Pharmacological characterization of EK112, a new combined angiotensin II and thromboxane A2 receptor antagonist

Abstract

The pharmacological characterization of EK112, a new combined angiotensin II and thromboxane A₂ receptor blocking agent, was examined in this study. EK112 was found to be a angiotensin II receptor antagonist, as revealed by its competitive antagonism of angiotensin II–induced smooth muscle contraction (pA₂ value of 7.63 ± 0.14) in rabbit aorta. It also had an angiotensin II blocking action in guinea pig ileum (pA₂ value of 7.87 ± 0.67). Additionally, EK112 also possessed thromboxane A₂ receptor blocking activity, since it competitively antagonized aortic contractile responses elicited by U46619 and PGF_2α(pK_B values of 6.67 ± 0.09 and 6.24 ± 0.09, respectively) in rat. In contrast, EK112 did not affect the contractile responses to many other receptor agonists. EK112 did not mimic that of the angiotensin-converting enzyme (ACE) inhibitor, captopril, to enhance the muscle contraction elicited by bradykinin in guinea pig ileum, suggesting that EK112 did not inhibit ACE. Neither cyclic AMP nor cyclic GMP content in rat aortic rings was changed by EK112. These data demonstrate that EK112 is a selective antagonist of angiotensin II and thromboxane A₂ receptor. The order of this blocking potency is angiotensin II receptor > thromboxane A₂ receptor.