15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and 1-amino-1-3-dicarboxycyclopentane

A growing number of studies support an important contribution of astrocytes to neurovascular coupling, i.e., the phenomenon by which variations in neuronal activity trigger localized changes in blood flow that serve to match the metabolic demands of neurons. However, since both constriction and dilations have been observed in brain parenchymal arterioles upon astrocyte stimulation, the specific influences of these cells on the vasculature remain unclear. Using acute brain slices, we present evidence showing that the specific degree of constriction of rat cortical arterioles (vascular tone) is a key determinant of the magnitude and polarity of the diameter changes elicited by signals associated with neurovascular coupling. Thus elevation of extracellular K+ concentration, stimulation of metabotropic glutamate receptors (mGluR), or 11,12-epoxyeicosatrienoic acid application all elicited vascular responses that were affected by the particular resting arteriolar tone. Interestingly, the data suggest that the extent and/or polarity of the vascular responses are influenced by a delimited set point centered between 30 and 40% tone. In addition, we report that distinct, tone-dependent effects on arteriolar diameter occur upon stimulation of mGluR during inhibition of enzymes of the arachidonic acid pathway [i.e., phospholipase A2, cytochrome P-450 (CYP) omega-hydroxylase, CYP epoxygenase, and cycloxygenase-1]. Our findings may reconcile previous evidence in which direct astrocytic stimulation elicited either vasoconstrictions or vasodilations and also suggest the novel concept that, in addition to participating in functional hyperemia, astrocyte-derived signals play a role in adjusting vascular tone to a range where dilator responses are optimal.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Arterioles; Astrocytes; Calcium; Cerebral Cortex; Cycloleucine; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; In Vitro Techniques; Paracrine Communication; Potassium; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Neuronal activity in the brain is thought to be coupled to cerebral arterioles (functional hyperemia) through Ca2+ signals in astrocytes. Although functional hyperemia occurs rapidly, within seconds, such rapid signaling has not been demonstrated in situ, and Ca2+ measurements in parenchymal arterioles are still lacking. Using a laser scanning confocal microscope and fluorescence Ca2+ indicators, we provide the first evidence that in a brain slice preparation, increased neuronal activity by electrical stimulation (ES) is rapidly signaled, within seconds, to cerebral arterioles and is associated with astrocytic Ca2+ waves. Smooth muscle cells in parenchymal arterioles exhibited Ca2+ and diameter oscillations ("vasomotion") that were rapidly suppressed by ES. The neuronal-mediated Ca2+ rise in cortical astrocytes was dependent on intracellular (inositol trisphosphate [IP3]) and extracellular voltage-dependent Ca2+ channel sources. The Na+ channel blocker tetrodotoxin prevented the rise in astrocytic [Ca2+]i and the suppression of Ca2+ oscillations in parenchymal arterioles to ES, indicating that neuronal activity was necessary for both events. Activation of metabotropic glutamate receptors in astrocytes significantly decreased the frequency of Ca2+ oscillations in parenchymal arterioles. This study supports the concept that astrocytic Ca2+ changes signal the cerebral microvasculature and indicate the novel concept that this communication occurs through the suppression of arteriolar [Ca2+]i oscillations and corresponding vasomotion. The full text of this article is available online at http://circres.ahajournals.org.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arterioles; Astrocytes; Boron Compounds; Calcium Channels; Calcium Signaling; Cerebral Cortex; Cerebrovascular Circulation; Cycloleucine; Electric Stimulation; Hyperemia; In Vitro Techniques; Indans; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Microscopy, Video; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neurons; Nifedipine; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Receptors, Metabotropic Glutamate; Sodium Channel Blockers; Sodium Channels; Synaptic Transmission; Tetrodotoxin