Effect of 2-chloroadenosine on cerebrovascular reactivity to hypercapnia in newborn pig.

The effect of local administration of vasodilative concentrations of the adenosine receptor agonist 2-chloroadenosine (2-CADO) on the hyperemic responses of the pial and parenchymal microcirculations to graded hypercapnia was determined. The cranial window and brain microdialysis-hydrogen clearance techniques were utilized in two groups of isoflurane-anesthetized newborn pigs to measure changes in pial diameters and local CBF, respectively, in response to graded hypercapnia in the absence and presence of 2-CADO. Progressive size-dependent dilations of pial arterioles [small = 41 +/- 7 microns (mean +/- SD), intermediate = 78 +/- 13 microns, and large = 176 +/- 57 microns in diameter] occurred in response to graded hypercapnia alone (PaCO2 = 58 and 98 mm Hg) and to superfusions of 2-CADO (10(-5) M) during normocapnia; the magnitude of the dilative response to each of these stimuli was inversely proportional to vessel size. When hypercapnia was induced concomitantly with 2-CADO superfusion, the dilative effects of each stimulus were directly additive. Similarly, local microdialysis infusion of 10(-5) M 2-CADO, which doubled CBF during normocapnia, did not affect the hyperemic response of the parenchymal circulation to graded hypercapnia (PaCO2 = 69 and 101 mm Hg). Our findings are consistent with the participation of adenosine in the mediation of cerebral hypercapnic hyperemia. If, however, adenosine is not involved in this dilative response, our results indicate that concomitant vascular and neuromodulatory actions induced by adenosine receptor stimulation do not affect the mechanism responsible for the hypercapnic hyperemic response.     

The role of adenosine in the vascular adaptation of neonatal cerebral blood flow during hypotension

This study investigated the potential role of adenosine in cerebral blood flow (CBF) regulation in the neonate during moderate and severe hypotension. Experiments were done in anesthetized, 1- to 3-day-old piglets. Regional CBF (determined by radiolabeled microsphere technique) and cerebral metabolic rate for O2 (CMRO2) were measured (a) during normotension and (b) during a 3-min period of moderate (58 +/- 9 mm Hg) or severe (36 +/- 7 mm Hg) hypotension produced by the inflation of a balloon catheter placed in the aortic root. Measurements of CBF and CMRO2 were performed successively after intracerebroventricular (i.c.v.) injections of vehicle (n = 17), the adenosine receptor blocker 8-phenyltheophylline (8-PT, 10 micrograms, n = 14), and the A2-receptor agonist 5'-N-(ethylcarboxamide)adenosine (NECA, 2 ng, n = 8). After i.c.v. administration of vehicle, none of the parameters studied was significantly altered by moderate hypotension, but severe hypotension decreased the total CBF (mean +/- SD) from 86 +/- 24 to 40 +/- 15 ml min-1 100 g-1 and CMRO2 from 3.2 +/- 0.8 to 1.8 +/- 1.0 ml min-1 100 g-1 (p less than 0.05). Administration of 8-PT did not alter these parameters during normotension, but significantly decreased CBF during moderate hypotension compared to postvehicle values (53 +/- 11 versus 81 +/- 12 ml min-1 100 g-1, p less than 0.05). This loss of autoregulation was completely reversed by NECA. During severe hypotension, 8-PT altered the CBF redistribution towards the brainstem.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of local infusion of adenosine and adenosine analogues on local cerebral blood flow

The purpose of this study was to determine the effects of local infusion of adenosine (ADO) and non-metabolized ADO analogues on local cerebral blood flow (CBF) and interstitial fluid (ISF) ADO levels. The brain dialysis technique was used to (a) deliver drugs locally to brain tissue, (b) estimate cerebral ISF ADO levels, and (c) measure local CBF (hydrogen clearance). Dialysis probes were implanted bilaterally in the caudate nuclei of ketamine-anesthetized rats. The probe on one side was perfused with artificial CSF while the contralateral probe was perfused with artificial CSF containing ADO (n = 5), or the ADO agonists 2-chloroadenosine (2-CADO; n = 4) or 5'-N-ethylcarboxamide adenosine (NECA; n = 4). When ADO was included in the artificial CSF at 10(-5), 10(-4), or 10(-3) M, a 30% increase in local CBF was detected only with 10(-3) M ADO. During perfusion with ADO, dialysate inosine and hypoxanthine levels increased, indicating that the cells adjacent to the probe metabolized the exogenous ADO. With 2-CADO included in the artificial CSF at 10(-6), 10(-5), or 10(-4) M, local CBF increased 18, 131, and 201%, respectively. Perfusion with artificial CSF containing 10(-7), 10(-6), or 10(-5) M NECA resulted in a 35, 112, and 187% increase in local CBF, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired cerebral autoregulation 24 h after induction of transient unilateral focal ischaemia in the rat

