Effect of Topical Adenosine Deaminase Treatment on the Functional Hyperemic and Hypoxic Responses of Cerebrocortical Microcirculation

Abstract

Summary:The purpose of this study was to investigate the possible importance of adenosine in cerebrocortical vasodilatation accompanying brain activation (epileptic seizures and direct electrical stimulation) and hypoxia (arterial hypoxia and cyanide poisoning of the brain cortex). In chloralose-anesthetized cats a circumscribed area of the brain cortex was treated with adenosine de aminase (Type III; Sigma), which potently deaminates adenosine to the nonvasoactive inosine. Cerebrocortical vascular volume and fluorescence of reduced nicotin amide adenine dinucleotide were measured in vivo by sur face fluororeflectometry. The responses of small pial and intracortical vessels to brain activation and hypoxia were studied in brain cortices superfused with artificial (mock) CSF and 5 Vlml adenosine deaminase. It was found that superficially applied adenosine deaminase readily dif fuses onto the brain cortex. Prolonged pretreatment ofThe mechanism by which cerebral vessels are di latated during arterial hypoxia and increased elec trical activity of the brain is still poorly understood (Astrup et aI., 1978; Kuschinsky and Wahl, 1978; Nilsson et aI., 1978; Rehncrona et aI., 1978;Siesjo, 1978; Winn et aI., 1981a; Dora, 1984a). Recently, attention has been focused on the importance of adenosine in controlling cerebrovascular tone (Nilsson et aI., 1978; Rehncrona et aI., 1978; Schrader et aI., 1980;Emerson and Raymond, 1981; Heistad et aI., 1981; Winn et aI., 1981a; Morii et aI., 1983). In theory, adenosine could fulfill a critical role in maintaining and adjusting cerebrovascular tone in the resting brain and during arterial hypoxia and epileptic seizures, respectively. Adenosine is a 44 7 the brain cortices with 0.025 Vlml adenosine deaminase eliminated almost completely the vasodilative effect of 10-7 mol/ml adenosine. The inhibitory effect of the en zyme on adenosine-induced cortical vasodilatation was specific, because 5 Vlml adenosine deaminase did not attenuate the vasodilative potency of 10-8 mol/ml 2-chlo roadenosine. Adenosine deaminase (5 Vlml) pretreatment of the brain cortices did not diminish the cerebrocortical vascular volume, which increased with arterial hypoxia, topical cyanide poisoning, and direct electrical stimula tion. However, it slightly decreased the vasodilative ef fect of epileptic seizures. On the basis of these results, it seems very unlikely that adenosine is a critical factor in the control of cerebrovascular tone during arterial hy poxia and brain activation.

Contribution of oxygen‐sensitive neurons of the rostral ventrolateral medulla to hypoxic cerebral vasodilatation in the rat.

“…Rather, the responses have been attributed to release of vasoactive substances from local non-vascular elements including neuronal perikarya, axon terminals and/or astrocytes. Adenosine (Meno, Ngai, Ibayashi & Winn, 1991) and/or nitric oxide (Iadecola, Pelligrino, Moskowitz & Lassen, 1994), two vasodilator molecules rapidly generated under hypoxia, have been popular candidate mediators, although not all evidence supports their role (Dora, Koller & Kovach, 1984;Pelligrino et al 1993). While the vascular and non-vascular elements have been considered to act locally within the cortex, there is also evidence that sites remote from the vascular targets may contribute.…”

Contribution of Flow-Dependent Vasomotor Mechanisms to the Autoregulation of Cerebral Blood Flow

“…This interpretation of “autoregulation” means adjusting CBF to the metabolic demands and to function of neural tissues. Although metabolic regulation of CBF [2, 5, 13, 14, 28] is obviously an important issue, in this review we define autoregulation to be vasomotor responses to changes in hemodynamic forces achieved by mechanisms intrinsic to the vascular wall, rendering the cerebral blood perfusion independent from changes in systemic blood pressure, and without activating metabolic, chemical, glial, neural and other (for example capillary blood flow regulation by pericytes) regulatory mechanisms [1, 2, 5–11, 18, 19, 29]. Because changes in pressure are accompanied by changes in flow, in vivo responses of cerebral vessels to changes in hemodynamics are most likely a combination of pressure and flow-induced mechanisms [30–33].…”

“…It has to ensure many roles: appropriate supply of nutrition and gas for cerebral tissue, fluid and gas exchange in the capillaries, maintenance of cerebral blood volume, thus intracranial volume and pressure in a very limited range. Obviously, such a complex function requires complex regulatory mechanisms ensured by the dynamic interaction of mechanotransduction, metabolic (for example adenosine), chemical (such as changes in pCO2, pH and pO2) and other factors, for example, recently there are emerging evidence regarding an important role for glial (astrocytes), pericytes and neural control of CBF [1–14]. …”

The Effect of Theophylline on Regional Cerebral Blood Flow Responses to Hypoxia in Newborn Piglets

“…The ability of such agents to alter vascular responses to adenosine and to alter flow responses to hypoxia has been advanced as evidence of the role of adenosine as a vasoregulator (27)(28)(29), although some controversy exists (30).…”