Delayed recovery of hypertension after single dose losartan in angiotensin II-infused conscious rats

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ObjectiveIn a conscious unrestrained rat model, it takes approximately 1 week for angiotensin II to increase blood pressure to maximum levels. We investigated the time required for hypertension to fully recover after acute angiotensin II receptor blockade in this angiotensin II dependent hypertensive model.DesignConscious unrestrained rats (n = 8) infused with 10 ng/kg per min angiotensin II for 21 days received losartan (10 mg/kg) on day 17 of angiotensin II infusion. Mean arterial pressure (MAP) and heart rate were monitored continuously. The acute pressor response to 50 ng/kg per min angiotensin II was monitored for 2 h on days 15, 17, 18, 19 and 20 of angiotensin II infusion. Plasma renin concentration (PRC) was measured daily.ResultsAngiotensin II increased MAP acutely by 26 ± 2 mmHg and by a further 23 ± 4 mmHg between days 4 and 8. Losartan acutely reduced MAP by 75 ± 2 mmHg; 24 h later MAP had partially recovered but remained suppressed by 47 ± 3 mmHg. MAP had not fully recovered 4 days later. Some 2 h after losartan, the acute pressor response to angiotensin II had fallen from 24 ± 2 mmHg to zero. This recovered to 13 ± 5 and 28 ± 2 mmHg 24 and 48 h post losartan. After losartan PRC rose from 0.1 ± 0.05 to above 1 ng/ml per h for less than 24 h.ConclusionA single dose of losartan reverses both the fast and slow pressor effects of continuous angiotensin II infusions. While losartan is metabolized, the fast vasoconstrictor effect recovers quickly but the slow pressor effect takes almost a week to build up again to maximum levels. Since the slow pressor effect is mediated via the AT1 receptor, any means of blocking the renin–angiotensin system is likely to keep blood pressure below maximum hypertensive levels for several days after the drug has disappeared from the circulation.

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