The molecular basis for insurmountable antagonism is still a matter of debate. The extent of this decline varies considerably from one antagonist to another and it seems to be unrelated to the potency of the antagonist to produce rightward shifts of the concentration-response curve ( Liu et al. Insurmountable antagonists are able to depress the maximal response. These are classified as surmountable antagonists ( Gaddum et al., 1955) and losartan is a typical example ( Mochizuki et al., 1995). Most antagonists produce parallel rightward shifts of the angiotensin II concentration-response curve, without affecting the maximal response. These experiments have shed light on the existence of different categories of selective AT 1 receptor antagonists. These studies include a preincubation step, in which the tissue is equilibrated with the antagonist, and an incubation step which comprises the consecutive addition of increasing concentrations of angiotensin II to generate a concentration-response curve. The effect of antagonists on AT 1 receptor function is traditionally studied by measuring their ability to antagonize angiotensin II-induced contraction of rabbit aorta rings/strips, a system with very small receptor reserve ( Zhang et al., 1993). These biological actions of angiotensin II are mediated by receptors of the AT 1 subtype ( Hodges et al., 1992). Angiotensin II, the effector peptide of the renin-angiotensin system, is an important regulator of the cardiovascular system which stimulates contraction of vascular smooth muscle cells and promotes their growth ( Timmermans et al., 1992).
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