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Abstract

Adenosine triphosphate (ATP), a potent vascular regulator in the cerebral circulation, initiates conducted vasomotor responses which may be impaired after pathological insults. We analyzed the mechanism of ATP-induced local vasomotor responses and their effect on conducted vasomotor responses in rat cerebral penetrating arterioles. Arterioles were cannulated and their internal diameter monitored. Vasomotor responses to ATP were observed in the presence or absence of inhibitors, or after endothelial impairment. Smooth muscle membrane potentials were measured in some vessels. Microapplication of ATP produced a biphasic response (constriction followed by dilation), which resulted in conducted dilation preceded by a membrane hyperpolarization. alpha,beta-methylene-ATP or pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) blunted the ATP-mediated constriction and enhanced local and conducted dilation. N(omega)-monomethyl-L-arginine, endothelial impairment and N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH) reduced the local dilation caused by ATP. The conducted dilation was attenuated by MS-PPOH and endothelial impairment, but not N(omega)-monomethyl-L-arginine or indomethacin. ATP-induced conducted dilation is preceded by membrane hyperpolarization. Local ATP induces initial local constriction via smooth-muscle P(2X1) and subsequent dilation via endothelial P(2Y) receptors. Nitric oxide, cytochrome P450 metabolites, and intermediate and large conductance K(Ca) channels mediate dilation caused by ATP. ATP-induced conducted dilation is dependent upon both the endothelium and cytochrome P450 metabolites. Copyright (c) 2008 S. Karger AG, Basel.

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Calcium dynamics in cortical astrocytes and arterioles during neurovascular coupling.

T. Nelson, Adrian D Bonev, Jessica Filosa (2004)

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.

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Conducted vascular responses: communication across the capillary bed.

Ryan Ellsworth, Louis Collins, T McCullough (1998)

Conducted vasomotor responses are important for the effective distribution of blood flow, although the mechanism by which these responses are initiated is not well understood. ATP, a substance which is released from circulating red blood cells in response to low PO2 and low pH, two conditions which are associated with decreased supply relative to demand, has been shown to initiate conducted vasodilation following its intraluminal application in first and second order arterioles. Since such low PO2 and low pH conditions would most likely occur on the venous side of the vasculature, we evaluated the response of the arteriolar and capillary networks to application of ATP into venules in the Saran-covered hamster cheek pouch retractor muscle using in vivo video microscopy. Intraluminal application of 40 and 400 pl of 10(-6) M ATP resulted in dose-dependent increases in arteriolar diameter > 450 microm upstream from the site of application. These changes in arteriolar diameter were accompanied by significant increases in red blood cell flux. In capillaries, red blood cell flux doubled in response to ATP administration. Since NO was previously determined to be involved in the vascular response to intraluminal ATP in arterioles, we evaluated its role in these responses. We found that systemic administration of l-NAME prior to ATP application eliminated any conducted response and this effect of l-NAME was reversed by the systemic administration of l-arginine. These data suggest that ATP, which is released from red blood cells in response to low PO2 and low pH, conditions which would be found in the venular microvasculature, may serve a role in distributing perfusion in response to alterations in supply. Copyright 1998 Academic Press.

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Responses of cerebral arterioles to ADP: eNOS-dependent and eNOS-independent mechanisms.

Frank M Faraci, Kathryn G. Lamping, Ryan Lynch (2004)

ADP mediates platelet-induced relaxation of blood vessels and may function as an important intercellular signaling molecule in the brain. We used pharmacological and genetic approaches to examine mechanisms that mediate responses of cerebral arterioles to ADP, including the role of endothelial nitric oxide synthase (eNOS). We examined responses of cerebral arterioles (control diameter approximately 30 microm) in anesthetized wild-type (WT, eNOS+/+) and eNOS-deficient (eNOS-/-) mice using a cranial window. In WT mice, local application of ADP produced vasodilation that was not altered by indomethacin but was reduced by approximately 50% by NG-nitro-L-arginine (L-NNA) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (inhibitors of NOS and soluble guanylate cyclase, respectively). In eNOS-/- mice, responses to ADP were largely preserved, and a significant component of the response was resistant to L-NNA (a finding similar to that in WT mice treated with L-NNA). In the absence of L-NNA, responses to ADP were markedly reduced by charybdotoxin plus apamin [inhibitors of Ca2+-dependent K+ channels and responses mediated by endothelium-derived hyperpolarizing factor (EDHF)] in both WT and eNOS-/- mice. Thus pharmacological and genetic evidence suggests that a significant portion of the response to ADP in cerebral microvessels is mediated by a mechanism independent of eNOS. The eNOS-independent mechanism is functional in the absence of inhibited eNOS and most likely is mediated by an EDHF.

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PubMed ID:: 18984964

PMC ID:: 2673330

DOI:: 10.1159/000167273

ScienceOpen disciplines: Chemistry

Keywords: Adenosine Triphosphate,analogs & derivatives,pharmacology,Amides,Animals,Arterioles,drug effects,physiology,Biological Factors,Cerebral Arteries,Cytochrome P-450 Enzyme System,Endothelium, Vascular,Male,Membrane Potentials,Nitric Oxide,Potassium Channels, Calcium-Activated,Prostaglandins,Pyridoxal Phosphate,Rats,Rats, Sprague-Dawley,Receptors, Purinergic P2,Vasodilation

Mechanism of ATP-induced local and conducted vasomotor responses in isolated rat cerebral penetrating arterioles.

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Karger: Cardiovascular System

Most cited references 10

Calcium dynamics in cortical astrocytes and arterioles during neurovascular coupling.

Conducted vascular responses: communication across the capillary bed.

Responses of cerebral arterioles to ADP: eNOS-dependent and eNOS-independent mechanisms.

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