Differential Inhibition of the Prejunctional Actions of Angiotensin II in Rat Atria by Valsartan, Irbesartan, Eprosartan, and Losartan

Abstract

The effects of valsartan and other nonpeptide angiotensin II type 1 (AT₁) receptor blockers on the prejunctional actions of angiotensin II were investigated in the isolated left atria of rat. Norepinephrine stores in rat atria were loaded with [³H]norepinephrine, and neuronal norepinephrine release was deduced from the radioactivity efflux. Angiotensin II (10⁻⁹ to 10⁻⁶ M) produced concentration-dependent enhancement of the electrical stimulation-induced efflux of [³H]norepinephrine from the preparation. Pretreatment of tissues with valsartan, irbesartan, eprosartan, or losartan (10⁻⁸ to 10⁻⁶ M) produced concentration-dependent inhibitions of the stimulation-induced efflux of radioactivity observed in the presence of angiotensin II (10⁻⁷ M). The AT₁ receptor blockers did not decrease the “basal” stimulation-induced overflow of radioactivity but rather selectively inhibited the angiotensin II-mediated augmentation of the response. Regression analyses of the inhibition of the angiotensin II-mediated response by valsartan, irbesartan, eprosartan, and losartan revealed corresponding log IC₅₀values (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 than those for eprosartan and losartan. Thus, valsartan is a potent inhibitor of the prejunctional facilitatory effect of angiotensin II on the release of norepinephrine from peripheral sympathetic nerves. This implies that the therapeutic domain of valsartan may be extended to include pathophysiological conditions such as congestive heart failure wherein prejunctional angiotensin II receptors apparently play a significant role. Whether the high potency of valsartan translates into a significant clinical advantage relative to the other agents tested remains to be ascertained.