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Vol. 292, Issue 1, 238-246, January 2000
The Hypertension and Vascular Disease Center, Wake Forest
University School of Medicine, Winston-Salem, North Carolina
This study was conducted to investigate whether the novel orally active
nonpeptide angiotensin II (Ang II) AT1 receptor
antagonist irbesartan interacts with the thromboxane
A2/prostaglandin endoperoxide H2
(TxA2/PGH2) receptor in canine coronary
arteries and human platelets. Coronary artery rings were isolated from
male dog hearts (n = 18) and isometric tension of
vascular rings was measured continuously at optimal basal tension in
organ chambers. Autoradiographic binding of [3H]SQ29,548,
a TxA2 receptor antagonist, in canine coronary sections was
determined. Blood for platelet aggregation studies was collected by
venous puncture from healthy human volunteers (n = 6) who were free of aspirin-like agents for at least 2 weeks. Vascular
reactivity and platelet aggregation in response to the TxA2
analogs U46619 and autoradioagraphic receptor binding to the
TxA2 receptor antagonist [3H]SQ29,548 were
studied with and without irbesartan. The TxA2 analog U46619
produced dose-dependent vasoconstriction in coronary rings
(EC50 = 11.6 ± 1.5 nM). Pretreatment with
irbesartan inhibited U46619-induced vasoconstriction, and the
dose-response curve was shifted to the right in a dose-dependent
manner. The EC50 of U46619 was increased 6- and 35-fold in
the presence of 1 and 10 µM of irbesartan without a change of maximal
contraction. At 1 µM, irbesartan is 2-fold more potent than the
AT1 receptor antagonist losartan in the inhibition of
U46619-induced vasoconstriction in canine coronary arteries. In
contrast, neither AT1 receptor antagonists (CV11974 and
valsartan), the AT2 receptor antagonist PD123319, nor the
angiotensin converting enzyme inhibitor lisinopril had any effect on
U46619-induced coronary vasoconstriction. Irbesartan did not change
potassium chloride-induced vasoconstriction; however, irbesartan did
inhibit the vasoconstriction mediated by another TxA2/PGH2 receptor agonist prostaglandin
F2
(PGF2). Neither the nitric oxide
synthase inhibitor
N
-nitro-L-arginine methyl ester
nor the cyclooxygenase inhibitor indomethacin had any effect on
irbesartan's attenuation of U46619-induced vasoconstriction.
Irbesartan specifically reversed U46619-preconstricted coronary artery
rings with and without endothelium in a dose-dependent manner.
Irbesartan at high concentrations significantly competed for
[3H]SQ29,548 binding in canine coronary sections. U46619
stimulated dose-dependent human platelet aggregation of platelet-rich
plasma. Preincubation with irbesartan significantly inhibited platelet aggregation in a concentration-dependent manner. In conclusion, the
dual antagonistic actions of irbesartan by acting at both the
AT1 and TxA2 receptors in blood vessels and
platelets may overall enhance its therapeutic profile in the treatment
of hypertension, atherosclerosis, and arterial thrombosis.
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