Tetrandrine (TTD) is a
calcium channel blocker with documented antifibrotic actions. In this study, for the first time, we identified that TTD can directly prevent in vitro human cardiac myofibroblast activation and limit in vivo myocardial
fibrosis. In vitro, cardiac myofibroblasts from human atrial biopsies (N = 10) were seeded in three-dimensional
collagen matrices. Cell-
collagen constructs were exposed to transforming growth factor-β1 (10 ng/ml), with or without TTD (1 and 5 μM) for 48 h.
Collagen gel contraction, myofibroblast activation (α-smooth muscle actin expression), expression of profibrotic mRNAs, and rate of
collagen protein synthesis were compared. TTD decreased
collagen gel contraction (79.7 ± 1.3 vs 60.1 ± 8.9%, P < 0.01), α-smooth muscle actin expression (flow cytometry),
collagen synthesis ([(3)H]
proline incorporation), and
collagen mRNA expression. Cell viability was similar between groups (
annexin positive cells: 1.7 vs. 1.4%). TTD inhibited
collagen gel contraction in the presence of T-type and
L-type calcium channel blockers, and the intracellular
calcium chelator BAPTA-AM (15 μM), suggesting that the observed effects are not mediated by
calcium homeostasis. In vivo, Dahl
salt-sensitive hypertensive rats were treated with variable doses of TTD (by
intraperitoneal injection over 4 wk) and compared with untreated controls (N = 12). Systemic blood pressure was monitored by tail cuff. Myocardial
fibrosis and left ventricular compliance were assessed by histology and passive pressure-volume analysis. Myocardial
fibrosis was attenuated compared with untreated controls (%
collagen area: 9.4 ± 7.3 vs 2.1 ± 1.0%, P < 0.01). Left ventricular compliance was preserved. In conclusion, TTD reverses human cardiac myofibroblast activation and myocardial
fibrosis, independent of
calcium channel blockade.