Cerebral blood flow (CBF) and cerebral autoregulation have been investigated 24 h after transient focal ischaemia in the rat. Cerebral blood flow was measured autoradiographically before and during a moderate hypotensive challenge, to test autoregulatory responses, using two CBF tracers, (99m)Tc-d,l-hexamethylproyleneamine oxide and 14C-iodoantipyrine. Prior to induced hypotension, CBF was significantly reduced within areas of infarction; cortex (28 +/- 20 compared with 109 +/- 23 mL/100 g/min contralateral to ischaemic focus, P = 0.001) and caudate (57 +/- 31 compared with 141 +/- 32 mL/100 g/min contralaterally, P = 0.005). The hypotensive challenge (mean arterial pressure reduced to 60 mmHg by increasing halothane concentration) did not compromise grey matter autoregulation in the contralateral hemisphere; CBF data were not significantly different at normotension and during hypotension. However, in the ipsilateral hemisphere, a significant volume of cortex adjacent to the infarct, which exhibited normal flow at normotension, became oligaemic during the hypotensive challenge (e.g. frontal parietal cortex 109 +/- 15% to 65 +/- 15% of cerebellar flow, P < 0.01). This resulted in a 2.5-fold increase in the volume of cortex which fell below 50% cerebellar flow (39 +/- 34 to 97 +/- 46 mm3, P = 0.003). Moderate hypotension induced a significant reduction in CBF in both ipsilateral and contralateral subcortical white matter (P < 0.01). In peri-infarct caudate tissue, CBF was not significantly affected by hypotension. In conclusion, a significant volume of histologically normal cortex within the middle cerebral artery territory was found to have essentially normal levels of CBF but impaired autoregulatory function at 24 h post-ischaemia.     

Opioids and the prostanoid system in the control of cerebral blood flow in hypotensive piglets

The interaction between opioid and prostanoid mechanisms in the control of cerebral hemodynamics was investigated in the conscious hypotensive piglet. Radiomicrospheres were used to determine regional cerebral blood flow (rCBF) in piglets pretreated with the opioid receptor antagonist, naloxone, or its vehicle, saline, during normotension, hypotension, and after the administration of indomethacin, a cyclooxygenase inhibitor, during hypotension. Hemorrhage (30 ml/kg) decreased systemic arterial pressure from 68 +/- 12 to 40 +/- 10 mm Hg but did not decrease blood flow to any brain region. Indomethacin treatment (5 mg/kg) of hypotensive piglets decreased blood flow to all brain regions within 20 min; this decrease in CBF resulted from increases in cerebral vascular resistance of 65 and 281% at 20 and 40 min after treatment, respectively. In hypotensive piglets, cerebral oxygen consumption was reduced from 2.62 +/- 0.71 to 0.53 +/- 0.27 ml 100 g-1 min-1 and to 0.11 +/- 0.04 ml 100 g-1 min-1 at 20 and 40 min following indomethacin, respectively. Treatment with naloxone (1 mg/kg) had no effect on rCBF, calculated cerebral vascular resistance, or cerebral oxygen consumption of normotensive or hypotensive piglets. However, decreases in CBF and oxygen consumption and increases in cerebral vascular resistance upon treatment of hypotensive piglets with indomethacin were attenuated in animals pretreated with naloxone. These data indicate that the removal of prostanoid modulation of an opioid-mediated constrictor influence on the cerebral circulation is a potential mechanism for the increase in cerebral vascular resistance that follows indomethacin treatment of hypotensive piglets.     

