Question:

Chronic hypertension is a risk factor for the development of atrial fibrillation (AF). Endothelin-1 (ET-1) is involved in cardiac remodeling and arrhythmogenic Ca signaling. It is not known, however, whether ET-1 signaling plays a role in hypertension-induced atrial tachyarrhythmias. Here we tested the hypothesis that ET-1 signaling is altered in spontaneously hypertensive rats (SHR) and that altered ET-1 signaling contributes to arrhythmogenic Ca signaling.

Methodology:

SHR and control Wistar-Kyoto (WKY) rats were studied at 6-8 months of age. mRNA expression was studied in atrial tissue by means of qPCR and protein expression using Western blotting. Functional effects of ET-1 (50nM) were assessed in isolated atrial myocytes electrically stimulated at 0.5Hz. Epifluorescence (Fura-2/AM) was used for characterization of global Ca transients (CaTs) and line scan confocal microscopy (Fluo-4/AM) for characterization of subcellular CaTs.

Results:

At 6-8 months of age, SHR exhibited compensated LV hypertrophy, but left atrial hypotrophy. Atrial expression of ET-1 (mRNA) was increased in SHR. ET_A receptor expression was unaltered at the mRNA level but selectively upregulated in left atria at the protein level. Furthermore, Galphaq expression (mRNA) was also upregulated in SHR. In atrial tissue slices from SHR, high frequency stimulation (5Hz vs 0.6Hz) for up to 20h caused further 2-fold upregulation of ET_A receptor expression. Exposure of atrial myocytes to 50nM ET-1 caused a 35% increase in systolic Ca in SHR (n=10), significantly larger than in WKY (18%, n=20). In SHR atrial myocytes treated with ET-1 rise time of the CaT tended to be longer (78 vs 50 ms, P=0.06) and fractional SR Ca release was larger (P<0.05) than in WKY. Confocal imaging revealed that the ET-1-induced increase in CaTs occurred in the subsarcolemmal as well as in the central cytoplasm. ET-1 also increased the fraction of atrial myocytes exhibiting arrhythmogenic Ca waves. This effect was comparable in SHR and WKY atrial myocytes.

Conclusions:

Atrial myocardium from 6-8 months old SHR revealed augmented ET-1 signaling as characterized by increased expression of ET-1, ET_A receptors, and Galphaq in atrial tissue as well as a larger CaT increase in ET-1-treated atrial myocytes. The arrhythmogenic effect of ET-1 together with the increased expression of ET-1 and ET_A receptors in atrial myocardium from SHR, which was further augmented by high frequency stimulation, suggests that ET-1 may be involved in the development of atrial tachyarrhythmias in hypertension.