Moxonidine improves cardiac structure and performance in SHR through inhibition of cytokines, p38 MAPK and Akt

Abstract

BACKGROUND AND PURPOSE Regression of left ventricular hypertrophy by moxonidine, a centrally acting sympatholytic imidazoline compound, results from a sustained reduction of DNA synthesis and transient stimulation of DNA fragmentation. Because apoptosis of cardiomyocytes may lead to contractile dysfunction, we investigated in spontaneously hypertensive rats (SHR), time‐ and dose‐dependent effects of in vivo moxonidine treatment on cardiac structure and function as well as on the inflammatory process and signalling proteins involved in cardiac cell survival/death. EXPERIMENTAL APPROACH 12 week old SHR received moxonidine at 0, 100 and 400 µg·kg−1·h−1, s.c., for 1 and 4 weeks. Cardiac function was evaluated by echocardiography; plasma cytokines were measured by elisa and hearts were collected for histological assessment of fibrosis and measurement of cardiac proteins by Western blotting. Direct effects of moxonidine on cardiac cell death and underlying mechanisms were investigated in vitro by flow cytometry and Western blotting. KEY RESULTS After 4 weeks, the sub‐hypotensive dose of moxonidine (100 µg) reduced heart rate and improved global cardiac performance, reduced collagen deposition, regressed left ventricular hypertrophy, inhibited Akt and p38 MAPK phosphorylation, and attenuated circulating and cardiac cytokines. The 400 µg dose resulted in similar effects but of a greater magnitude, associated with blood pressure reduction. In vitro, moxonidine inhibited norepinephrine‐induced neonatal cardiomyocyte mortality but increased fibroblast mortality, through I1‐receptor activation and differential effects on downstream Akt and p38 MAPK. CONCLUSIONS AND IMPLICATIONS While the antihypertensive action of centrally acting imidazoline compounds is appreciated, new cardiac‐selective I1‐receptor agonists may confer additional benefit.

The urinary bladder of spontaneously hypertensive rat demonstrates bladder hypertrophy, inflammation, and fibrosis but not hyperplasia

“…The causes of arterial smooth muscle hypertrophy and myocardial fibrosis are unknown. Inhibition of cytokines, p38 MAPK and Akt improves cardiac structure and performance in SHR by reducing collagen deposition and left ventricular hypertrophy [42]. Consistently, our results showed an increased level of cytokine production in the urinary bladder and the up-regulation of ERK1/2 activity.…”

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

“…3A). These findings in STZ rats are supported by similar responses caused by chronic moxonidine administration in other model systems including SHRs and cardiomyocytes (Aceros et al, 2011; El-Ayoubi et al, 2004; Ernsberger et al, 1999; Hamilton et al, 1993; Mukaddam-Daher, 2012). Second, we present a novel molecular mechanism for the favorable cardiovascular and redox effects of moxonidine in diabetes based on recent evidence that identified DAPK3 as an upstream activator of MAPKs, and as a mediator of oxidative stress and hypertension (Usui et al, 2012).…”

Moxonidine-induced central sympathoinhibition improves prognosis in rats with hypertensive heart failure

“…The lower end (shorter arm) of the cannula (Alzetbrain infusion kit 2; DURECT Corporation, Cupertino, California, USA) was placed at a depth of 3.5 mm from the dura, and the upper end (longer arm) was connected to an osmotic minipump (Alzet Model 2006; DURECT Corporation) for chronic ICV infusion of moxonidine (4 mmol/l; infusion rate 0.15 ml/h for 42 days) or vehicle [artificial cerebrospinal fluid (aCSF) pH 7.4] as a control at 0.15 ml/h for 42 days. This approach was used to observe the direct central sympathoinhibitory effect of a much smaller dose of moxonidine to exclude potential peripheral actions of moxonidine, such as on the kidney and heart [10,21,22]. Moxonidine was obtained from Sigma Aldrich Corporation (St Louis, Missouri, USA) and dissolved in aCSF.…”