Effects of lactic acid infusions and pH on cerebral blood flow and metabolism

To determine the effects of lactic acidemia versus lactate on CBF, we infused lactic acid, either buffered with NaOH (L + NaOH) or with added NaCl (L + NaCl), to attain similar osmolalities in 18 piglets. CBF (microsphere technique), pH, blood gases, plasma osmolality, and cerebral arteriovenous differences of O2 content and lactic acid concentrations were measured prior to, at 30 min of a lactic acid infusion, and 15 and 90 min after completion of the infusion. Control arterial pH was comparable between groups (7.50 +/- 0.02 vs. 7.49 +/- 0.02, X +/- SE); during and following L + NaCl and L + NaOH, values were (p less than 0.05) 7.09 +/- 0.03, 7.35 +/- 0.02, and 7.46 +/- 0.02 vs. 7.58 +/- 0.03, 7.61 +/- 0.01, and 7.57 +/- 0.03, respectively. PaCO2 remained unchanged and osmolality rose by 15% in both groups during infusions and persisted throughout the study period. For L + NaCl piglets, CBF (ml/min.100 g) rose from 136 +/- 15 to 198 +/- 26 (p less than 0.05) at 30 min of infusion and remained elevated at 201 +/- 25 and 207 +/- 28 at 15 and 90 min following the infusion, respectively. Similarly, for L + NaOH piglets, CBF rose from 130 +/- 25 to 196 +/- 31 (p less than 0.05) with the infusion and was 174 +/- 17 and 166 +/- 21 at 15 and 90 min afterward, respectively. Although lactic acid infusion increases CBF, the associated metabolic acidemia is not responsible for changes in CBF.     

Increases in cerebral interstitial fluid adenosine concentration during hypoxia, local potassium infusion, and ischemia

This study used the brain dialysis technique to test the hypothesis that the adenosine concentration of cerebral interstitial fluid increases during situations in which cerebral oxygen supply is inadequate for oxygen demand. Sealed 300-micron hollow dialysis fibers were implanted in the caudate nucleus of pentobarbital-anesthetized rats and perfused at 2 microliter/min with artificial cerebrospinal fluid. In vitro tests indicated the recovery of adenosine, inosine, and hypoxanthine from the external medium to be approximately 20% at 2 microliter/min and close to 100% at 0.1 microliter/min. Three in vivo interventions were tested: hypoxia/hypotension (PaO2 = 41.9 mm Hg; MABP = 42.8 mm Hg; n = 9), local potassium infusion (n = 4), and cerebral anoxia/ischemia (n = 10). These interventions produced 10-, 4-, and 30-fold increases in perfusate adenosine concentration, respectively, as well as increases in perfusate concentrations of inosine and hypoxanthine. A separate group of rats (n = 9) perfused at 0.1 microliter/min yielded estimates of cerebral interstitial fluid adenosine, inosine, and hypoxanthine concentrations of 1.26, 3.30, and 7.19 microM, respectively. These results are consistent with the adenosine hypothesis for the regulation of CBF.     

The role of adenosine in CBF increases during hypoxia in young vs aged rats

The role of adenosine in the regional cerebral blood flow (rCBF) response to hypoxia was evaluated in young (6 month) and aged (26-28 month) F344 rats using theophylline, an adenosine antagonist. Regional CBF was measured with radioactive microspheres under control anesthetized conditions (70% N2O, 30% O2) and at two levels of hypoxia (CaO2 = 8.7-9.0 ml . 100ml-1 and 3.2-3.7 ml . 100ml-1). Without theophylline infusion, CBF increases were similar between young and aged rats during moderate hypoxia but were increased more in young during severe hypoxia. Intracerebrovascular theophylline infusion significantly attenuated the increase in CBF during both moderate and severe hypoxia and decreased the difference between young and aged rats. Theophylline infusion produced no significant effect on the increase in CBF produced by hypercapnia, indicating the specificity of the treatment for hypoxic induced CBF changes and adenosine release. Intracerebrovascular infusion of adenosine had no effect on CBF, presumably due to the presence of the blood brain barrier. The results suggest that adenosine plays a major role in CBF increases during both moderate and severe hypoxia and in the difference in response to hypoxia between young and aged rats.     

