No abstract

This study was designed to examine the anti-hypertensive effect of the combination therapy of captopril with losartan by oral administration using both independent and cross-over experimental protocols. In independent experimental protocols, four different groups of spontaneous hypertensive rats (SHR) were treated for 1 or 2 weeks: control, captopril (20 mg/kg/day), losartan (20 mg/kg/day), and combination captopril (10 mg/kg/day) with losartan (10 mg/kg/day). In cross-over protocols, each SHR received all four treatments for 1 or 3 days with an interval of several days between each injection for washing-out and return to high blood pressure (BP) levels. BP and heart rate (HR) were measured in conscious telemetered SHR. According to the results from the independent protocol, regardless of a 1- or 2-week administration period, combination therapy with low doses of captopril and losartan had a greater anti-hypertensive effect than individual high-dose monotherapy. Similarly, results from the cross-over protocol showed that regardless of 1-day or 3-day administration, the decrease in BP in the 11(th) and 12(th) hour after administration was greatest with the combination of low-dose captopril and losartan. Therefore, combination therapy with low doses of captopril with losartan lowered BP to a greater extent than a high dose of either individual monotherapy.

The beneficial effects of losartan and rosuvastatin on neointimal formation have been well characterized, but little is known about the combined treatment benefit of these two drugs. This study was designed to investigate the synergistic effect of losartan combined with rosuvastatin on the magnitude of protective action in vascular injury mediated by cuff-induced neointimal formation model in vivo. Losartan at 20 mg/kg or rosuvastatin at 40 mg/kg significantly decreased both the neointimal formation and BrdU-positive cells in neointima, indicating the inhibition of cell proliferation including a progress of DNA synthesis. The combination treatment used lower doses of losartan with rosuvastatin (10 + 20 & 5 + 10 mg/kg, respectively) that proved to be significant in decreasing the neointimal formation and BrdU incorporation. These results were comparable to the diminution attained with monotherapy of either drug in higher doses. Interaction index measured by isobolar method indicated drug synergism in these two combinations of both drugs at lower doses. Therefore, the administration of losartan and rosuvastatin in combination with low doses synergistically decreased in cuff-induced neointimal formation by reducing cell proliferation, suggesting that this drug synergism may be fully effective with, lower adverse effects, for the treatment of vascular remodeling such as restenosis.

To examine drug synergism between angiotensin II AT1-receptor blocker and Ca(2+) channel blocker for lowering blood pressure (BP), telmisartan and lercanidipine were orally injected into to telemetered-spontaneous hypertensive rats and BP was monitored. The highest doses of both drugs (7.66 mg/kg of telmisartan and 1.92 mg/kg of lercanidipine) were clinically relevant at 80 and 20 mg human equivalent doses, respectively, and denoted as dose 1. After constructing the dose-response curve using 0 (vehicle-treated control), 1/16, 1/8, 1/4, 1/2 and 1 doses, all possible combinations of both drugs were tested. Drug synergism in combination therapy of telmisartan with lercanidipine was assessed by calculating the interaction index (γ) as evaluated by γ < 1. We found statistically significant drug synergism in the investigated (telmisartan: lercandipine) combinations of (1/8:1/4), (1/4:1) and (1/8:1). Our results suggest that the combination therapy of telmisartan and lercanidipine at lower doses are effective in lowering BP, and also reduce side effects caused by maximal doses of each drug. Therefore, drug combination of AT1-receptor blocker with Ca(2+) channel blocker is a clinically important tool for the management of hypertension and hypertension-related cardiovascular risks.