Differential inhibition of the prejunctional actions of angiotensin II in rat atria by valsartan, irbesartan, eprosartan, and losartan

The effects of valsartan and other nonpeptide angiotensin II type 1 (AT(1)) receptor blockers on the prejunctional actions of angiotensin II were inve stigated in the isolated left atria of rat. Norepinephrine stores in rat at ria were loaded with [H-3] norepinephrine, and neuronal norepinephrine rele ase was deduced from the radioactivity efflux. Angiotensin II (10(-9) to 10 (-6) M) produced concentration-dependent enhancement of the electrical stim ulation-induced efflux of [H-3] norepinephrine from the preparation. Pretre atment of tissues with valsartan, irbesartan, eprosartan, or losartan (10(- 8) to 10(-6) M) produced concentration- dependent inhibitions of the stimul ation-induced efflux of radioactivity observed in the presence of angiotens in II (10(-7) M). The AT(1) receptor blockers did not decrease the "basal" stimulation-induced overflow of radioactivity but rather selectively inhibi ted the angiotensin II-mediated augmentation of the response. Regression an alyses of the inhibition of the angiotensin II-mediated response by valsart an, irbesartan, eprosartan, and losartan revealed corresponding log IC50 va lues (log M, with 95% confidence intervals) of -7.78 (-8.19, -7.51), -7.65 (-8.02, -7.40), -7.12 (-7.37, -6.86), and -6.75 (-7.00, -6.40), indicating that the IC50 values for valsartan and irbesartan are significantly lower t han those for eprosartan and losartan. Thus, valsartan is a potent inhibito r of the prejunctional facilitatory effect of angiotensin II on the release of norepinephrine from peripheral sympathetic nerves. This implies that th e therapeutic domain of valsartan may be extended to include pathophysiolog ical conditions such as congestive heart failure wherein prejunctional angi otensin II receptors apparently play a significant role. Whether the high p otency of valsartan translates into a significant clinical advantage relati ve to the other agents tested remains to be ascertained.