Role of angiotensin II AT1 and AT2 subtype receptors in the regulation of atrial natriuretic peptide expression in salt-restricted rats

Previous studies have suggested that angiotensin II modulates ANP secretion and this action appears to be largely independent from its hemodynamic effects. In order to explore the contribution of angiotensin II AT₁ (AT₁r) and AT₂ (AT₂r) receptor subtypes in the regulation of cardiac ANP, we studied the effects of selective antagonists of these receptors on ANP mRNA levels in the cardiac chambers of salt-restricted rats. Thirty-one Sprague-Dawley rats (12 weeks-old) weighing 250-350 g were studied during a low salt regimen and randomly assigned to the following treatment groups: AT₁r-blockade (losartan) (10 mg/kg/day) (n = 18), AT₂r-blockade (PD123319) (50 μg/kg/min) (n = 6), Control (salt-restriction) (n = 7). Treatments were maintained for 7 days; subsequently, 12 rats from the AT₁r-blockade group were subdivided in to two groups: AT₁r/AT₂r-blockade (losartan+PD123319) (n = 6) and AT₁r-blockade/vehicle (losartan+vehible) (n = 6), and treated for 7 additional days. Systolic blood pressure was significantly reduced by AT₁r-blockade (p <0.001), while it was not affected by AT₂r-blockade. Concomitant treatment with both antagonists (AT₁r/AT₂r-blockade) restored blood pressure values to baseline (p <0.001 vs. AT₁r-blockade, p = n.s. vs Control). Atrial ANP mRNA was reduced by AT₁r-blockade (-42 %, p <0.05) and did not change during AT₂r-blockade alone. On the contrary, concomitant treatment with both antagonists resulted in a further significant inhibition of ANP expression (-65 % and -36 % vs Control and AT₁r-blockade, respectively, both p <0.05). ANP expression in ventricles was not affected by any of these treatments. Our results demonstrate that angiotensin II tonically modulates cardiac ANP expression in our experimental model. In particular, angiotensin II receptor subtypes AT₁r and AT₂r regulate atrial ANP mRNA levels through a synergic action and independently from blood pressure changes.