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Vol. 298, Issue 2, 469-476, August 2001
Departments of Pharmacology and Toxicology (L.C., X.T.G., J.V.H.,
M.K.), Medicine (Q.F., X.L.), and Pathology (S.C.), University of
Western Ontario, London, Ontario, Canada
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.
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