Effects of adenosine and its analogues on porcine basilar arteries: are only A2 receptors involved?

The aim of this study was to test the effect of adenosine and four of its analogues, 5'-(N-ethyl)carboxamidoadenosine (NECA), 2-chloroadenosine (2-CADO), L-phenylisopropyladenosine (L-PIA), and N6-cyclohexyl-adenosine (CHA), on prostaglandin (PG) F2 alpha-constricted pig basilar arteries, and from their rank order of potency determine the receptor type involved. The order of potency for the relaxation of the PGF2 alpha constriction was NECA greater than adenosine, 2-CADO greater than L-PIA greater than CHA, which is in keeping with the A2 receptor subtype. The study also investigated the effects of a known adenosine antagonist, namely, the xanthine derivative 8-phenyltheophylline, which at concentrations having no intrinsic effect (10(-8) and 10(-7) M) produced a significant shift to the right only for the NECA dose-response curve.     

Hemodynamic sequelae of ventricular tachyarrhythmias on cerebral blood flow

Abstract

The present experiments were designed to compare the behavior of cerebral blood flow (CBF) during acute moderate and severe hypotensive episodes induced by either ventricular tachycardias (VT) or by hemorrhage. Using the microsphere method CBF was determined in 20 Sprague-Dawley rats during sinus rhythm (Group A), in 28 animals during high-rate VT (Group B) and in 10 animals after hemorrhage (Group C). According to the decrease in blood pressure and with respect to the lower threshold of cerebral autoregulation Group B was divided into subgroups (B₁: 80-130 mmHg; B₂: 50-80 mmHg) retrospectively. While CBF remaIned constant In Group B₁ (0.98 ± 0.3 ml g^-1 min_-1 vs. 1.01 ± 0.32 In controls, NS), CBF decreased markedly during severely hypotensive VT in Group B₂ (0.52 ± 0.2 ml g_-1 min_-1, p < 0.001 vs. A; p < 0.05 vs. C) and during hypovolemic hypotension in Group C (0.77 ± 0.22 ml g_-1 min_-1 vs. A; NS). Cerebrovascular resistance and autoregulation indices indicated a maintenance of CBF regulation during hypovolemic hypotension and a failure during normovolemic hypotension. These findings indicate that the autoregulatory ability of the brain is substantially more stable during hypovolemic hypotension than during normovolemic hypotension. Therefore, the hemodynamic sequelae of acute hypotensive episodes on CBF depend on the underlying cause of hypotension. [Neural Res 1998; 20: 549-554]     

Effects of topical adenosine analogs and forskolin on rat pial arterioles in vivo

We utilized the closed window technique to study the in vivo responses of rat pial arterioles to superfused adenosine agonists. Adenosine and its analogs dilated pial arterioles and exhibited the following order of potency: 5'N-ethylcarboxamide adenosine (NECA) greater than 2-chloroadenosine (2-CADO) greater than adenosine = R-N6-phenylisopropyladenosine (R-PIA) = S-PIA greater than N6-cyclohexyladenosine (CHA). This potency profile suggests that cerebral vasodilation is mediated through the A2 receptor. Forskolin (10(-9) M) potentiated the vasodilation caused by 10(-6) M NECA, thus implicating adenylate cyclase activation during NECA-induced vasodilation and providing further support for involvement of the A2 receptor.     

Cerebral hemodynamics in chronic hypoxic hypoxia

The effects of chronic-hypoxic hypoxia on cerebral blood flow and its regulating mechanisms were investigated by means of intracardiac injection of radioactively labelled microspheres. In a gas chamber designed and constructed for the purpose, adult cats were exposed to stepwise decreasing inspiratory oxygen concentrations (for 4.5 months with a final O2 concentration of 8 vol%). Using animals adapted to hypoxic hypoxia, responsiveness of cerebral blood flow either to alterations in systemic arterial pressure (SAP) or to alterations in arterial blood oxygen tension (PaO2) were assessed. Flow measurement was done under three different conditions: normoxic normotension (PaO2 greater than 100 mmHg; SAP greater than 100 mmHg), hypoxic normotension (PaO2 = 30 mmHg; SAP greater than 100 mmHg), or normoxic hypotension (PaO2 greater than 100 mmHg; SAP = 60 mmHg). Hematocrit values continuously increased to 56% during the process of adaptation to hypoxia. There was also a remarkable increase in cardiac output of hypoxia-adapted animals subjected to hypoxia and to normoxia. Chronic-hypoxic hypoxia led to increased cerebral blood flow, which persisted even when animals were returned to normoxia. Under hemorrhagic hypotension, cerebral blood flow fell significantly in animals adapted to chronic-hypoxic hypoxia but did not fall short of the absolute values in controls. The relative reduction in cerebral blood flow might be attributable to the decrease in cardiac output and to altered blood viscosity. This implied that, even in animals subjected to long-standing graded hypoxic hypoxia, autoregulatory capacity might be partly preserved.     

