Building a better antipsychotic: receptor targets for the treatment of multiple symptom dimensions of schizophrenia.

Attempts to develop selective ("magic bullet") drugs for the treatment of schizophrenia have been frustrated by the complex etiology of the disease. The symptomatology of schizophrenia does not appear to arise from a single neurobiological entity, but rather may be derived from pathology at one or more receptor types. This has prompted multifactorial approaches to the development of new therapeutics, as embodied by polypharmacy and an alternative (or augmentative) strategy known as "intramolecular polypharmacy," in which a single drug possesses the capacity to affect multiple receptor types.

Peroxynitrite diminishes myogenic tone in cerebral arteries: role of nitrotyrosine and F-actin.

This study investigated the effect of peroxynitrite (OONO(-))-induced nitrosylation of filamentous (F)-actin on myogenic tone in isolated and pressurized posterior cerebral arteries (PCAs). Immunohistochemical staining was used to determine 3-nitrotyrosine (NT) and F-actin content in vascular smooth muscle after exposure to 10(-7) M or 10(-4) M OONO(-) for 5 or 60 min in isolated third-order PCAs (n = 37) from male Wistar rats pressurized to 75 mmHg in an arteriograph chamber, quantified with confocal microscopy. Additionally, the role of K(+) channels in OONO(-)-induced dilation was investigated with 3 microM glibenclamide or 10 mM tetraethylammonium chloride before OONO(-) exposure.

Peroxynitrite diminishes myogenic activity and is associated with decreased vascular smooth muscle F-actin in rat posterior cerebral arteries.

Background And Purpose: This study investigated the effect of peroxynitrite (ONOO-) on pressure-induced myogenic activity and vascular smooth muscle (VSM) actin of isolated posterior cerebral arteries (PCAs).

Methods: Histochemical staining of nitrotyrosine (NT) was used to demonstrate the presence of ONOO- in the cerebrovasculature after 1 hour of middle cerebral artery occlusion with 30 minutes of reperfusion. To determine the effect of ONOO- on pressure-induced myogenic activity, third-order PCAs from nonischemic animals were isolated and mounted in an arteriograph chamber.