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JS Zhang, JC Van Meel, M Pfaffendorf and PA Van Zwieten
Department of Pharmacotherapy, Academic Medical Centre, University of Amsterdam, The Netherlands.
BIBS 222, a nonpeptide benzimidazole derivative, displayed insurmountable angiotensin II (Ang II) receptor antagonism in the rabbit aorta (pKB = 7.9), whereas it antagonized Ang II-induced phasic contractions in the rat portal vein in a surmountable manner (pA2 = 8.7, slope = 1.02). The mechanism of the different types of antagonism induced by BIBS 222 in vascular preparations was investigated. Using the slowly dissociating Ang II receptor antagonist sarile, we found that the calculated KA values for Ang II in the rat portal vein and in the rabbit aorta were different (6.0 x 10(-8) M vs. 2.0 x 10(-9) M). The estimated receptor reserve at the maximal response for the effect of Ang II in the rat portal vein amounts to 63%, whereas in rabbit aortic rings it is about 9%. In the presence of the disulfide-reducing agent dithiothreitol (0.5 mM), which led to the inactivation of about 70% of the Ang II receptors in the rat portal vein, BIBS 222 (10(-6) M) shifted the concentration-response curve for Ang II to the right and reduced the maximal response by 24 +/- 4.4% (P < .05). In conclusion, rat portal vein possesses a larger receptor reserve for Ang II than rabbit aortic rings. The surmountable Ang II receptor antagonism induced by BIBS 222 may be caused by the large receptor reserve in this preparation. Alternatively, different KA values for Ang II in these tissues may suggest the existence of two subpopulations of Ang II subtype 1 receptors, accounting for the cross-tissue behavior of BIBS 222.
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