12/22/2023 0 Comments Insurmountable antagonismRecent studies also suggested the efficacy of AT 1 antagonists as remedies for heart failure (8,9), neointimal thickening after carotid injury (10), and atherosclerosis.ĪT 1-receptor antagonists are categorized as either insurmountable (noncompetitive) or surmountable (competitive) according to their ability to shift the concentration-response curve of AII to the right with or without reduction of the maximal response, respectively (11). Several nonpeptide AT 1 antagonists have already been discovered and evaluated as antihypertensive drugs (6,7). The AT 1 subtype is believed to mediate most of physiological functions of AII, whereas the physiological functions of the AT 2 subtype are not yet clear. The AT 1 subtype of the AII receptor is blocked by compounds such as losartan (2-4), whereas the AT 2 subtype is blocked by other compounds such as PD123319 (5). The angiotensin II (AII) receptor, which is the final action site in the system, is one of the most important therapeutic targets for cardiovascular diseases. The renin-angiotensin system plays an important role for the regulation of cardiovascular function in mammals (1). Because of the variations observed with the four compounds, mechanisms of insurmountable antagonism may not be uniform among AT 1-receptor antagonists. The differences between association rate with and dissociation rate from the AT 1 receptor of E4177 and 606A were slight, in spite of the clear difference between their action in the contraction study. These results obtained in the aorta were consistent with their characteristics observed in the AII binding study in the rabbit adrenal cortical membrane in cases of EXP3174 and CV11974. AII-induced contraction of 606A- or E4177-treated aorta recovered easily by washout, but that of CV11974-treated aorta was hard to recover by washout. However, the suppression of contraction by 606A and E4177 changed little with the length of the pretreatment period. The longer the pretreatment period with EXP3174 or CV11974, the more effectively the antagonists suppressed AII-induced contraction. ![]() However, in AII-induced contraction studies with rabbit aorta, 606A, EXP3174, and CV11974 inhibited the contraction noncompetitively, whereas E4177 inhibited competitively. Four antagonists, 606A, EXP3174, CV11974, and E4177, showed equipotent competitive antagonism when they were added simultaneous with -AII in binding experiments. To elucidate the causes of the difference, we studied how several antagonists associate with and dissociate from AT 1-receptor sites by using rabbit adrenal cortical membrane. Angiotensin AT 1-receptor antagonists can be classified into two types, surmountable and insurmountable ones, based on the way they inhibit angiotensin II (AII)-induced vasoconstriction.
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