Hydrogen sulfide has been recently studied as a potential treatment for many cardiovascular disorders. Here, we describe its role in I/R- induced cardiac hypertrophy and arrhythmia model. Thirty six Sprague Dawley rats were used in the present study. Rats were randomly divided into 6 groups, G 1(n = 6/group): control negative: received saline, G2, I/R rats, (I/R, n = 6), after right nephrectomy, the rats were subjected to left kidney ischemia for 45 minutes followed by reperfusion:,G3, I/R rats in which rats were treated by NaHS, the donor of H2S 5 mg/kg/day×14 days intraperitoneal,G4, I/R rats in which rats were treated by the blocker of H2S aminooxyacetic acid 10 mg/kg/day×14 days intraperitoneal,G5, I/R rats in which rats were treated by converting enzyme inhibitor (Captopril) 50 mg/Kg/day ×14 days and, G6, I/R rats in which rats were treated by NaHS, the donor of H2S and the ATP-sensitive potassium (KATP) channel blocker (Glibenclamide) 20 mg/kg/day ×14 days. NaHS led to a highly significant decrease in the duration of ventricular action potential indicated by QTc. Furthermore, it decreased, significantly, both of mean blood pressure and plasma renin activity. Moreover, H2S donor and converting enzyme inhibition increased the expression of CX-43. While I/R + H2S donor (NaHS) + KATP channel block led to a non-significant decreased in the duration of QTc interval. This showed that hydrogen sulfide generation has a potential therapeutic role in IR-induced cardiac hypertrophy and arrhythmia via amelioration of CX - 43 expression and opening of KATP channels.