【Background and Purpose】Cardiac hypertrophy is a major risk factor of cardiovascular morbidity and mortality. The study was aimed to investigate the in-vivo effects of KMUP-1, a novel xanthine-based phosphodiesterase inhibitor, in a rat model of cardiac hypertrophy. The mechanisms of action of KMUP-1 were also explored.【Methods】Cardiac hypertrophy was induced by daily intraperitoneal injection of isoproterenol for 10 days in male Wistar rats. In the treatment group, KMUP-1 was administered one hour before each dose of isoproterenol. After 10 days, effects of KMUP-1 on survival and cardiac hypertrophy were examined. The relations of these effects to the NO/cGMP/PKG-1 pathway and hypertrophy signaling pathways (calcineurin A and ERK1/2) were examined. To further evaluate the role of NOS in the effects of KMUP-1, a NOS inhibitor, N-omega-nitro-L-arginine (L-NNA) was administered along with KMUP-1.【Results】KMUP-1 attenuated the cardiac hypertrophy and fibrosis, improved the survival of rats with isoproterenol-induced hypertrophy. Serum NOx and myocardial eNOS, cGMP and PKG-1 were all increased by KMUP-1. The activation of calcineurin A and ERK/1/2 in isoproterenol-treated rats were also attenuated by KMUP-1. All above effects were blunted by simultaneously administration of L-NNA.【Conclusions】KMUP-1 attenuates cardiac remodeling and improves survival in rats with isoproterenol-induced cardiac hypertrophy. These effects are mediated, at least in part, by NOS activation.