Attenuation of compensatory right ventricular hypertrophy and heart failure following monocrotaline-induced pulmonary vascular injury by the Na+-H+ exchange inhibitor cariporide.
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.
Chen
L
L
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada.
Gan
X T
XT
Haist
J V
JV
Feng
Q
Q
Lu
X
X
Chakrabarti
S
S
Karmazyn
M
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis; D048429:Cell Size / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D016686:Monocrotaline; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D011042:Poisons; D011651:Pulmonary Artery / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D011042:Poisons; D012333:RNA, Messenger; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D016686:Monocrotaline; C093373:cariporide; D009320:Atrial Natriuretic Factor