Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G protein-coupled receptor whose ligand has only been discovered recently. Using a reverse pharmacology paradigm with a stable cell line expressing GHS-R, we purified an endogenous ligand for GHS-R from rat stomach and named it "ghrelin," after a word root ("ghre") in Proto-Indo-European languages meaning "grow." Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin is orexigenic; it is secreted from the stomach and circulates in the bloodstream under fasting conditions, indicating that it transmits a hunger signal from the periphery to the central nervous system. Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates.

https://www.physiology.org/doi/pdf/10.1152/physrev.00012.2004

Ghrelin: Structure and Function

Background Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. Methods We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). Results Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P<0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P<0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated pat...

https://www.nejm.org/doi/pdf/10.1056/NEJM199602013340504

A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension

Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY3-36 (PYY3-36), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut–hypothalamic pathway.

BRIEF COMMUNICATION ARISING: Gut hormone PYY3-36 physiologically inhibits food intake

One hundred years have passed since Felix Hoffman, working at Bayer Industries, reported the successful synthesis of acetylsalicylic acid as the first nonsteroidal antiinflammatory drug (NSAID).1,2 At the suggestion of Hermann Dreser, Bayer's chief pharmacologist at the time,3 the compound was called “aspirin” and was purported to represent a convenient mechanism for the delivery of salicylic acid in the treatment of rheumatic diseases, menstrual pain, and fever.2 Approximately 40 years elapsed before Douthwaite and Lintott4 provided endoscopic evidence that aspirin could cause gastric mucosal damage. Numerous reports have corroborated this observation,5–8 and the introduction of more potent agents . . .

Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.

Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

In 10 cats with chronic gastric fistulas, gastric acid dose-response curves to natural and synthetic caeruleins, pentagastrin and histamine with and without addition of natural or synthetic caeruleins

Effect of caeruleins on histamine-induced gastric secretion and peptic ulcers in cats.

Three synthetic preparations of big gastrin (G-34), little gastrin (G-17) and minigastrin (G-14) have been compared with regard to gastric acid stimulatory potency, rate of disappearance and the relation between acid secretion and the change in serum immunoreactive gastrin in gastric fistula and Heidenhain pouch dogs. Equimolar graded doses (12.5 to 200 pmol/kg-hr) of G-14, G-17 and G-34 produced similar rates of acid secretion with equal ED50 for all three gastrin peptides. Equimolar doses of G-14 and G-17 also resulted in similar increments in serum immunoreactive gastrin, but those of G-34 caused approximately two to three times greater increments in serum gastrin than did G-14 or G-17. The disappearance half-times determined by measuring serum gastrin at short intervals after discontinuation of equimolar dose (1000 pmol/kg-hr) infusions of each gastrin peptide were 1.75, 4.85 and 11.53 min for G-14, G-17 and G-34, respectively. The calculated space of distribution was similar for all three gastrin preparations and ranged from 20-30% body weight. These results indicate that the three major gastrin components differ in half-times and in relating secretory potency, in that relatively higher molar concentrations of G-34 than G-14 or G-17 were required to produce equal rates of acid secretion.

Comparison of biological activity and disappearance rates of synthetic big gastrin, little gastrin and minigastrin in the dog.

The effects of dibutyryl cyclic AMP (db cAMP) on gastric secretion and blood flow were determined in studies on anesthetized and conscious dogs. In 6 experiments on animals under chloralose-urethane anesthesia, gastric secretion, gastric mucosal and left gastroepiploic artery blood flows were measured. In 8 experiments on 4 conscious dogs with gastric fistulas and Heidenhain pouches, gastric secretion and gastric mucosal blood flow were measured in both the stomach and pouch. Gastric secretion was stimulated with intravenous histamine at a dose of 80 microgram/kg-hr for 3 hours, in each of the above experiments. In the second hour db cAMP was infused intravenously at a dose of 0.5 mg/kg-min. In all experiments db cAMP increased gastric mucosal blood flow, but only in the first group of dogs was there an increase in gastric acid secretion. It is concluded that db cAMP at the dose employed, had a vasodilator effect on the gastric mucosa, which does not appear to depend upon the secretory response to the drug.

Effect of dibutyryl cyclic AMP on gastric secretion and mucosal blood flow.

Intravenous amino acids and fat stimulated pancreatic secretion

Effect of orally administered 15(R)-15-methyl prostaglandin E2 and/or an anticholinergic drug on meal-induced gastric acid secretion and serum gastrin level in man

S J Konturek

Papers

Effect of caeruleins on histamine-induced gastric secretion and peptic ulcers in cats.

Comparison of biological activity and disappearance rates of synthetic big gastrin, little gastrin and minigastrin in the dog.

Effect of dibutyryl cyclic AMP on gastric secretion and mucosal blood flow.

Intravenous amino acids and fat stimulated pancreatic secretion

Effect of orally administered 15(R)-15-methyl prostaglandin E2 and/or an anticholinergic drug on meal-induced gastric acid secretion and serum gastrin level in man