The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

This review addresses pharmacological, structural and functional relationships among H2-histamine receptors and H1-histamine receptors in the mammalian heart. The role of both receptors in the regulation of force and rhythm, including their electrophysiological effects on the mammalian heart, will then be discussed in context. The potential clinical role of cardiac H2-histamine-receptors in cardiac diseases will be examined. The use of H2-histamine receptor agonists to acutely increase the force of contraction will be discussed. Special attention will be paid to the potential role of cardiac H2-histamine receptors in the genesis of cardiac arrhythmias. Moreover, novel findings on the putative role of H2-histamine receptor antagonists in treating chronic heart failure in animal models and patients will be reviewed. Some limitations in our biochemical understanding of the cardiac role of H2-histamine receptors will be discussed. Recommendations for further basic and translational research on cardiac H2-histamine receptors will be offered. We will speculate whether new knowledge might lead to novel roles of H2-histamine receptors in cardiac disease and whether cardiomyocyte specific H2-histamine receptor agonists and antagonists should be developed.

Effects of sex steroid receptor agonists and antagonists on the expression of the FOXL2 transcription factor and its target genes AMH and CYP19A1 in the neonatal porcine ovary

Recently, we have demonstrated that neonatal exposure to androgen and estrogen agonists or antagonists influenced the number of ovarian follicles in piglets. Since the FOXL2 transcription factor is required for proper ovarian follicle formation and activation, the objective of the study was to examine effects of exposure of the neonatal porcine ovary to testosterone propionate (TP; an androgen), flutamide (FLU; an antiandrogen), 4-tert-octylphenol (OP; compound with estrogenic activity), ICI 182,780 (ICI; an antiestrogen), and methoxychlor (MXC; compound with estrogenic, antiestrogenic and antiandrogenic properties) on FOXL2 expression and expression of its target genes, AMH and CYP19A1. Piglets were injected subcutaneously with TP, FLU, OP, ICI, MXC, or corn oil (control) between postnatal days 1 and 10 (n = 4/each group). Ovaries were excised from the 11-day-old piglets and the expression of FOXL2, AMH and CYP19A1 were examined using immunohistochemistry and/or real-time PCR and Western blot. FOXL2 was localized in stroma cells surrounding egg nests and in granulosa cells. TP, OP and MXC increased both FOXL2 and AMH mRNAs, while FLU and ICI decreased CYP19A1 mRNA. The increased FOXL2 protein abundance was found in all examined groups. In addition, TP, OP, ICI and MXC increased AMH protein abundance, while TP, FLU and OP decreased CYP19A1 protein abundance. In conclusion, neonatal exposure to sex steroid receptor agonists and antagonists increased FOXL2 expression at mRNA and/or protein levels and affected FOXL2 target genes in the ovaries of 11-day-old piglets. Therefore, it seems that impaired ovarian folliculogenesis induced by altered steroid milieu during the neonatal development period in pigs may, at least in part, involve FOXL2.

Somatostatin receptor radionuclide therapy in neuroendocrine tumors

Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE has been approved for the treatment of gastroenteropancreatic NETs. An understanding of benefits and risks is important for the appropriate implementation of this therapy. This review summarizes study data supporting the use of radiolabeled somatostatin analogs for the treatment of advanced NETs and highlights risks, including potential toxicities in specific populations. Key ongoing clinical trials, including randomized studies, are designed to better define the position of PRRT within the broader therapeutic landscape. Preclinical and early-phase human studies are focused on the development of novel somatostatin-receptor agonists and antagonists, new radionuclides, and radiosensitizing combination therapies.

Dopamine antagonists for the treatment of drug addiction: PF-4363467 and related compounds

Drug addiction refers to an out-of-control and compulsive use of substances, which can reach epidemic magnitudes. It is a health concern throughout the world and has major economic impact. Dopamine receptor agonists and antagonists have been cited as molecular targets for the treatment of drug addiction. In this report, the main idea is to analyze the new D3R/D2R ligands that are proposed for the treatment of drug abuse, in terms of their electron donor/acceptor properties. Substances catalogued as agonists represent good electron donors, whereas antagonists represent good electron acceptors. HOMO and LUMO eigenvalues indicate that more energy is necessary to remove an electron from the antagonists, and likewise more energy is gained when antagonists accept an electron. The combination of two molecules (PF-592379 and PNU-177864) produces a new compound (PF-4363467) with properties that are intermediate. Irrespective of the characteristics of the receptor, the classification of ligands is important, in order to further understanding of the reaction mechanism of these compounds. This may help in the design of new molecules for the treatment of drug addiction.