Bimatoprost and prostaglandin F(2 alpha) selectively stimulate intracellular calcium signaling in different cat iris sphincter cells.
Bimatoprost is a synthetic analog of prostaglandin F(2 alpha) ethanolamide (prostamide F(2 alpha)), and shares a pharmacological profile consistent with that of the prostamides. Like prostaglandin F(2 alpha) carboxylic acid, bimatoprost potently lowers intraocular pressure in dogs, primates and humans. In order to distinguish its mechanism of action from prostaglandin F(2 alpha), fluorescence confocal microscopy was used to examine the effects of bimatoprost, prostaglandin F(2 alpha) and 17-phenyl prostaglandin F(2 alpha) on calcium signaling in resident cells of digested cat iris sphincter, a tissue which exhibits contractile responses to both agonists. Constant superfusion conditions obviated effective conversion of bimatoprost. Serial challenge with 100 nM bimatoprost and prostaglandin F(2 alpha) consistently evoked responses in different cells within the same tissue preparation, whereas prostaglandin F(2 alpha) and 17-phenyl prostaglandin F(2 alpha) elicited signaling responses in the same cells. Bimatoprost-sensitive cells were consistently re-stimulated with bimatoprost only, and prostaglandin F(2 alpha) sensitive cells could only be re-stimulated with prostaglandin F(2 alpha). The selective stimulation of different cells in the same cat iris sphincter preparation by bimatoprost and prostaglandin F(2 alpha), along with the complete absence of observed instances in which the same cells respond to both agonists, strongly suggests the involvement of distinct receptors for prostaglandin F(2 alpha) and bimatoprost. Further, prostaglandin F(2 alpha) but not bimatoprost potently stimulated calcium signaling in isolated human embryonic kidney cells stably transfected with the feline- and human-prostaglandin F(2 alpha) FP-receptor and in human dermal fibroblast cells, and only prostaglandin F(2 alpha) competed with radioligand binding in HEK-feFP cells. These studies provide further evidence for the existence of a bimatoprost-sensitive receptor that is distinct from any of the known prostaglandin receptor types.
Spada
Clayton S
CS
Department of Biological Sciences, Pharmaceutical Research and Development, Allergan, Inc., Irvine, CA 92612-1599, USA. spada_clayton@allergen.com
Krauss
Achim H-P
AH
Woodward
David F
DF
Chen
June
J
Protzman
Charles E
CE
Nieves
Amelia L
AL
Wheeler
Larry A
LA
Scott
David F
DF
Sachs
George
G
D000577:Amides; D000818:Animals; D000069580:Bimatoprost; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D002415:Cats; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology; D003008:Cloprostenol / Q000031:analogs & derivatives; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D007498:Iris / Q000187:drug effects* / Q000378:metabolism; D008055:Lipids / Q000494:pharmacology*; D018613:Microscopy, Confocal / Q000379:methods; D009119:Muscle Contraction / Q000187:drug effects
D000577:Amides; D018679:Cholinergic Agonists; D008055:Lipids; D003008:Cloprostenol; C027042:17-phenylprostaglandin F2alpha; D002217:Carbachol; D015237:Dinoprost; D000069580:Bimatoprost; D002118:Calcium