Chemical stimulation of the rostral ventrolateral medullary pressor area decreases cerebral blood flow in anesthetized rats.

In urethane-anesthetized, paralyzed and artificially ventilated rats, the neurons in the rostral ventrolateral medullary pressor area (VLPA) were chemically stimulated by microinjections of L-glutamate (1.7-5.0 nmole in 100 nl of 0.9% sodium chloride solution) and the cerebral blood flow (CBF) was determined using a combination of labeled microspheres (57Co, 113Sn and 46Sc). In one group of rats (n = 11), unilateral chemical stimulation of the VLPA produced a significant (P less than 0.01) increase in arterial blood pressure (ABP), a significant (P less than 0.05) decrease in CBF, and a significant (P less than 0.01) increase in cerebrovascular resistance (CVR) in the cerebral cortex ipsilateral to the stimulated VLPA. The CBF was 52 +/- 3 (mean +/- S.E.M.) and 48 +/- 4 ml.min-1.(100 g)-1 before and during the chemical stimulation of VLPA; the CVR was 1.9 +/- 0.1 and 2.6 +/- 0.3 mmHg per ml.min-1.(100 g)-1 before and during the stimulation. In order to measure CBF at normotension, moderate hypotension was induced by controlled hemorrhage in another group of rats (n = 8). Unilateral chemical stimulation of the VLPA in these rats increased ABP but it remained within normotensive range. The CBFs of ipsilateral and contralateral cerebral cortices decreased significantly (P less than 0.05) from 57 +/- 14 to 41 +/- 9 and from 50 +/- 12 to 39 +/- 9 ml.min-1.(100 g)-1, respectively. The CVRs of ipsilateral and contralateral cortices increased significantly (P less than 0.05) from 2.6 +/- 0.6 to 3.5 +/- 0.8 and from 2.7 +/- 0.5 to 3.5 +/- 0.8 mmHg/[ml.min-1.(100 g)-1], respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

A cerebral vasoconstrictive effect of some adenosine analogues. A study of adenosine analogues on local cerebral blood flow and glucose utilisation in the rat

Local CBF (LCBF) in the rat was determined using [14C]iodoantipyrine autoradiography. Adenosine and 5'-(N-ethyl)carboxamidoadenosine in a 15-min infusion had no significant effect on LCBF, although there was a tendency to increase. N6-Cyclohexyladenosine (CHA) and 2-chloroadenosine (2-CADO) significantly decreased LCBF in a number of brain regions. Laser-Doppler experiments using CHA confirmed that CHA decreased CBF and that this change was monophasic. Further experiments involving the use of [14C]2-deoxyglucose autoradiography showed that the unexpected vascular effects of CHA and 2-CADO were not a consequence of a decreased metabolic demand. The available data do not allow us to identify the mechanism of action by which the known vasodilators CHA and 2-CADO were able to cause a vasoconstriction and a decrease in LCBF.     

Cerebrovascular effects of sodium nitroprusside in the anaesthetized baboon: a positron emission tomographic study.

