Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA‐salt hypertensive rats
S Mirkovic, AML Seymour, A Fenning… - British journal of …, 2002 - Wiley Online Library
British journal of pharmacology, 2002•Wiley Online Library
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. 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 …
to attenuate the remodelling and associated functional changes, especially an increased
cardiac stiffness, in DOCA‐salt hypertensive rats. 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 …
- 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.
- 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.
- 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.
- 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.
- 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.
- Thus, pirfenidone and amiloride reverse and prevent cardiac remodelling and the increased cardiac stiffness without reversing the increased vascular responses to noradrenaline.
British Journal of Pharmacology (2002) 135, 961–968; doi:10.1038/sj.bjp.0704539
Wiley Online Library