Evidence for a functional cardiac interaction between losartan and angiotensin-(1-7) receptors revealed by orthostatic tilting test in rats

Abstract

1. Studies have shown that the angiotensin II (Ang II) AT1 receptor antagonist, losartan, accentuates the orthostatic hypotensive response in anesthetized rats, and there is evidence indicating that this effect is not exclusively mediated by AT1 receptors. 2. We investigated whether the pronounced orthostatic cardiovascular response observed in losartan-treated rats involves an interference with angiotensin-(1-7) (Ang-(1-7)) receptors. 3. Urethane-anesthetized rats were submitted to orthostatic stress (90 degree head-up tilt for 2 min). Intravenous injection of losartan (1 mg kg(-1), n=9) significantly accentuated the decrease in mean arterial pressure (MAP) induced by head-up tilt (-33+/-6% after losartan vs -15+/-8% control tilt). This effect was accompanied by a significant bradycardia (-8+/-3% after losartan vs -3+/-3% control tilt). Another AT1 antagonist, candesartan, did not potentiate the decrease of MAP and did not change the cardiac response induced by head-up tilt. Strikingly, administration of the Ang-(1-7) antagonist, A-779 (10 nmol kg(-1), n=5), totally reversed the bradycardic effect caused by losartan and this effect was accompanied by a tendency towards attenuation of the hypotensive response caused by losartan. 4. These findings indicate that the marked orthostatic cardiovascular response is specific for losartan, and that it may be due, in part, to an interaction of this antagonist with Ang-(1-7) receptors, probably at the cardiac level.

Figure 1

Changes in MAP and HR to 90° head-up tilt, before any treatment (control tilt) and at 60 and 120 min (designated tilt 2 and 3, respectively) after intravenous injection of: panel a, vehicle (0.9% NaCl, 1 ml kg⁻¹, n=5); panel b, losartan (1 mg kg⁻¹, n=9); panel c, candesartan (1 mg kg⁻¹, n=5); panel d, losartan+A-779 (losartan, 1 mg kg⁻¹; A-779 10 nmol kg⁻¹; n=5). Percent changes were calculated from pre-tilt basal values at the respective times as shown in Table 1. Bar indicates the duration of the maneuver (0–120 s). ^*P<0.05 tilt 2 vs control tilt; ^†P<0.05 tilt 3 vs control tilt (paired t-test).