Acid–base regulation and sensing: Accelerators and brakes in metabolic regulation of cerebrovascular tone

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Abstract

Metabolic regulation of cerebrovascular tone directs blood flow to areas of increased neuronal activity and during disease states partially compensates for insufficient perfusion by enhancing blood flow in collateral blood vessels. Acid–base disturbances frequently occur as result of enhanced metabolism or insufficient blood supply, but despite definitive evidence that acid–base disturbances alter arterial tone, effects of individual acid–base equivalents and the underlying signaling mechanisms are still being debated. H + is an important intra- and extracellular messenger that modifies cerebrovascular tone. In addition, low extracellular [HCO 3 –] promotes cerebrovascular contraction through an endothelium-dependent mechanism. CO 2 alters arterial tone development via changes in intra- and extracellular pH but it is still controversial whether CO 2 also has direct vasomotor effects. Vasocontractile responses to low extracellular [HCO 3 –] and acute CO 2-induced decreases in intracellular pH can counteract H +-mediated vasorelaxation during metabolic and respiratory acidosis, respectively, and may thereby reduce the risk of capillary damage and cerebral edema that could be consequences of unopposed vasodilation. In this review, the signaling mechanisms for acid–base equivalents in cerebral arteries and the mechanisms of intracellular pH control in the arterial wall are discussed in the context of metabolic regulation of cerebrovascular tone and local perfusion.

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Hélène Girouard, Costantino Iadecola (2006)

The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction.

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Experimental efforts to understand how the brain represents, stores and processes information require high-fidelity recordings of multiple different forms of neural activity within functional circuits. Thus, creating improved technologies for large-scale recordings of neural activity in the live brain is a crucial goal in neuroscience. Over the past two decades, the combination of optical microscopy and genetically encoded fluorescent indicators has become a widespread means of recording neural activity in nonmammalian and mammalian nervous systems, transforming brain research in the process. In this review, we describe and assess different classes of fluorescent protein indicators of neural activity. We first discuss general considerations in optical imaging and then present salient characteristics of representative indicators. Our focus is on how indicator characteristics relate to their use in living animals and on likely areas of future progress.

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Spermatozoa undergo a poorly understood activation process induced by bicarbonate and mediated by cyclic adenosine 3',5'-monophosphate (cAMP). It has been assumed that bicarbonate mediates its effects through changes in intracellular pH or membrane potential; however, we demonstrate here that bicarbonate directly stimulates mammalian soluble adenylyl cyclase (sAC) activity in vivo and in vitro in a pH-independent manner. sAC is most similar to adenylyl cyclases from cyanobacteria, and bicarbonate regulation of cyclase activity is conserved in these early forms of life. sAC is also expressed in other bicarbonate-responsive tissues, which suggests that bicarbonate regulation of cAMP signaling plays a fundamental role in many biological systems.