PHARMACOLOGICAL EVIDENCE FOR THROMBOXANE RECEPTOR HETEROGENEITY - IMPLICATIONS FOR THE EYE

The pharmacological activity of two novel thromboxane A(2) (TxA(2))-mi metics, AGN191976 and AGN192093, was investigated in vitro, using stan dard organ bath assays and human platelets, to determine potency and s electivity at various prostanoid (PG-) receptors. The effects of these compounds on intraocular pressure in Beagle dogs were then compared w ith U-46619, a widely employed and structurally different TP receptor agonist. AGN191976 and AGN192093 were highly potent TP-receptor agonis ts in the rat aorta (EC50 of 0.32 and 1.3 nM, respectively) and human myometrium. Both compounds were approximately 10 to 50 fold more poten t than U-46619. These contractile responses could be blocked with a po tent TP-receptor antagonist, SQ29548. platelets, AGN191976 (EC50=16.3 nM) and U-46619 (EC50=538.3 nM) potently aggregation (TP-receptor medi ated effect), whereas AGN192093 was a much weaker agonist (EC50=37.9 m u M) AGN192093 was not a partial agonist in platelets, since it did no t antagonize aggregation induced by AGN191976, U-46619, arachidonic ac id or ADP. These results provide evidence for a subdivision of TP-rece ptors, and AGN192093 appears to be able to distinguish between TP-rece ptors in smooth muscle and platelets, In the Beagle dog eye, both AGN1 91976 and AGN192093 were highly potent and efficacious ocular hypotens ives. Single 2.5 mu g doses of drug decreased IOP by 11.4 (AGN191976) and 7.7 mm Hg (AGN192093) relative to the contralateral control eye. I n contrast, U-46619 did not lower IOP. AGN191976, but not U-46619, inc reased outflow facility in these animals, which is consistent with the ir effects on IOP. Neither compound caused miosis which is EP-receptor mediated in the dog. These studies suggest the existence of heterogen eous populations of TP-receptors. AGN191976 and AGN192093, two novel T P-receptor agonists, appear to be useful tools for the pharmacological distinction of TP-receptor subtypes.