This study investigated the role of adenosine in the regulation of neonatal cerebral blood flow (CBF) during moderate (arterial PO2 = 47 +/- 9 Torr) and severe (arterial PO2 = 25 +/- 4 Torr) hypoxia. Twenty-eight anesthetized and ventilated newborn piglets were assigned to four groups: 8 were injected intravenously with the vehicle (controls, group 1); 13 received an intravenous injection of 8-phenyltheophylline (8-PT), a potent adenosine receptor blocker, either 4 mg/kg (group 2, n = 6, mean cerebrospinal fluid (CSF) levels less than 1 mg/l) or 8 mg/kg (group 3, n = 7, mean CSF levels less than 3.5 mg/l); and 7 received an intracerebroventricular injection of 10 micrograms 8-PT (group 4). During normoxia, CBF was not altered by vehicle or 8-PT injections. In group 1, 10 min of moderate and severe hypoxia increased total CBF by 112 +/- 36 and 176 +/- 28% (SE), respectively. Compared with controls, the cerebral hyperemia during moderate hypoxia was not altered in group 2, attenuated in group 3 (to 53 +/- 13%, P = NS), and completely blocked in group 4 (P less than 0.01). CBF increase secondary to severe hypoxia was attenuated only in group 4 (74 +/- 29%, P less than 0.05). CSF concentrations of adenosine and adenosine metabolites measured by high-performance liquid chromatography increased during hypoxia. Arterial O2 content was inversely correlated (P less than 0.005) to maximal CSF levels of adenosine (r = 0.73), inosine (r = 0.87), and hypoxanthine (r = 0.80).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of hypoxia on the levels of adenosine, inosine and hypoxanthine in the cerebrospinal fluid (CSF) was determined by HPLC in newborn (1- to 3-day-old, n = 6) and 1-month-old (n = 5) piglets. Serial CSF samples (q 60 s) were obtained from the cisterna magna during normoxia and a 5-min hypoxia test (PaO₂ = 26.5 ± 2.9 Torr). In normoxia, newborns had a lower mean (± SEM) CSF concentration of adenosine (0.72 ± 0.17 vs. 2.60 ± 0.44 μM) and a higher concentration of hypoxanthine (4.88 ± 0.41 vs. 1.39 ± 0.60 μM) than the mature piglets (p < 0.05). In all animals, hypoxia induced an increase in CSF levels of adenosine and its metabolites between 2 and 4 min. However, peak adenosine concentrations were higher in mature (4.17 ± 1.41 μM) than in newborn (1.55 ± 0.29 μM) piglets (p < 0.05). These data might explain deficient vasodilator adaptation required for neonatal CBF regulation.

Summary: This study investigated the potential role of adenosine in cerebral blood flow (CBF) regulation in the neonate during moderate and severe hypotension. Exper iments were done in anesthetized, 1-to 3-day-old piglets. Regional CBF (determined by radio labeled microsphere technique) and cerebral metabolic rate for Oz (CMROz) 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 CMROz were performed successively after intracerebroventricular (i. c. v. ) injections of vehicle (n = 17), the adenosine receptor blocker 8-phenyltheophylline (8-PT, 10 /Lg, 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 param eters studied was significantly altered by moderate hy potension, but severe hypotension decreased the total Autoregulation (i.e., the maintenance of a con stant cerebral blood flow (CBF) over a range of systemic blood pressure) exists in the neonates (Hernandez et aI., 1980; Laptook et aI., 1982 Laptook et aI., , 1983 Papile et aI., 1985; Leffler et aI., 1986) albeit at a narrower range relative to adults. It is due to an adaptation of the cerebral resistance vessels that constrict in response to an increase in cerebral per fusion pressure and dilate in response to a decrease Received March 3, 1990; revised November 5, 1990; accepted November 9, 1990.Address correspondence and reprint requests to Dr. N. Lau dignon at Department of Pharmacology and Therapeutics, The Montreal Children's Hospital, Room A-604, 2300 Tupper Street, Montreal, Quebec, H3H IP3, Canada.Abbreviations used: CO, cardiac output; COD, cerebral oxy gen delivery; CVR, cerebral vascular resistance; EHNA, erythro-9-(2-hydroxy-3-nonyl)adenine; i. c. v. , intracerebro ventricular; NECA, 5'-N-(ethylcarboxamide)adenosine; 8-PT, 8-phenyltheophylline. 424CBF (mean ± SD) from 86 ± 24 to 40 ± 15 ml min -I 100 g-l and CMROz from 3. 2 ± 0. 8 to 1. 8 ± 1. 0 ml min -I 100 g-I (p < 0. 05). Administration of 8-PT did not alter these parameters during normotension, but significantly de creased CBF during moderate hypotension compared to postvehicle values (53 ± 11 versus 81 ± 12 ml min -I 100 g-l, P < 0. 05). This loss of autoregulation was com pletely reversed by NECA. During severe hypotension, 8-PT altered the CBF redistribution towards the brain stem. Mean normotensive CSF concentrations of adeno sine (0. 76 ± 0. 26 /LM) increased during moderate (l.40 ± 1. 78 /LM) and severe (2. 60 ± 2. 56/LM, p < 0.05) hypoten sion. These data suggest that, in the newborn, adenosine is an important mediator of the cerebral adaptive re sponse to hypotension, even within the range of autoreg ulation.