Influence of angiotensin II subtype 2 receptor (AT(2)R) antagonist, PD123319, on cardiovascular remodelling of aged spontaneously hypertensive rats during chronic angiotensin II subtype 1 receptor (AT(1)R) blockade

Cardiac AT(2)R expression is upregulated in the normal process of aging. In this study we determined the contribution of AT(2)R to chronic antihypertensive and remodelling effects of AT(1)R blockade in aged hypertensive rats. Adult (20 weeks) and senescent (20 months) spontaneously hypertensive rats (SHRs) were treated with either the AT(1)R antagonist, candesartan cilexetil (2 mg/kg/day), the AT(2)R antagonist, PD123319 (10 mg/kg/day), or a combination of the 2 compounds. Mean arterial pressure (MAP) and left ventricular volume were markedly decreased by candesartan cilexetil, however, simultaneous treatment with PD123319 had no additional effect on either parameter. Perivascular fibrosis was significantly reduced by candesartan cilexetil in aged animals only, and this effect was reversed by concomitant PD123319 administration. Vascular hypertrophy was reduced by candesartan cilexetil, and these effects were reversed by simultaneous PD123319. These results suggest that AT(2)R stimulation does not significantly influence the antihypertensive effect of chronic AT(1)R blockade, but plays a role in the regulation of vascular structure. The severe degree of cardiac perivascular fibrosis in senescent animals was regressed by AT(1)R blockade and this effect was reversed by simultaneous AT(2)R inhibition, demonstrating an antifibrotic role of AT(2)R stimulation in the aging hypertensive heart.