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Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats
K Numaguchi1, K Egashira, M Takemoto
1Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University Faculty of Medicine, Fukuoka, Japan.
Abstract:
The aim of the present study was to investigate the effects of long-term blockade of nitric oxide synthesis with the L-arginine analogue N omega-nitro-L-arginine methyl ester (L-NAME) for 8 weeks on coronary vascular and myocardial structural changes. Four groups of Wistar-Kyoto rats were studied: those with no treatment, those treated with L-NAME 1 g/L (3.7 mmol/L in drinking water), those treated with L-NAME 0.1 g/L (0.37 mmol/L in drinking water), and those treated with L-NAME 1.0 g/L and hydralazine 120 mg/L (0.6 mmol/L in drinking water). After 8 weeks, the heart was excised, and the degrees of structural changes in coronary arteries (wall-to-lumen ratio and perivascular fibrosis), myocardial fibrosis, and myocyte size were quantified by an image analyzer. Chronic inhibition of nitric oxide synthesis increased arterial pressure compared with control animals. Chronic inhibition of nitric oxide synthesis caused significant microvascular remodeling (increased wall-to-lumen ratio and perivascular fibrosis). Cardiac hypertrophy was also observed after chronic inhibition of nitric oxide synthesis. Coadministration of hydralazine prevented arterial hypertension but did not affect microvascular remodeling and cardiac hypertrophy induced by the chronic inhibition of nitric oxide synthesis. In addition, chronic inhibition of nitric oxide synthesis caused scattered lesions of myocardial fibrosis, which was significantly attenuated by cotreatment with hydralazine. These results suggest that long-term blockade of nitric oxide synthesis caused coronary microvascular remodeling and cardiac hypertrophy in rats in vivo by a mechanism other than arterial hypertension. In contrast, arterial hypertension contributed to the development of myocardial fibrosis induced by long-term blockade of nitric oxide synthesis.
Insights
Long-term blockade of nitric oxide synthesis in rats caused coronary microvascular remodeling and cardiac hypertrophy, independent of increased blood pressure. Hydralazine prevented hypertension but not these structural changes.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
Background:
- Nitric oxide (NO) plays a crucial role in regulating vascular tone and cardiac function.
- Chronic inhibition of NO synthesis can lead to cardiovascular complications.
- Understanding the specific structural impacts of NO blockade is essential for cardiovascular research.
Purpose of the Study:
- To investigate the long-term effects of inhibiting nitric oxide synthesis on coronary vascular and myocardial structures.
- To determine the role of arterial hypertension in mediating these structural changes.
- To assess the impact of co-administering hydralazine on NO blockade-induced alterations.
Main Methods:
- Wistar-Kyoto rats were treated for 8 weeks with varying doses of N omega-nitro-L-arginine methyl ester (L-NAME) to inhibit nitric oxide synthesis.
- A separate group received L-NAME concurrently with hydralazine.
- Coronary artery wall-to-lumen ratio, perivascular fibrosis, myocardial fibrosis, and myocyte size were quantified using an image analyzer.
Main Results:
- Chronic L-NAME administration significantly increased arterial pressure and induced coronary microvascular remodeling (increased wall-to-lumen ratio, perivascular fibrosis).
- Cardiac hypertrophy was observed in rats with inhibited nitric oxide synthesis.
- Hydralazine prevented hypertension but did not ameliorate microvascular remodeling or cardiac hypertrophy.
- Myocardial fibrosis was attenuated by hydralazine, suggesting hypertension contributes to this specific pathology.
Conclusions:
- Long-term blockade of nitric oxide synthesis induces coronary microvascular remodeling and cardiac hypertrophy through mechanisms independent of elevated arterial pressure.
- Arterial hypertension plays a role in the development of myocardial fibrosis associated with nitric oxide synthesis inhibition.
- These findings highlight distinct pathways through which NO deficiency impacts cardiac structure.