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Research ArticleCARDIOVASCULAR

Attenuation of Compensatory Right Ventricular Hypertrophy and Heart Failure following Monocrotaline-Induced Pulmonary Vascular Injury by the Na+-H+ Exchange Inhibitor Cariporide

Ling Chen, Xiaohong Tracey Gan, James V. Haist, Qingping Feng, Xiangru Lu, Subrata Chakrabarti and Morris Karmazyn
Journal of Pharmacology and Experimental Therapeutics August 2001, 298 (2) 469-476;
Ling Chen
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Xiaohong Tracey Gan
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James V. Haist
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Qingping Feng
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Xiangru Lu
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Subrata Chakrabarti
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Morris Karmazyn
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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

  • 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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Journal of Pharmacology and Experimental Therapeutics: 298 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 2
1 Aug 2001
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Research ArticleCARDIOVASCULAR

Attenuation of Compensatory Right Ventricular Hypertrophy and Heart Failure following Monocrotaline-Induced Pulmonary Vascular Injury by the Na+-H+ Exchange Inhibitor Cariporide

Ling Chen, Xiaohong Tracey Gan, James V. Haist, Qingping Feng, Xiangru Lu, Subrata Chakrabarti and Morris Karmazyn
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 469-476;

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Research ArticleCARDIOVASCULAR

Attenuation of Compensatory Right Ventricular Hypertrophy and Heart Failure following Monocrotaline-Induced Pulmonary Vascular Injury by the Na+-H+ Exchange Inhibitor Cariporide

Ling Chen, Xiaohong Tracey Gan, James V. Haist, Qingping Feng, Xiangru Lu, Subrata Chakrabarti and Morris Karmazyn
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 469-476;
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