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Chronic administration of moxonidine suppresses sympathetic activation in a rat heart failure model
R Van Kerckhoven1, T A van Veen, F Boomsma
1Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, Netherlands. vankerckhoven@farma.fgg.eur.nl
Abstract:
Excessive sympathetic activity contributes to cardiovascular abnormalities, which negatively affect the prognosis of heart failure. The present study evaluated the effects of moxonidine, an imidazoline I(1) receptor agonist, on sympathetic activation and myocardial remodelling in a rat heart failure model. Rats were subjected to coronary artery ligation, and treated with moxonidine, 3 or 6 mg/kg/day, from 1 to 21 days after myocardial infarction. After 21 days, heart rate and blood pressure were measured in conscious, chronically instrumented rats. Plasma catecholamine levels were determined by high-performance liquid chromatography. Effects on post-myocardial infarction remodelling were evaluated from the ventricular weight body weight ratio and interstitial collagen deposition, measured morphometrically in the interventricular septum remote from the infarcted area. Moxonidine dose-dependently decreased myocardial infarction induced tachycardia but did not affect myocardial infarction reduced blood pressure. Plasma noradrenaline levels, which were elevated after myocardial infarction, decreased below sham-values with 6 mg/kg/day moxonidine. Ventricular weight-body weight ratio as well as interstitial collagen were significantly elevated in myocardial infarcted rats, and restored to sham values with 6 mg/kg/day moxonidine. These data suggest that moxonidine suppresses myocardial infarction induced sympathetic activation in a dose-dependent way as indicated by reduced heart rate and plasma noradrenaline levels. Furthermore, post-myocardial infarction remodelling may be attenuated at a higher dose-range of moxonidine as shown by normalisation of ventricular weight body weight ratio and interstitial collagen.
Insights
Moxonidine, an imidazoline I(1) receptor agonist, reduced sympathetic overactivity and cardiac remodeling in rats post-heart attack. This suggests potential benefits for heart failure prognosis by targeting sympathetic activation.
Area of Science:
- Cardiovascular Pharmacology
- Heart Failure Research
- Sympathetic Nervous System Modulation
Background:
- Excessive sympathetic activity exacerbates cardiovascular dysfunction and worsens heart failure prognosis.
- Myocardial infarction (MI) triggers sympathetic activation and adverse cardiac remodeling.
- Imidazoline I(1) receptor agonists represent a therapeutic target for managing sympathetic overactivity.
Purpose of the Study:
- To investigate the effects of moxonidine on sympathetic activation and myocardial remodeling in a rat model of heart failure.
- To determine the dose-dependent efficacy of moxonidine in mitigating post-MI cardiac abnormalities.
- To assess moxonidine's impact on heart rate, blood pressure, plasma catecholamines, and cardiac structural changes.
Main Methods:
- A rat model of myocardial infarction was established using coronary artery ligation.
- Rats received daily oral administration of moxonidine (3 or 6 mg/kg/day) for 21 days post-MI.
- Physiological parameters (heart rate, blood pressure), plasma catecholamine levels, and cardiac remodeling markers (ventricular weight-to-body weight ratio, interstitial collagen deposition) were assessed.
Main Results:
- Moxonidine dose-dependently reduced tachycardia induced by myocardial infarction.
- High-dose moxonidine (6 mg/kg/day) significantly decreased elevated plasma noradrenaline levels to below sham control values.
- Moxonidine treatment, particularly at the higher dose, normalized the increased ventricular weight-to-body weight ratio and interstitial collagen deposition in infarcted hearts.
Conclusions:
- Moxonidine effectively suppresses sympathetic activation post-myocardial infarction, as evidenced by reduced heart rate and plasma noradrenaline levels.
- Higher doses of moxonidine demonstrate significant potential in attenuating adverse post-MI cardiac remodeling.
- These findings support moxonidine's therapeutic utility in managing heart failure by targeting sympathetic overactivity and structural changes.