Long-lasting AT1 receptor binding and protection by Candesartan: comparison to other biphenyl-tetrazole sartans

The ability of biphenyltetrazole AT1 receptor antagonists (BTsartans) to block angiotensin II (Ang II)- mediated responses has been extensively investigated in vascular tissues and, more recently, in Chinese Hamster Ovary cells expressing the human AT1 receptor. When pre-incubated, BTsartans acted surmountably (only shifting the Ang II concentration-response curve to the right, prototype: losartan) or insurmountably (also decreasing the maximal response). It was shown that all BTsartans are competitive with Ang II and that the insurmountable behaviour of some of them reflects their ability to form tight, long lasting complexes with the receptor. Partial insurmountable antagonism can be explained by the co-existence of tight- and loose complexes. The proportion of insurmountable antagonism depends on the BTsartan in question and positively correlates to its potency and dissociation rate. The order is: candesartan > EXP3174 (the active metabolite of losartan) > valsartan > irbesartan >> losartan. Computer-assisted simulations (COPASI programme) were performed to explore how tight binding may contribute to a long lasting clinical effect. The simulations suggest that slow dissociation does not tangibly prolong receptor occupancy if the free drug is eliminated at a slower pace (as is the case for BTsartans). Yet, the situation is quite different when comparing the efficacy of fast- and slow dissociating antagonists to protect the receptor against fluctuations in natural messenger concentration. Indeed, at equal receptor occupancy, insurmountable antagonists were found to offer a sizeable bonus protection. Hence, slow receptor dissociation and slow antagonist elimination may act in synergy to produce long-lasting receptor protection.