Interaction of ACE inhibitors and AT1-receptor blockers on maximum blood pressure response in spontaneous hypertensive rats

Abstract

This study in spontaneous hypertensive rats (SHR) was designed to determine whether a greater fall in blood pressure (BP) could be achieved with the combination of an angiotensin-converting enzyme inhibitor (ACE-I) and an AT 1 -receptor blocking drug than with higher doses of either drug alone.The peak effect of captopril occurred 3-4 hours post-dose and a plateau response was achieved with 10 mg/kg. The peak effect of losartan occurred 7-8 hours post-dose and a plateau response was achieved with 10 mg/kg. Increasing the dose of either drug caused no greater fall in BP, but increased the duration of the effect.Captopril, 10 mg/kg, administered with losartan 10 mg/kg caused a greater fall in BP than captopril or losartan, 20 mg/kg. This was present after acute doses or after one week of daily therapy.The combination of ACE-I and AT 1 -blocking drugs is more effective than either therapy alone and may be a useful combination to manage hypertension and/or cardiac failure. IntroductionThe effect of the renin-angiotensin system (RAS) on blood pressure (BP) may be interrupted by inhibiting the conversion of angiotensin I (Ang I) to angiotensin II (Ang II) by angiotensin-converting enzyme inhibitors (ACE-I) or by blocking the effect of Ang II by AT 1 -receptor blocking drugs.

Synergistic decrease in blood pressure by captopril combined with losartan in spontaneous hypertensive rats

“…or the combination (10 mg/kg + 10 mg/kg, i.p.) (Morgan et al, 2002a). Since our current data showed the greatest reduction of BP at 11-12 h after dosing, this apparent discrepancy might result from the different rates of drug absorption owing to different routes of administration.…”

“…Each rat in the second group (n=8) received all four treatments as 3-day administrations with an interval of several days between each injection for washing-out. The change in SBP by the four different treatments in each rat was examined in the 3 rd and 4 th h, the 7 th and 8 th h, the 11 th and 12 th h and the 23 rd and 24 th h after 1-day or 3-day administration as previously described (Morgan et al, 2002a).…”

“…Likewise, combination therapy of benazeprilat and valsartan in conscious telemetered SHR was more efficacious than high doses of individual monotherapy (Webb et al, 1998b). Recently, the combined intraperitoneal treatment of captopril with losartan was applied to conscious SHR using the telemetry system, and the combination had greater BP-lowering effects than either drug as monotherapy (Morgan et al, 2002a;Morgan et al, 2002b). Since most of antihypertensive drugs are oral formulation, the experiments for lowering BP should be designed by oral administration.…”

Effect of candesartan and lisinopril alone and in combination on blood pressure and microalbuminuria

“…16,17 The results are similar to our studies in rats of the effect of combining ACE-I and ARBs. 11,12 When low doses of both are combined, the effect on peak BP response is more than additive (i.e. synergistic).When plateau doses of the two drug classes were used, there was a slightly greater fall in BP with the combination than with maximum doses of either drug as monotherapy.…”

“…10 In rats, there is a synergistic effect by combining low doses of both drugs and a small, but less than additive, effect by combining large doses of each drug class. 11,12 Rats used in experiments are inbred and have similar genetic composition and thus would be expected to respond in a similar fashion. In humans the situation is different.While ACE is the major pathway of converting Ang I to Ang II, there are also alternative tissue conversion pathways.…”