Potential of ghrelin receptor ligands in the treatment of cardiovascular disease

DailyUpdates 18th March 2004. Ghrelin receptor antagonists are expected to provide a novel approach to obesity while receptor agonists may be of benefit to the treatment of cardiovascular disease. Japanese researchers have now published data describing how ghrelin reduces blood pressure and how effects on blood pressure may be avoided during the use of ghrelin receptor antagonists to treat obese patients, a population that frequently suffers from hypertension.

It is estimated that somewhere between 34 and 61 million people in the US are obese and in much of the world this incidence is increasing by about 1% per year. As a general guide, obesity increases the likelihood of death from all causes by 20%, and plays a major role in the development of coronary heart disease, stroke, diabetes and gall bladder disease. The world obesity market has been predicted to reach $1.4 billion by 2008 with an average annual growth rate of 12.5%.

There are various approaches to obesity including the reduction of food intake (anorectics) in obese individuals and the use of statins to limit subsequent dislipidemia. Ghrelin is an orexigenic peptide originally isolated from the stomach and in a recent report published by LeadDiscovery, the proof of concept for the development of ghrelin receptor antagonists as anorectics is discussed (click here for the report). In this report the effects of ghrelin on the cardiovascular system are discussed.

In vitro, ghrelin increases myocardial contractility and vasodilatation and inhibits apoptosis of cardiomyocytes and endothelial cells. Administration of ghrelin to healthy humans reduced cardiac afterload and increased cardiac output without an increase in heart rate and data both from patients and from animal models suggests that ghrelin receptor agonists may be of benefit in the treatment of heart failure.

In a upcoming paper due to be published in the journal Hypertension, Japanese researchers describe how the intracerebroventricular administration of ghrelin into the nucleus of the solitary tract significantly decreased the mean arterial pressure and heart rate and also suppressed the renal sympathetic nerve activity. In contrast, administration of ghrelin into other regions of the brain including the area postrema, as well as the rostral, and caudal ventrolateral medulla caused no significant cardiovascular changes. This corresponded with immunohistochemical data revealing that the receptor for ghrelin was expressed in the neuronal cells of the nucleus of the solitary tract and the dorsal motor nucleus of the vagus, but not in the cells of the area postrema.

These results suggest that ghrelin acts at the nucleus of the solitary tract to suppress sympathetic activity and to decrease arterial pressure in rats, and offers one possible mechanism for the cardiovascular effects of ghrelin in humans. While this supports the use of ghrelin receptor agonists in the treatment of cardiovascular disease it urges caution in the use of ghrelin receptor antagonists in patients with cardiovascular disease.

Many obese individuals also suffer from hypertension and hence the development of single treatments that treat both dyslipidemia as well as hypertension may have advantages over therapeutics that target only one of these cardiovascular risk factors. Ghrelin receptor antagonists are unlikely to have this advantage based on current data and furthermore if the promising anorectic potential of such molecules is to be exploited their exposure to the CNS should be minimized to avoid cardiovascular side effects.

(source DailyUpdates 18th March; for a full abstract of the original paper see Hypertension. 2004 Mar 1 [Epub ahead of print])

In this edition of DailyUpdates, LeadDiscovery also highlights data from a phase II trial of cetuximab in patients with refractory colorectal cancer ...heme oxygenase as a potential target for asthma and other airway inflammatory disorders...data describing the critical role of CXCR2 in hyperoxia-induced lung injury...and much more.