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Published on: August 18, 2014
Urinary responses to acute moxonidine are inhibited by natriuretic peptide receptor antagonist
Rouwayda El-Ayoubi1, Ahmed Menaouar, Jolanta Gutkowska
1Laboratory of Cardiovascular Biochemistry, Centre hospitalier de l'Université de Montréal-Hotel-Dieu, and Department of Medicine, Université de Montréal, Montreal (Quebec), Canada.
Abstract:
We have previously shown that acute intravenous injections of moxonidine and clonidine increase plasma atrial natriuretic peptide (ANP), a vasodilator, diuretic and natriuretic hormone. We hypothesized that moxonidine stimulates the release of ANP, which would act on its renal receptors to cause diuresis and natriuresis, and these effects may be altered in hypertension. Moxonidine (0, 10, 50, 100 or 150 microg in 300 microl saline) and clonidine (0, 1, 5 or 10 microg in 300 microl saline) injected intravenously in conscious normally hydrated normotensive Sprague-Dawley rats (SD, approximately 200 g) and 12-14-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) dose-dependently stimulated diuresis, natriuresis, kaliuresis and cGMP excretion, with these effects being more pronounced during the first hour post-injection. The actions of 5 microg clonidine and 50 microg moxonidine were inhibited by yohimbine, an alpha2-adrenoceptor antagonist, and efaroxan, an imidazoline I1-receptor antagonist. Moxonidine (100 microg) stimulated (P<0.01) diuresis in SHR (0.21+/-0.04 vs 1.16+/-0.06 ml h(-1) 100 g(-1)), SD (0.42+/-0.06 vs 1.56+/-0.19 ml h(-1) 100 g(-1)) and WKY (0.12+/-0.04 vs 1.44+/-0.21 ml h(-1) 100 g(-1)). Moxonidine-stimulated urine output was lower in SHR than in SD and WKY. Moxonidine-stimulated sodium and potassium excretions were lower in SHR than in SD, but not WKY, demonstrating an influence of strain but not of pressure. Pretreatment with the natriuretic peptide antagonist anantin (5 or 10 microg) resulted in dose-dependent inhibition of moxonidine-stimulated urinary actions. Anantin (10 microg) inhibited (P<0.01) urine output to 0.38+/-0.06, 0.12+/-0.01, and 0.16+/-0.04 ml h(-1) 100 g(-1) in SD, WKY, and SHR, respectively. Moxonidine increased (P<0.01) plasma ANP in SD (417+/-58 vs 1021+/-112 pg ml(-1)) and WKY (309+/-59 vs 1433+/-187 pg ml(-1)), and in SHR (853+/-96 vs 1879+/-229 pg ml(-1)). These results demonstrate that natriuretic peptides mediate the urinary actions of moxonidine through natriuretic peptide receptors.
Insights
Moxonidine and clonidine stimulate the release of atrial natriuretic peptide (ANP), a hormone that promotes urination and sodium excretion. These effects are mediated by ANP acting on renal receptors, with some differences observed in hypertensive rats.
Area of Science:
- Pharmacology
- Nephrology
- Cardiovascular Physiology
Background:
- Previous studies indicated that moxonidine and clonidine increase plasma atrial natriuretic peptide (ANP).
- ANP is a hormone known for its vasodilator, diuretic, and natriuretic properties.
- Hypertension may alter the renal response to ANP-mediated effects.
Purpose of the Study:
- To investigate if moxonidine stimulates ANP release.
- To determine if ANP mediates diuresis and natriuresis induced by moxonidine.
- To examine potential alterations in these effects in the context of hypertension.
Main Methods:
- Intravenous administration of moxonidine and clonidine to normotensive (Sprague-Dawley, Wistar-Kyoto) and spontaneously hypertensive rats (SHR).
- Dose-dependent assessment of diuresis, natriuresis, kaliuresis, and cGMP excretion.
- Pharmacological blockade using yohimbine (alpha2-adrenoceptor antagonist) and efaroxan (imidazoline I1-receptor antagonist).
- Administration of anantin (natriuretic peptide antagonist) to evaluate ANP's role.
- Measurement of plasma ANP levels.
Main Results:
- Moxonidine and clonidine dose-dependently stimulated diuresis, natriuresis, kaliuresis, and cGMP excretion, effects more pronounced in the first hour.
- The actions of clonidine and moxonidine were inhibited by yohimbine and efaroxan.
- Moxonidine-stimulated urine output and electrolyte excretion were lower in SHR compared to normotensive rats, suggesting strain-specific influences.
- Anantin significantly inhibited moxonidine-induced urinary effects.
- Moxonidine administration led to a significant increase in plasma ANP levels across all rat strains.
Conclusions:
- Natriuretic peptides are confirmed to mediate the urinary actions of moxonidine.
- These effects are mediated through natriuretic peptide receptors.
- While hypertension (SHR) showed some altered responses, the primary mechanism involves ANP, indicating strain-specific, rather than pressure-specific, influences on these pathways.
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