Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats.
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 microg 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.
Mirkovic
Stevo
S
Department of Physiology and Pharmacology, School of Biomedical Sciences, The University of Queensland, Australia.
Seymour
Anne-Marie L
AM
Fenning
Andrew
A
Strachan
Anna
A
Margolin
Solomon B
SB
Taylor
Stephen M
SM
Brown
Lindsay
L
D000584:Amiloride / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001682:Biological Availability; D003094:Collagen / Q000032:analysis; D003900:Desoxycorticosterone; D005355:Fibrosis; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology*; D009638:Norepinephrine / Q000494:pharmacology; D011728:Pyridones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017673:Sodium Chloride, Dietary; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; D017673:Sodium Chloride, Dietary; D014662:Vasoconstrictor Agents; D003900:Desoxycorticosterone; D000584:Amiloride; D003094:Collagen; C093844:pirfenidone; D009638:Norepinephrine