  RESULTS
  In isoprenaline-treated rats, cardiac hypertrophy and dysfunction were found. This was associated with upregulated myocardial leptin protein and OBRb receptor mRNA. Immunohistochemical assay of ETA was upregulated, accompanied with downregulation of FKBP12.6 (calstabin 2) in isoprenaline-treated rats. These effects were significantly reversed by CPU0213. HPLC assay presented an increased plasma level of CPU0213 by erythromycin, but no change in its effects.
  
  
  CONCLUSIONS
  CPU0213 improved isoprenaline-induced cardiomyopathy by modulating ETA, leptin and FKBP12.6. However, erythromycin increased plasma levels but did not change its effects.
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Yu-Si
authors.initials: YS
authors.lastname: Cheng
authors.forename: De-Zai
authors.initials: DZ
authors.lastname: Dai
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D015536:Down-Regulation; D065128:Endothelin Receptor Antagonists; D004917:Erythromycin / Q000494:pharmacology*; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol; D020738:Leptin / Q000378:metabolism*; D008297:Male; D011720:Pyrazoles / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C513821:CPU0213; D065692:Cytochrome P-450 CYP3A Inhibitors; D065128:Endothelin Receptor Antagonists; D020738:Leptin; D011720:Pyrazoles; D017466:Receptors, Endothelin; D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D007545:Isoproterenol