Research Paper
Subject Category: Cardiovascular and pulmonary pharmacology
British Journal of Pharmacology (2008) 153, 459–467; doi:10.1038/sj.bjp.0707588; published online 3 December 2007
Control of left ventricular mass by moxonidine involves reduced DNA synthesis and enhanced DNA fragmentation
P-A Paquette1, D Duguay2, R El- Ayoubi1, A Menaouar1, B Danalache1, J Gutkowska1, D DeBlois2 and S Mukaddam-Daher1
- 1Laboratory of Cardiovascular Biochemistry, Centre Hospitalier de L'Université de Montréal Research Center, Campus Hotel-Dieu and Department of Medicine, Université de Montréal, Montréal, Quebec, Canada
- 2Department of Pharmacology, Université de Montréal, Montréal, Quebec, Canada
Correspondence: Dr S Mukaddam-Daher, Laboratory of Cardiovascular Biochemistry, CHUM Research Center, 3840 St-Urbain Street (7-133), Montréal, Quebec, Canada H2W 1T8. E-mail: suhayla.mukaddam-daher@umontreal.ca
Received 17 May 2007; Revised 10 October 2007; Accepted 19 October 2007; Published online 3 December 2007.
Abstract
Background and purpose:
Left ventricular hypertrophy (LVH) is a maladaptive process associated with increased cardiovascular risk. Regression of LVH is associated with reduced complications of hypertension. Moxonidine is an antihypertensive imidazoline compound that reduces blood pressure primarily by central inhibition of sympathetic outflow and by direct actions on the heart to release atrial natriuretic peptide, a vasodilator and an antihypertrophic cardiac hormone. This study investigated the effect of moxonidine on LVH and the mechanisms involved in this effect.
Experimental approach:
Spontaneously hypertensive rats were treated with several doses of moxonidine (s.c.) over 4 weeks. Blood pressure and heart rate were continuously monitored by telemetry. Body weight and water and food intake were measured weekly. Measurements also included left ventricular mass, DNA content, synthesis, fragmentation, and apoptotic/anti-apoptotic pathway proteins.
Key results:
The decrease in mean arterial pressure stabilized at 
-10 mm Hg after 1 week of treatment and thereafter. Compared to vehicle-treated rats (100%), left ventricular mass was dose- and time-dependently reduced by treatment. This reduction remained significantly lower after normalizing to body weight. Moxonidine reduced left ventricular DNA content and inhibited DNA synthesis. DNA fragmentation transiently, but significantly increased at 1 week of moxonidine treatment and was paralleled by elevated active caspase-3 protein. The highest dose significantly decreased the apoptotic protein Bax and all doses stimulated anti-apoptotic Bcl-2 after 4 weeks of treatment.
Conclusions and implications:
These studies implicate the modulation of cardiac DNA dynamics in the control of left ventricular mass by moxonidine in a rat model of hypertension.
Keywords:
left ventricular hypertrophy, hypertension, moxonidine, apoptosis, DNA fragmentation, DNA synthesis
Abbreviations:
ABTS, 2,2'-azino-di-(3- ethylbenzthiazoline sulphonate; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; AT1, angiotensin receptor type 1; AT2, angiotensin receptor type 2; HPS, heamatoxylin, phloxine, saffron; LV, left ventricle; LVH, left ventricular hypertrophy; LVM, left ventricular mass; OD, optical density; RAAS, renin–angiotensin–aldosterone system; SHR, spontaneously hypertensive rat; SNS, sympathetic nervous system; TDT, deoxynucleotidyl transferase
