The shortening of action potential duration (APD) and effective refractory period (ERP) are generally regarded as pivotal factors for the occurrence of reentry-based atrial fibrillation (AF). During AF, impaired atrial contraction causes the atria to dilate or stretch and induce the secretion of Ang II from cardiomyocytes. Stretch of the atrial membrane up-regulates the slow component of delayed rectifier K+ current (IKs). Blockade of angiotensin II subtype 1 receptors (AT1R) attenuates this increase in IKs. The present study aimed to examine effects of irbesartan, a selective AT1R blocker (ABR), on both the enhancement of IKs and the shortening of action potential duration (APD) induced by stretching atrial myocytes for exploring the mechanisms underlying the prevention of AF by ABR. Adult female Hartley guinea pigs (weighing 250-350g) were anaesthetized with pentobarbital sodium (80 mg kg-1, I.P.) and single atrial myocytes were enzymatically dissociated from the hearts of using a retrograde Langendorff perfusion method. Hyposmotic solution (Hypo-S) was used to stretch guinea pig atrial myocytes. IKs and APD were recorded using the whole-cell patch-clamp technique. Values are means ± S.E.M., compared by one-way ANOVA with Newman-Keuls post-hoc test. The result shows that therapeutically-relevant concentrations of irbesartan (1-50 μM) attenuated the Hypo-S-induced increase (but not baseline) levels of atrial IKs and shortening of APD90. Hypo-S increased the IKs by 113.4±9.96% (n = 18), whereas Hypo-S + 1 μM irbesartan and Hypo-S + 50 μM irbesartan only increased the IKs by 74.5±8.49% (n = 10; p < 0.05 vs. Hypo-S) and 70.3± 9.34% (n = 16; p < 0.05 vs. Hypo-S), respectively. In addition, Hypo-S shortened the APD90 by 19.03±1.36% (n = 17), whereas Hypo-S + 1 μM irbesartan and Hypo-S + 50 μM irbesartan shortened the APD90 by 12.05 ± 1.38 (n = 9; p < 0.01 vs. Hypo-S) and 12.0 ± 1.46 (n = 14; p < 0.01 vs. Hypo-S), respectively. The above data suggest that actions of irbesartan on electrical changes induced by stretching atrial myocytes are associated with blocking AT1R and may be beneficial for treating AF that is accompanied by atrial dilation and prolongation of the effective refractory period.