Attenuation of compensatory right ventricular hypertrophy and heart failure following monocrotaline-induced pulmonary vascular injury by the Na+-H+ exchange inhibitor cariporide

J Pharmacol Exp Ther. 2001 Aug;298(2):469-76.


Pulmonary hypertension results in compensatory right ventricular (RV) hypertrophy. We studied the role of the Na+-H+ exchange (NHE) in the latter process by determining the effect of the NHE-1 inhibitor cariporide after monocrotaline-induced pulmonary artery injury. Sprague-Dawley rats received a control or cariporide diet for 7 days, at which time they were administered either monocrotaline (60 mg/kg) or its vehicle. Twenty-one days later, monocrotaline control, but not cariporide-fed animals, demonstrated increased RV weights and cell size of 65 and 52%, respectively. Monocrotaline alone significantly increased RV systolic pressure and end diastolic pressure by 70 and 94%, respectively, whereas corresponding values with cariporide were significantly reduced to 33 and 42%. Central venous pressure increased by 414% in control animals, which was significantly reduced by cariporide. Monocrotaline treatment produced a decrease in cardiac output of 28 and 8% in the absence or presence of cariporide (P < 0.05 between groups), respectively. Although body weights were significantly lower in both monocrotaline-treated groups compared with vehicle treatment, with cariporide the net gain in body weight was twice that seen in the monocrotaline-treated animals without cariporide. Monocrotaline also increased RV NHE-1 and atrial natriuretic peptide mRNA expression, which was abrogated by cariporide. Monocrotaline-induced myocardial necrosis, fibrosis, and mononuclear infiltration was completely prevented by cariporide. Cariporide had no effect on monocrotaline-induced pulmonary intimal wall thickening. Our results demonstrate that cariporide directly attenuates myocardial dysfunction after monocrotaline administration independent of pulmonary vascular effects. NHE-1 inhibition may represent an effective adjunctive therapy that selectively targets myocardial hypertrophic responses in pulmonary vascular injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / pharmacology*
  • Atrial Natriuretic Factor / biosynthesis
  • Cell Size / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Guanidines / pharmacology*
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Hemodynamics / drug effects
  • Hypertrophy, Right Ventricular / drug therapy*
  • Hypertrophy, Right Ventricular / pathology
  • Hypertrophy, Right Ventricular / physiopathology
  • Lung / pathology
  • Lung Diseases / chemically induced
  • Lung Diseases / pathology
  • Lung Diseases / physiopathology*
  • Male
  • Monocrotaline*
  • Myocardium / pathology
  • Organ Size
  • Poisons*
  • Pulmonary Artery / pathology
  • Pulmonary Circulation / drug effects*
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Hydrogen Exchangers / antagonists & inhibitors*
  • Sulfones / pharmacology*


  • Anti-Arrhythmia Agents
  • Enzyme Inhibitors
  • Guanidines
  • Poisons
  • RNA, Messenger
  • Sodium-Hydrogen Exchangers
  • Sulfones
  • Monocrotaline
  • cariporide
  • Atrial Natriuretic Factor