title: L-type calcium channel antagonism - Translation from in vitro to in vivo.
abstract: BACKGROUND
  Although therapeutically beneficial in the treatment of certain diseases, L-type calcium channel antagonism can result in unwanted off-target pharmacology leading to adverse drug reactions and to the termination of the development of otherwise promising compounds. In the present study three marketed calcium channel inhibitors, nifedipine, verapamil and diltiazem were profiled in a series of in vitro and ex-vivo assays in an effort to determine the ability of these assays to discriminate, between dihydropyridine versus non-dihydropyridine-like compounds, and how well they can predict the cardiovascular effects observed in a conscious telemetered rat model.
  
  
  METHODS
  Standard calcium channel antagonists were profiled in radioligand binding, patch clamp and calcium flux assays. In addition, cardiovascular endpoints related to calcium channel activity were also examined in ex vivo tissue bath preparations, including relaxation of pre-constricted rat aorta and the guinea pig Langendorff isolated heart model. The data generated were correlated with in vivo blood pressure and heart rate data from conscious telemetered rats.
  
  
  RESULTS
  Our results show that the binding, FLIPR and aorta assays allow differentiation of the compounds in two distinct classes of L-type calcium channel antagonists, and are good predictors of in vivo outcomes.
  
  
  CONCLUSIONS
  These results suggest that in vitro and ex vivo profiling remains a valuable tool in predicting potential in vivo cardiovascular safety issues, and can aid in the selection of novel development compounds that show inherent inhibitory activity against L-type calcium channels.
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, La Jolla, CA 92121, United States; Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Bernard
authors.initials: B
authors.lastname: Fermini
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, La Jolla, CA 92121, United States; Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Ramirez
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, La Jolla, CA 92121, United States; Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Sunny
authors.initials: S
authors.lastname: Sun
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, La Jolla, CA 92121, United States; Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Asser
authors.initials: A
authors.lastname: Bassyouni
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, La Jolla, CA 92121, United States; Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hemkens
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, La Jolla, CA 92121, United States; Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Todd
authors.initials: T
authors.lastname: Wisialowski
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, La Jolla, CA 92121, United States; Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT 06340, United States. Electronic address: stephen.jenkinson@pfizer.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Jenkinson
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002460:Cell Line; D004110:Diltiazem / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D000067268:Isolated Heart Preparation / Q000379:methods; D008297:Male; D009543:Nifedipine / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D057170:Translational Research, Biomedical / Q000379:methods*; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine
keywords: Aorta; Calcium channel; Diltiazem; In vitro; In vivo; L-type; Langendorff; Nifedipine; Rat telemetry; Verapamil