Cardiovascular activities of natural and synthetic GH secretagogues.

Ghrelin, a 28 amino acid peptide endowed with a potent GH releasing activity, has been recently isolated in human and rat stomach as a natural ligand of the orphan Growth Hormone Secretagogues (GHS)-receptor type 1a which, in turn, had been identified as specific receptor for synthetic GHS. Synthetic GHS are a family of peptidyl and non-peptidyl molecules that were invented in the late 70s as met-enkephalin derivatives devoid of any opioid activity. However, ghrelin and synthetic GHS are much more than simply GH secretagogues and, acting on central and pheripheral GHS-receptors, they show other actions including stimulation of lactotroph and corticotroph secretion, orexigenic effect, influence on gastro-entero-pancreatic and gonadal functions, metabolic, cardiovascular and anti-proliferative effects. GHS-receptors are highly expressed in the cardiovascular system to mediate biologic activities. Peptidyl GHS protect against post-ischemic ventricular dysfunction in aged as well as in GHD rats, improve cardiac performances after myocardial infarction, protect against diastolic dysfunction of myocardial stunning in rabbits and, similarly to ghrelin, they enhance cardiac contractility in animals with heart failure. In humans, the acute administration of hexarelin increases left ventricular ejection fraction in normal subjects, in hypopituitaric patients with severe GHD, and in patients with ischemic myocardial disease without any variations of mean blood pressure, heart rate and catecholamine levels. Recently, it has been reported that ghrelin administration in normal young volunteers is followed by a reduction of cardiac afterload and an increase of cardiac output without any change in heart rate. The cardivascular activites of natural and synthetic GHS suggest potential pharmaco-therapeutic implications. Theorectically, GHS analogs could be designed to protect from coronaric ischemia and /or to prevent dilated cardiomyopathy improving cardiac performances.