KMUP-1 attenuates isoprenaline-induced cardiac hypertrophy in rats through NO/cGMP/PKG and ERK1/2/calcineurin A pathways.

Abstract

BACKGROUND AND PURPOSE:

To determine whether KMUP-1, a novel xanthine-based derivative, attenuates isoprenaline (ISO)-induced cardiac hypertrophy in rats, and if so, whether the anti-hypertrophic effect is mediated by the nitric oxide (NO) pathway.

EXPERIMENTAL APPROACH:

In vivo, cardiac hypertrophy was induced by injection of ISO (5 mg.kg(-1).day(-1), s.c.) for 10 days in Wistar rats. In the treatment group, KMUP-1 was administered 1 h before ISO. After 10 days, effects of KMUP-1 on survival, cardiac hypertrophy and fibrosis, the NO/guanosine 3'5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) and hypertrophy signalling pathways [calcineurin A and extracellular signal-regulated kinase (ERK)1/2] were examined. To investigate the role of nitric oxide synthase (NOS) in the effects of KMUP-1, a NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA) was co-administered with KMUP-1. In vitro, anti-hypertrophic effects of KMUP-1 were studied in ISO-induced hypertrophic neonatal rat cardiomyocytes.

KEY RESULTS:

In vivo, KMUP-1 pretreatment attenuated the cardiac hypertrophy and fibrosis and improved the survival of ISO-treated rats. Plasma NOx (nitrite and nitrate) and cardiac endothelial NOS, cGMP and PKG were all increased by KMUP-1. The activation of hypertrophic signalling by calcineurin A and ERK1/2 in ISO-treated rats was also attenuated by KMUP-1. All these effects of KMUP-1 were inhibited by simultaneous administration of L-NNA. Similarly, in vitro, KMUP-1 attenuated hypertrophic responses and signalling induced by ISO in neonatal rat cardiomyocytes.

CONCLUSIONS AND IMPLICATIONS:

KMUP-1 attenuates the cardiac hypertrophy in rats induced by administration of ISO. These effects are mediated, at least in part, by NOS activation. This novel agent, which targets the NO/cGMP pathway, has a potential role in the prevention of cardiac hypertrophy.

• Authors: Jwu-Lai Yeh, Jong-Hau Hsu, Ping-Ju Wu, Shu-Fen Liou, Chung-Pin Liu, Ing-Jun Chen, Bin-Nan Wu, Zen-Kong Dai, Jiunn-Ren Wu
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 159 Issue 5 Pg. 1151-60 (Mar 2010) ISSN: 1476-5381 [Electronic] England
• PMID: 20132211 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Piperidines
• Xanthines
• KMUP 1
• Nitric Oxide
• Nitric Oxide Synthase
• Cyclic GMP-Dependent Protein Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Calcineurin
• Cyclic GMP
• Isoproterenol

Topics

• Animals
• Calcineurin (metabolism)
• Cardiomegaly (mortality, prevention & control)
• Cyclic GMP (metabolism)
• Cyclic GMP-Dependent Protein Kinases (metabolism)
• Disease Models, Animal
• Drug Delivery Systems
• Fibrosis
• Isoproterenol (toxicity)
• Male
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase (drug effects, metabolism)
• Piperidines (pharmacology)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)
• Survival Rate
• Xanthines (pharmacology)