Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats

Abstract

1. This study has administered pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) or amiloride to attenuate the remodelling and associated functional changes, especially an increased cardiac stiffness, in DOCA-salt hypertensive rats. 2. In control rats, the elimination half-life of pirfenidone following a single intravenous dose of 200 mg kg-1 was 37 min while oral bioavailability at this dose was 25.7%. Plasma pirfenidone concentrations in control rats averaged 1.9±0.1 μg ml-1 over 24 h after 14 days' administration as a 0.4% mixture in food. 3. Pirfenidone (approximately 250-300 mg kg-1 day-1 as 0.4% in food) and amiloride (1 mg kg-1 day-1 sc) were administered for 2 weeks starting 2 weeks post-surgery. Pirfenidone but not amiloride attenuated ventricular hypertrophy (2.69±0.09, UNX 2.01±0.05. DOCA-salt 3.11±0.09 mg kg-1 body wt) without lowering systolic blood pressure. 4. Collagen deposition was significantly increased in the interstitium after 2 weeks and further increased with scarring of the left ventricle after 4 weeks; pirfenidone and amiloride reversed the increases and prevented further increases. This accumulation of collagen was accompanied by an increase in diastolic stiffness constant; both amiloride and pirfenidone reversed this increase. 5. Noradrenaline potency (positive chronotropy) was decreased in right atria (neg log EC50: Control 6.92±0.06; DOCA-salt 6.64±0.08); pirfenidone but not amiloride reversed this change. Noradrenaline was a more potent vasoconstrictor in thoracic aortic rings (neg log EC50: control 6.91±0.10; DOCA-salt 7.90±0.07); pirfenidone treatment did not change noradrenaline potency. 6. Thus, pirfenidone and amiloride reverse and prevent cardiac remodelling and the increased cardiac stiffness without reversing the increased vascular responses to noradrenaline.