The Dose-Dependent Effects of Spironolactone on TGF-1 Expression and the Vulnerability to Atrial Fibrillation in Spontaneously Hypertensive Rats.

Objective: This study tends to assess the dose-dependent effects of spironolactone on TGF-1 expression, atrial fibrosis, and the vulnerability to atrial fibrillation in spontaneously hypertensive rats (SHRs) and tries to clarify the association of atrial fibrosis with the vulnerability to atrial fibrillation.

Methods: Forty 20-week-old male SHRs were randomly divided into 4 groups (10 rats per group): 3 spironolactone groups were lower-dose group (10 mg·kg·d, dissolved in 2 ml saline solution, group SL), medium-dose group (40 mg·kg·d, dissolved in 2 ml saline solution, group SM), higher-dose group (80 mg·kg·d, dissolved in 2 ml saline solution, group SH) and one hypertension group (2 ml saline solution for stomach gavage, group H). Ten matched homologous WKY rats were set as the control group (group C). After 7 weeks of gavage, a multiple electroconductive physiological recorder was used to detect atrial electrical parameters, including P-wave duration, PR interval, and atrial effective refractory period (AERP), the inducibility, and duration of atrial fibrillation. HE staining was used to determine myocardial cell size. Masson staining was used to detect the deposition of the interstitial collagen fibers in atrial muscle. The expression of TGF-1 was detected by immunohistochemistry and western blot.

Results: Compared with group C, the myocardial cell size, atrial fibrosis, TGF-1 expression, P-wave duration, PR interval, AERP, inducibility, and duration of atrial fibrillation in group were conspicuously increased ( < 0.05); compared with group H, there was no significant difference in the myocardial cell size, atrial fibrosis, TGF-1 expression, and electrophysiological indexes in group SH upon spironolactone intervention ( > 0.05); compared with group H, the myocardial cell size, atrial fibrosis, the expression of TGF-1, P-wave duration, PR interval, the inducibility, and duration of atrial fibrillation in the group SL and group SM were all decreased ( < 0.05); compared with group SM, the effect in the group SL was more prominent ( < 0.01).

Conclusion: Hypertension can lead to cardiomyocyte hypertrophy, deposition of interstitial fibrosis in myocardial tissue, and an increase in the vulnerability to atrial fibrillation. Spironolactone showed a certain dose-dependent effect in SHRs. Lower-dose spironolactone was superior to higher-dose spironolactone in the aspect of reducing hypertensive atrial fibrosis and TGF-1 expression, as well as preventing the occurrence of atrial fibrillation.