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Regression of hypertensive myocardial fibrosis by Na(+)/H(+) exchange inhibition
Horacio E Cingolani1, Oscar R Rebolledo, Enrique L Portiansky
1Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas and Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, Argentina. cicmes@infovia.com.ar
Insights
Longer treatment with the Na(+)/H(+) exchanger (NHE)-1 inhibitor cariporide normalized myocardial fibrosis and stiffness in spontaneously hypertensive rats (SHR). This suggests NHE-1 inhibition may be a viable therapeutic strategy for hypertensive heart disease.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Physiology
Background:
- Previous studies showed 1-month Na(+)/H(+) exchanger (NHE) inhibition regressed cardiomyocyte hypertrophy but not myocardial fibrosis in spontaneously hypertensive rats (SHR).
- Hypertension is associated with cardiomyocyte hypertrophy, myocardial fibrosis, and increased cardiac stiffness.
Purpose of the Study:
- To investigate if longer-duration NHE-1 inhibition with cariporide could reduce myocardial fibrosis and stiffness in SHR.
- To evaluate the effects of cariporide on cardiomyocyte size, collagen content, collagen synthesis, and myocardial stiffness over time.
Main Methods:
- Spontaneously hypertensive rats (SHR) received daily treatment with 3.0 mg/kg of the NHE-1 inhibitor cariporide.
- Evaluations included cardiomyocyte cross-sectional area, myocardial collagen volume fraction, collagen synthesis markers, and myocardial stiffness (length-tension relation).
- Measurements were taken at 1, 2, and 3 months of treatment.
Main Results:
- Systolic blood pressure showed a slight decrease after 1 month, with no further changes.
- Cardiomyocyte size normalized, and myocardial fibrosis progressively decreased to normal levels after 2 and 3 months.
- Myocardial stiffness and collagen type I synthesis normalized after 3 months of treatment. Left ventricular weight also decreased.
Conclusions:
- Administration of an NHE-1 inhibitor for 2 or 3 months normalized collagen type I synthesis, myocardial collagen volume fraction, and stiffness in SHR.
- Longer-duration NHE-1 inhibition effectively reverses established myocardial fibrosis and stiffness in this hypertensive model.
- These findings suggest potential therapeutic benefits of NHE-1 inhibitors for managing hypertensive heart disease complications.
Abstract:
We have recently reported that the inhibition of the Na(+)/H(+) exchanger (NHE) during 1 month in spontaneously hypertensive rats (SHR) is followed by regression of cardiomyocyte hypertrophy but not of myocardial fibrosis. The aim of this study was to evaluate whether a treatment of longer duration could reduce myocardial fibrosis and stiffness. SHR received 3.0 mg/kg per day of the specific NHE-1 inhibitor cariporide; the effect on cardiomyocyte cross-sectional area, myocardial collagen volume fraction, collagen synthesis, and myocardial stiffness (length-tension relation in left papillary muscles) was evaluated at several time points (after 1, 2, or 3 months). A slight decrease of approximately 5 mm Hg in systolic blood pressure was observed after 1 month of treatment with no further changes. After 2 and 3 months of treatment, the size of cardiomyocytes remained within normal values and myocardial fibrosis progressively decreased to normal level. Accordingly, myocardial stiffness and the serum levels of the carboxyterminal propeptide of procollagen type I, a marker of collagen type I synthesis, were normalized after 3 months. Left ventricular weight decreased from 910+/-43 (in untreated SHR) to 781+/-21 mg (treated SHR) after 3 months of treatment. No difference in body weight between treated and untreated SHR was observed after this period of treatment. The present data allow us to conclude that in the SHR the administration of an NHE-1 inhibitor for 2 or 3 months leads to the normalization of collagen type I synthesis, myocardial collagen volume fraction, and stiffness.
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