Background and Purpose-This study investigated the effect of peroxynitrite (ONOO Ϫ ) 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 Ϫ in the cerebrovasculature after 1 hour of middle cerebral artery occlusion with 30 minutes of reperfusion. To determine the effect of ONOO Ϫ on pressure-induced myogenic activity, third-order PCAs from nonischemic animals were isolated and mounted in an arteriograph chamber. Diameter in response to changes in pressure was determined in the absence and presence of ONOO Ϫ (10 Ϫ8 to 10 Ϫ4 mol/L). Filamentous actin (F-actin) and globular actin (G-actin) were quantified using confocal microscopy in PCAs with and without exposure to ONOO Ϫ . Results-NT staining of vascular cells was greater in ischemic brain versus sham animals (56Ϯ3% versus 35Ϯ3%;PϽ0.01). Addition of low concentrations of ONOO Ϫ (Յ10 Ϫ6 mol/L) to isolated PCAs caused constriction from 129Ϯ16 m to 115Ϯ15 m (PϽ0.01), whereas concentrations Ͼ10 Ϫ6 mol/L caused dilation of spontaneous tone and loss of myogenic activity in the physiological range of 50 to 125 mm Hg, increasing diameter from 130Ϯ6 to 201Ϯ5 m at 75 mm Hg (PϽ0.01). In addition, the diminished myogenic activity was associated with a 4.5-fold decrease in F-actin content of VSM and a 27% increase in G-actin content (PϽ0.01). Conclusions-This study demonstrates that ONOOϪ affects the myogenic activity of cerebral arteries and causes F-actin depolymerization in VSM, a consequence that could promote vascular damage during reperfusion injury and further brain injury.

Summary: 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.Atypical antipsychotics are a well-known example of this approach; each atypical possesses a unique portfolio of activities at receptors that may contribute to therapeutic effects (as well as side effects). In this article we present a discussion of some of the receptor targets that are currently thought to mediate symptoms of schizophrenia, as well as their possible implications for the design of future multifunctional antipsychotics.

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

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