Candesartan Causes Long-lasting Antagonism of the Angiotensin II Receptor-mediated Contractile Effects in Isolated Vascular Preparations: a Comparison with Irbesartan, Losartan and its Active Metabolite (EXP-3174)

Abstract

Candesartan is a new angiotensin II type 1 (AT 1 ) receptor blocker. It displays insurmountable antagonism of angiotensin II responses, binding tightly to and dissociating slowly from the AT 1 -receptor. The purpose of this study was to compare the duration of angiotensin II antagonism by the AT 1 -receptor blockers candesartan, irbesartan, losartan and its active metabolite EXP-3174 in an isolated tissue preparation. The contractile response to angiotensin II was studied in the isolated portal vein of the rat, during incubation with AT1-receptor blockers and after an extensive washout period. The portal vein preparation was pre-stretched to a passive force of 5 mN in an organ bath filled with oxygenated Krebs' buffer at 37°C. The contractile tension developed by the vascular smooth muscles was monitored using a force-displacement transducer. The contractile response to repeated administration of angiotensin II was recorded before, during and following exposure (for 30-180 min) to candesartan, 0.1-1 nmol/l, irbesartan, 1-50 nmol/l, losartan, 30-100 nmol/l, and EXP-3174, 1-10 nmol/l. Drug exposure was followed by washing for up to 2 h. Candesartan produced a long-lasting blockade of the vascular contractile response to angiotensin II, as shown by maintenance of inhibition during the washout period. This effect of candesartan was independent of drug concentration and exposure time prior to washing. Irbesartan, losartan and EXP-3174 also blocked the angiotensin II-mediated contraction. However, in contrast to candesartan, the responses to angiotensin II rapidly returned towards baseline values during the washout period. The relatively short-lasting blockade by irbesartan, losartan and EXP-3174 was also independent of drug concentration and exposure time prior to washout. It is concluded that the AT 1 -receptor blockers differ in their ability to inhibit angiotensin II-mediated vascular contraction, with candesartan producing longer-lasting blockade than irbesartan, losartan and EXP-3174. The mechanism of the persistent inhibitory effect of candesartan is at present unclear. Possible explanations include tight binding and slow dissociation from the AT 1 -receptor, tissue accumulation resulting in 'local( dissociation and reassociation to the AT 1 -receptor, and stimulation of internalization of the AT 1 -receptor.