Abstract
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.
Footnotes
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This study was funded by a grant from the Canadian Institutes of Health Research. Dr. Karmazyn is a Career Investigator of the Heart and Stroke Foundation of Ontario.
- Abbreviations:
- RV
- right ventricle
- ANP
- atrial natriuretic peptide
- MCT
- monocrotaline
- NHE-1
- Na+-H+exchange isoform 1
- LV
- left ventricle
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- dNTP
- deoxynucleotide triphosphate
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- PKC
- protein kinase C
- DEPC
- diethyl pyrocarbonate
- Received February 14, 2001.
- Accepted May 1, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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