Comparison of rat and dog models of vasodilatation and lipolysis for the calculation of a therapeutic index for GPR109A agonists.
BACKGROUND
GPR109A is the receptor mediating both the antilipolytic and vasodilatory effects of nicotinic acid. In order to develop agonists for GPR109A with improved therapeutic indices we have sought to optimize animal models that evaluate both nicotinic acid-mediated inhibition of lipolysis and stimulation of vasodilatation. The rat and the dog have previously been used to study the antilipolytic effects of nicotinic acid, but no optimal vasodilatation model exits in either species.


METHODS
We have developed a vasodilatation model in the rat that measures changes in ear perfusion using laser Doppler flowmetry. In the dog, we have developed a model of vasodilatation measuring changes in red color values in the ear, using a spectrocolorimeter. Effects of GPR109A agonists on lipolysis were measured in both species after oral dosing of compounds, and measuring plasma levels of free fatty acids.


RESULTS
In both rat and dog, GPR109A agonists induce dose- and time-dependent vasodilatation, similar to that observed in humans. Vasodilatation is inhibited in both species with cyclooxygenase inhibitors or a specific DP1 receptor antagonist, indicating that, as in man, nicotinic acid-induced vasodilatation in rats and dogs is mainly mediated by the release of PGD(2).


CONCLUSIONS
Our results show that both rat and dog are useful models for the characterization of GPR109A agonists. A therapeutic index for GPR109A agonists can be calculated in either species.
Carballo-Jane
Ester
E
Department of Pharmacology, Merck Research Laboratories, Rahway, NJ, USA. ester_carballojane@merck.com
Gerckens
Lynn S
LS
Luell
Silvi
S
Parlapiano
Allison S
AS
Wolff
Michael
M
Colletti
Steven L
SL
Tata
James R
JR
Taggart
Andrew K P
AK
Waters
M Gerard
MG
Richman
Jeremy G
JG
McCann
Margaret E
ME
Forrest
Michael J
MJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D016903:Drug Monitoring / Q000379:methods; D005230:Fatty Acids, Nonesterified / Q000097:blood; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007279:Injections, Subcutaneous; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D023421:Models, Animal; D009525:Niacin / Q000008:administration & dosage / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005230:Fatty Acids, Nonesterified; D000960:Hypolipidemic Agents; D018722:Nicotinic Agonists; D011719:Pyrazines; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; C027696:acipimox; D007213:Indomethacin