AT1 blockade inhibits angiotensinogen and ppET-1 gene overexpression without affecting the onset of myocardial hypertrophy in acutely pressure overloaded pigs

Acute pressure overload causes prompt release of cardiac angiotensin II with early myocyte overexpression of angiotensinogen (AGTN) and prepro-endothelin-1 (ppET-1) genes, followed by increased IGF-I mRNA expression. Aim of the present study was to investigate the role of AT1 angiotensin receptors in the activation of these cardiac growth factor genes in vivo. Forty-eight pigs (35±5 kg) underwent aortic banding (transtenotic gradient =60 mmHg) and eight animals were sham operated. Three days before surgery animals were randomized to valsartan 80 mg/die, or placebo. AT-1 receptor blockade was demonstrated by the 60% reduction in mean blood pressure response to ANG II infusion (1-10 µg/kg). At baseline, 3, 6, 12, 24 hours and 2, 3 and 4 days after surgical procedure, echocardiographic and hemodynamic measurements were performed and strain (1/wall thickness) and end systolic stiffness constant (Ksm) (a preload and afterload independent contractility index) were calculated. Cardiac AGTN, pp-ET-1, and IGF-I mRNA expression was measured by RT-PCR using specific primers with GAPDH as internal standard. AT1 blockade did not alter acute left ventricular loading conditions because neither pressure nor ventricular dimensions at 3 hours differed between placebo- and valsartan-treated animals. Likewise the maximum effect of loading on myocardium, as indicated by strain, was unaffected by AT1 blockade. Left ventricular hypertrophy progressively developed with no difference between groups (LVM at 72 h, p < 0.01 vs baseline for both, ns between groups). However, Ksm rapidly recovered in placebo-treated animals (ns vs baseline at 12 h), whereas in AT1 blocked animals Ksm was depressed at 12 and 24 hours (p<0.05) and end-systolic wall stress (ESS) was still elevated up to 48 hours. The growth factor mRNA expression was modified by AT-1 receptor blockade which abolished the prompt increase in AGTN (16 times at 3 h) and ppET-1 mRNA levels (112 times at 6 h) which followed aortic banding in placebo-treated animals. Conversely, the upregulation of IGF-I mRNA was almost unaffected (10 times at 24 h). In conclusion AT1 receptors play a physiological role in the cardiac adaptive response to acute pressure overload and their blockade dramatically reduces the AGTN and ppET-1 gene expression impairing the recovery of myocardial contractility.