The objective of the present study is to examine cardiovascular protective action of a newly developed transdermal patch by incorporating bisoprolol and isosorbide dinitrate in spontaneously hypertensive rats. As the combination therapy with these two synergistic drugs at low doses through a suitable form of administration could provide optimal therapeutic benefit, we further evaluated the effects of a 42 d period of anti-hypertensive treatment in spontaneously hypertensive rats. Rats were divided into the following five groups： control （blank patch）, bisoprolol fumarate tablets （BP-FT, 20.0 mg/kg, i.g.）, bisoprolol transdermal patch （BP-TP, 20.0 mg/kg）, isosorbide dinitrate transdermal patch （ISDN-TP, 20.0 mg/kg）, and the combination of BP and ISDN in a transdermal patch at low doses （8 and 12 mg/kg, respectively）. The effects of treatment were evaluated via biochemical indicators related to cardiovascular protection, structure and function. The combination therapy had synergistic anti-hypertensive effects and significantly reduced blood pressure with the benefit of controlling blood pressure variability compared to BP-FT and BP-TP. The combined treatment also reduced heart rate as well as BP-FT and BP-TP, while ISDN-TP had no evident effects on blood pressure, heart rate, and cardiovascular protection. Combination therapy was superior to BP-TP and BP-FT at increasing blood atrial natriuretic peptide and nitric oxide, while also reducing cardiac hydroxyproline and endothelin-1 with no difference in blood endothelin-1 and cardiac malondialdehyde levels. Cardiovascular remodeling differed among the groups, with the combination therapy reducing cardiac hypertrophy and the aortic media/lumen ratio. The consequential improvements in relaxation in response to cumulative concentrations of acetylcholine may explain the associated improvement in endothelial function. Combi- nation treatment with a transdermal patch exhibited a synergistic therapeutic effect. Such favorable cardiovascular effects wit
