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Evidence for load-dependent and load-independent determinants of cardiac natriuretic peptide production
1University of Ottawa Heart Institute, Ottawa Civic Hospital, Ontario, Canada.
Insights
Hypertension and cardiac hypertrophy increase natriuretic peptide (NP) production. Ramipril treatment effectively reduces both, with higher doses normalizing all parameters, while lower doses target hypertrophy and collagen levels.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Molecular Biology
Background:
- Hypertension and cardiac hypertrophy increase cardiac natriuretic peptide (NP) production.
- The distinct roles of cardiac load and hypertrophy in NP synthesis are unclear.
- This study investigates NP regulation in response to aortic banding and ACE inhibition.
Purpose of the Study:
- To determine the contributions of cardiac load and hypertrophy to natriuretic peptide (NP) production.
- To evaluate the effects of different ramipril dosages on hypertension, cardiac hypertrophy, and NP levels.
- To assess ramipril's impact on ventricular remodeling markers like collagen and myosin heavy chain (MHC) isoforms.
Main Methods:
- Rats underwent suprarenal aortic banding to induce hypertension and hypertrophy.
- Rats were treated with high-dose (1 mg/kg) or low-dose (10 µg/kg) ramipril post-banding.
- Measurements included blood pressure, cardiac hypertrophy markers, plasma and ventricular NP levels, NP mRNA, collagen III mRNA, and beta-MHC mRNA.
Main Results:
- Aortic banding increased blood pressure, cardiac weight, NP levels, and collagen III and beta-MHC mRNA.
- High-dose ramipril normalized all measured parameters.
- Low-dose ramipril normalized cardiac weight and collagen III mRNA but not blood pressure or beta-MHC mRNA.
Conclusions:
- Natriuretic peptide production is independently regulated by blood pressure and hypertrophy.
- Cardiac load is a more significant driver of left ventricular NP production than hypertrophy alone.
- Low-dose ramipril effectively reverses hypertrophy and collagen deposition, but not beta-MHC isoform changes, indicating independent regulation.
- Atrial NP production remains unaffected by aortic banding or ACE inhibition.
Background:
In hypertension with cardiac hypertrophy, the specific contributions to increased production of the cardiac natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) by load and the hypertrophic process are not known. In the present work we determine ANF and BNP synthesis and secretion in the aortic-banded rat treated with dosage schedules of the ACE inhibitor ramipril that result in the prevention or regression of both hypertension and hypertrophy (high dosage) or in the prevention or regression of hypertrophy alone with persistent hypertension (low dosage). Myosin heavy chain (MHC) isoform switch was studied as an indicator of ventricular cardiocyte hypertrophy as well as the levels of collagen III mRNA as a measure of changes in extracellular matrix.
Methods And Results:
Ramipril was administered for 6 weeks just after suprarenal aortic banding, or rats were banded for 6 weeks, after which ramipril was administered during the following 6 weeks. Banding caused an increase in blood pressure, left ventricular weight-to-body weight ratio, plasma and ventricular NP, ventricular NP mRNA, collagen III, and beta-MHC mRNA. Ramipril at 1 mg/kg normalized all these parameters while ramipril at 10 micrograms/kg normalized left ventricular weight-to-body weight ratio but not blood pressure. Plasma and ventricular NP content and mRNA levels were partially normalized by ramipril (10 micrograms/kg). Ramipril (10 micrograms/kg) prevented increased collagen III mRNA levels but did not affect beta-MHC mRNA levels.
Conclusions:
(1) NP production and secretion in aortic-banded rats are independently related to increased blood pressure and hypertrophy. (2) A load-dependent component is more important than a load-independent component in regulating left ventricular NP production. (3) ANF production is more sensitive than BNP production to the load-independent component. (4) Low-dose ramipril treatment reverses hypertrophy and the increased collagen III expression but does not reverse the increased beta-MHC isoform expression, suggesting that these are independently regulated processes. (5) Aortic banding and ACE inhibition do not affect atrial NP production and content.
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