The effects of sodium nitroprusside (SNP), a potent hypotensive agent, on cerebral blood flow (CBF) have been extensively studied in clinical and experimental situations but the results remain controversial. Whereas its properties would predict a dilatation of cerebral blood vessels, most studies report either no change or a decrease in CBF. The aim of this study was to investigate the effects of SNP on CBF, cerebral blood volume (CBV), and cerebral oxygen metabolism (CMRO2), by means of positron emission tomography in the anaesthetized baboon. Measurements were performed during normotension (mean arterial pressure (MABP): 97+/-16 mm Hg) and repeated following SNP-induced hypotension (MABP: 44+/-9 mm Hg). Sodium nitroprusside led to an increase in CBF and CBV (+30% and +37%, respectively, P<0.05), whereas no change in CMRO2 was noted. Linear regression analysis of CBF values as a function of MABP confirmed that CBF increases when MABP is reduced by SNP. The comparison between these cerebrovascular changes and those found during trimetaphan-induced hypotension in our previously published studies further argues for a direct dilatatory effect of SNP on cerebral blood vessels.     

Brain interstitial adenosine and sagittal sinus blood flow during systemic hypotension in piglet

We sampled, using the brain dialysis technique, interstitial fluid adenosine from the frontal cortex of newborn piglets subjected to hemorrhagic hypotension while measuring sagittal sinus blood flow, cerebrovascular resistance (CVR), and cerebral O2 delivery. In group 1 (n = 8), MABP was reduced in successive steps from 76 to 30 mm Hg with decrements of approximately 10 mm Hg. At 60 mm Hg, CVR decreased by 19% (p less than 0.001), but sagittal sinus blood flow and interstitial fluid adenosine remained unchanged. At 50 mm Hg, both sagittal sinus blood flow and CVR decreased by 19% (p less than 0.001) and interstitial fluid adenosine rose 4.7-fold (p less than 0.05). At 40 and 30 mm Hg, sagittal sinus blood flow decreased further but CVR remained steady, whereas interstitial fluid adenosine rose 10- and 16-fold, respectively. In group 2 (n = 7), an abrupt reduction of MABP from 80 to 47 mm Hg produced no change in sagittal sinus blood flow and a 29% decrease in CVR (p less than 0.01). Interstitial fluid adenosine increased twofold (p less than 0.01). In group 3 (n = 7), an abrupt reduction of MABP from 79 to 40 mm Hg decreased sagittal sinus blood flow and CVR by 24 and 30%, respectively (p less than 0.01). Interstitial fluid adenosine rose threefold (p less than 0.01). In groups 1, 2, and 3, the increases in interstitial fluid adenosine accompanied decreases in cerebral O2 delivery. In group 4 (n = 7), artificial CSF with a PO2 of 152 mm Hg was perfused through the brain dialysis cannula during graded hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence that adenosine A2 and dopamine autoreceptors antagonistically regulate tyrosine hydroxylase activity in rat striatal synaptosomes

Incubation of rat striatal synaptosomes with the adenosine receptor agonist 2-chloroadenosine (2-CADO) produced a concentration-dependent increase of dopamine (DA) synthesis (about 50% of control value). The effect was not additive with the stimulation produced by either 10 microM forskolin or 2 mM dibutyryl cyclic AMP. Pretreatment of striatal synaptosomes with 2-CADO produced an activation of tyrosine hydroxylase (TH) which withstood washing and lysing of the tissue. This activation was largely independent of the presence of Ca2+ ion in the preincubation medium and, when analyzed as a function of different concentrations of the pterin cofactor 6-methyl-5,6,7,8-tetrahydropterin (0.08-0.4 mM), it was associated with an apparent increase in the Vmax of the enzyme. Quinpirole, a selective D2 DA receptor agonist, reduced control synaptosomal DA synthesis and caused a persistent inhibition of TH activity. When added together with 2-CADO, quinpirole depressed the stimulation of DA synthesis and TH activity produced by the adenosine analog. The effect of quinpirole was stereospecifically antagonized by the D2 DA antagonist sulpiride. Quinpirole also inhibited the activation of TH elicited by a submaximal concentration of forskolin, but not that produced by dibutyryl cyclic AMP. The inhibitory effect of quinpirole on basal and 2-CADO-stimulated TH activities was mimicked by DA. These results indicate that presynaptic DA autoreceptors and adenosine A2 receptors interact antagonistically in controlling DA synthesis in rat striatal synaptosomes presumably by exerting opposite inputs on a presynaptic adenylate cyclase system.     

