Characterization of endothelin receptors in the anesthetized ferret: a novel model for investigating the functional ET(B) receptor subtypes.
The pharmacology of endothelin (ET)-1, big ET-1, ET-3, and S6c were characterized in the anesthetized ferret to assess whether this species would provide a new and suitable nonrodent model to be used in characterization of endothelin antagonists. Unlike other species such as dog, rabbit, and rat, the ferret exhibited a dose-dependent pressor response to both ET-1 and big ET-1 with no preceding vasodilatory response. The median effective concentration (ED50) values were 0.047+/-0.009 and 0.469+/-0.003 nmol/kg for ET-1 and big ET-1, respectively. ET-3 and S6c, however, were found to elicit a transient vasodilatory response preceding the pressor response, with ED50 values of 0.23+/-0.09 and 0.18+/-0.03 nmol/kg, respectively. The rank potency of the agonists for the pressor response was found to be ET-1 > S6c > big ET-1 > ET-3. The ET(A)-specific antagonist BQ-123 was shown to block only partially the ET-1 and big ET-1 pressor response with median antagonistic dose (AD50) of 0.24+/-0.11 and 0.015+/-0.005 mg/kg, i.v., respectively, and blockade of the ET(A) receptor did not uncover an ET(B)-induced vasodilation. The dual ET(A/B) antagonist L-754,142 completely antagonized the ET-1 and big ET-1 pressor responses with AD50 values of 0.195+/-0.063 and 0.019+/-0.006 mg/kg, respectively. The ET(B) antagonist BQ-788 blocked the depressor response of S6c entirely but was unable to antagonize the pressor response completely. BQ-123 was shown to antagonize the S6c pressor response partially, suggesting a possible interaction between the ET(A) and ET(B) receptors in the ferret. The unexpected absence of an ET-1-mediated depressor response but the presence of ET-3 and S6c vasodilation in this species supports the theory that there may be subtypes of the ET(B) receptor. These studies demonstrate that the anesthetized ferret provides a suitable model for assessing the physiological potencies of the endothelins and may provide a tool for further understanding of the diversity of the ET(B) receptor.
Krause
S M
SM
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Nolan
N A
NA
Clayton
F C
FC
Walsh
T F
TF
Williams
D L
DL
D000758:Anesthesia; D000818:Animals; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D019334:Endothelin-3 / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology*; D005289:Ferrets; D008954:Models, Biological; D011311:Pressoreceptors / Q000187:drug effects; D011498:Protein Precursors / Q000494:pharmacology*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000145:classification / Q000378:metabolism*; D014757:Viper Venoms / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D016232:Endothelins; D011498:Protein Precursors; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6