Prehypertensive Preconditioning Improves Adult Antihypertensive and Cardioprotective Treatment

Abstract

Transient prehypertensive treatment (TPT) causes prolonged antihypertensive and cardioprotective effects. Reduced angiotensin sensitivity has been attributed to those effects. We hypothesize that prehypertensive preconditioning by angiotensin II type 1 receptor (AT1R) blockade improves cardiovascular protection of late-onset AT1R blockade in a model of spontaneous hypertensive heart-failure rats (SHHF/Mcc-fa cp ). TPT (4 -8 weeks of age) consisted of AT1R blockade (5 mg/kg candesartan) or vehicle. Candesartan-pretreated SHHF (5 mg/ kg/day candesartan; weeks 4 -8) received during adulthood (20 -28 weeks of age) either candesartan at a dose of 1.5 or 5 mg/kg/day or vehicle. Vehicle-pretreated SHHF received either candesartan (5 mg/kg/day) or vehicle during adulthood. Blood pressure telemetry and longitudinal echocardiography were performed between weeks 20 and 28. Final examination included cardiac and vascular morphometry and measurement of the AT1R signaling and receptor internalization (ATRAP). Combined juvenile and adult AT1R blockade caused lower mean arterial pressure (MAP) than adult AT1R blockade alone (84 Ϯ 5 versus 97 Ϯ 5 mm Hg; P Ͻ 0.05). Cardiac and vascular hypertrophy was lower. Juvenile treatments were associated with a reduced cardiovascular AT1R expression and enhanced ATRAP expression. Combined juvenile and reduced adult AT1R blockade resulted in MAP similar to that with adult AT1R blockade alone (92 Ϯ 3 versus 97 Ϯ 5 mm Hg). We conclude that prehypertensive preconditioning improves adult treatment effects in SHHF. Those effects correlate with reduced cardiovascular AT1R expression and enhanced receptor internalization, suggesting reduced angiotensin sensitivity in pretreated SHHF. Moreover, preconditioning allows a reduction of adult AT1R blockade without loss of protection. Therefore, prehypertensive preconditioning may offer a tool to improve treatment efficacy in humans.The awareness of hypertension is poor and, consequently, so is appropriate antihypertensive treatment (Cutler et al., 2008). Therefore, alternative treatment strategies for hypertension and cardiovascular complications are of particular interest. The trial of preventing hypertension (TROPHY) was the first clinical study to demonstrate that a transient prehypertensive treatment (TPT) could successfully delay new onset of hypertension in a cohort of prehypertensive subjects 2 years after withdrawal of an angiotensin II type 1 receptor (AT1R) blocker compared with placebo (Julius et al., 2006). However, TROPHY raised the concern that TPT was a promotion for earlier use of antihypertensive drugs rather than a reliable and efficient addition to antihypertensive treatment (AHT) (Baumann and van den Born, 2006;Grassi, 2006;Meltzer, 2006;Persell and Baker, 2006;Nesbitt, 2007). Indeed, this context has not been investigated in detail. Thus, it remains unclear whether TPT is as effective in blood pressure-lowering and end-organ protection as continuous AHT starting at adulthood. Up to now, the potential preconditioning effects o...

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