Age dependent NMDA contribution to impaired hypotensive cerebral hemodynamics following brain injury

Previous studies have observed that fluid percussion brain injury (FPI) impaired NMDA induced pial artery dilation (PAD) in an age dependent manner. Unrelated studies observed a similar age dependent impairment of hypotensive cerebral autoregulation after FPI. This study was designed to test the hypothesis that NMDA receptor activation contributes to impairment of cerebral autoregulation during hypotension after FPI in an age dependent manner. Therefore, the role of NMDA in impaired hypotensive cerebrovascular regulation after FPI was compared in newborn and juvenile pigs equipped with a closed cranial window. Ten minutes of hypotension (10-15 ml blood/kg) decreased mean arterial blood pressure uniformly in both groups (approximately 44%). In the newborn, hypotensive PAD was blunted within 1 h of FPI but partially protected by pretreatment with the NMDA antagonist MK801 (1 mg/kg i.v.) (34+/-1 vs. 8+/-1 vs. 25+/-2% for sham control, FPI, and FPI-MK801, respectively). Cerebral blood flow (CBF) was reduced during normotension by FPI, further reduced by hypotension, but both were partially protected by MK801 in the newborn (56+/-5, 35+/-2, and 16+/-1 vs. 62+/-6, 45+/-3, and 30+/-2 ml/min 100 g for normotension, normotension-FPI, and hypotension-FPI in the absence and presence of MK801, respectively). In contrast, blunted hypotensive PAD was protected significantly less by MK801 in the juvenile (32+/-2 vs. 7+/-2 vs. 16+/-2% for sham control, FPI, and FPI-MK801, respectively). Similarly, MK801 had less protective effect on normotensive and hypotensive CBF values post FPI in the juvenile. These data indicate that NMDA receptor activation contributes to impaired hypotensive cerebral hemodynamics following brain injury in an age dependent manner.     

Effect of adenosine on human cerebral blood flow as determined by positron emission tomography

The effect of intravenous infusion of adenosine on CBF was studied in seven patients with cerebral arteriovenous malformation. The patients were examined with positron emission tomography with controlled ventilation using [15O] water and [11C] fluoromethane as tracers. Total and regional CBF were determined before and during infusion of adenosine at rates producing a reduction of the MABP by approximately 10-40%. Six patients were normoventilated, and one was hyperventilated. Mean CBF in areas with normal brain tissue was 54 ml/100 g/min before adenosine infusion under normoventilation. Adenosine infusion increased mean CBF with 23-85%. Mean CVR was decreased with 43-65% and exceeded the percentage reduction of MABP in all normoventilated subjects. In the hyperventilated patient, the reduction of CVR was similar to the reduction of MABP, and CBF was unaffected, except for the 30% increase in the thalamus. It is concluded that intravenous administration of adenosine produces marked cerebral vasodilation in normoventilated subjects and that this response can be counteracted by hyperventilation.     

Effect of adenosine on total and regional cerebral blood flow of the newborn piglet

The effect of adenosine on total and regional CBF, measured by radiolabeled microspheres, was assessed in 16 anesthetized and ventilated newborn (1-3 days old) piglets. They received a ventriculocisternal perfusion containing either CSF alone (controls, n = 5) or CSF mixed with two different concentrations of adenosine (15 min each) randomly assigned using the following doses: 0.1 microM, 10 microM, 100 microM, 1 mM (n = 4), or 10 mM (n = 6). Mean CSF adenosine concentration (by HPLC) before perfusion was 0.6 +/- 0.4 microM. Total and regional CBF were not altered by the perfusion of CSF alone. All adenosine concentrations, except at low doses, increased total and regional CBF, without altering the cerebral metabolic rate for oxygen. Brainstem blood flow was increased by a mean of 110, 145, 306, and 378% with 10 microM, 100 microM, 1 mM, and 10 mM concentrations, respectively. Except for the highest concentration, CBF response was dose dependent in each region of the brain with the following order of potency: brainstem greater than periventricular area greater than telencephalon, midbrain, total brain, and cerebellum. These data indicate that, in the newborn, adenosine is a potent vasodilator of cerebral vessels. If the newborn brain can synthesize appropriate concentrations of adenosine, this nucleoside may play a major role in regional CBF regulation during the neonatal period.