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2013). Additionally, AT1 receptors have been shown to couple to Rac1/STAT3 signaling pathways regulating gene expression and protein synthesis in atrial myocytes (Tsai et al. 2008b), so that the effect of candesartan in this study may have been through a change in the expression of proteins regulating connexin�\43 phosphorylation. Atrial fibrosis Our results are in contrast to a previous study of atrial remodeling in rats made hypertensive by administration of the nitric oxide synthase (NOS) inhibitor, nitro�\�ة\l�\arginine�\methyl�\ester (l�\NAME) via the drinking water for 8 weeks (Okazaki et al. 2006). Although, as found in this study, oral treatment with hydralazine was without effect on atrial fibrosis, treatment with candesartan at a dose (0.1 mg/kg/day) lower than that used in this study significantly reduced the area of interstitial fibrosis see more (Okazaki et al. 2006). It is possible that the signaling processes underlying atrial fibrosis in the NOS inhibition model differ from those underlying the fibrosis in the atria of SHR, such that AT1 receptors contributed to the former and not to the latter remodeling and candesartan coadministration with l�\NAME sufficed to inhibit the development of the fibrosis. Oral treatment with the ARB, losartan, has also been shown to be effective in reducing the atrial fibrosis in a coronary Vatalanib (PTK787) 2HCl artery ligation model of heart failure in rats (Yoon et al. 2013). In that study, the administration of Docetaxel supplier losartan was started from the time of surgery so that the ARB was able to inhibit the development of fibrosis and atrial remodeling (Yoon et al. 2013). We have previously shown that, in contrast to these two studies, fibrosis of the left atria in spontaneously hypertensive rats is evident as early as 12�C14 weeks of age (Choisy et al. 2007). Thus, our data suggest that oral treatment with candesartan is not effective in the regression of the atrial fibrosis induced by long�\term systemic hypertension in rats. Substrate for arrhythmia Atrial interstitial fibrosis, and associated conduction abnormalities, have previously been suggested to contribute to a substrate for atrial tachyarrhythmia/atrial fibrillation in SHR hearts (Choisy et al. 2007; Lau et al. 2013). Therefore, the effects of candesartan and hydralazine treatment on the inducibility of atrial tachyarrhythmias following burst pacing would have been of considerable interest. However, in contrast to previous studies in which atrial tachyarrhythmias could be induced in 83% of hearts (Choisy et al. 2007), in this study it was only possible to induce tachyarrhythmias in three of the 15 hearts (20%). The low inducibility of atrial tachyarrhythmias is likely related to the small size of the left atria of SHR hearts in this study (60 �� 3 mg) as compared with our previous study (98 �� 7 mg, n = 22; P