The rle of adenosine on regulation of cerebral blood flow in the newborn /

The high vulnerability of the newborn brain to oxygen deficit strongly suggests a relative inadequacy in the adaptive cerebral vessel dilation. We hypothesized that this neonatal deficiency might be due to an insufficient brain adenosine production and/or a decreased sensitivity of the cerebral vessels to adenosine, a crucial metabolic regulator of adult cerebral blood flow. This hypothesis was tested on newborn (1-3 day old) and older pigs as the experimental model. Our findings are as follows: (1) Adenosine induced a concentration-dependent vasodilation of the newborn cerebral vessels, especially in the brain stem and periventricular area. (2) The cerebrospinal fluid concentration of adenosine and adenosine metabolites increased during both hypoxic-hypoxia and systemic hypotension. During hypoxia, these levels were inversely correlated to the arterial oxygen content and positively correlated to the increase in cerebral blood flow. (3) Adenosine receptor antagonism by 8-phenyltheophylline completely blocked the cerebral hyperemia during moderate hypoxia, partially reversed it during severe hypoxia, and abolished autoregulation (i.e. the maintenance of a constant cerebral blood flow over a wide range of systemic blood pressure). Moreover, adenosine receptor blockade altered the regional redistribution of cerebral blood flow during severe hypoxia and hypotension. (4) Cerebrospinal fluid concentrations of adenosine during normoxia and hypoxia were lower in the newborn than in the older animals. (5) Relative to adult internal carotid arteries (important cerebral resistance vessels), newborn vessels were less sensitive to adenosine.These data demonstrate that adenosine is a potent dilator of the cerebral vessels and an important mediator of the regional cerebral adaptive response to brain oxygen deficit in the newborn. Brain interstitial concentrations of adenosine and the cerebral vessel sensitivity to adenosine are lower in the newborn than in the older individual. These findings may explain the relative deficiency in the adaptation of the newborn cerebral vasculature during brain oxygen deficit, leading to an unusual vulnerability to hypoxic-ischemic encephalopathy

Effect of Phenobarbital on Cerebral Blood Flow in the Newborn Piglet under Stress

Heart rate, cardiac output, mean arterial blood pressure (MABP), and cerebral blood flow (CBF) were measured in 12 newborn piglets (6 controls and 6 pretreated with 20 mg/kg phenobarbital), under two different stresses: pain stimulation and intravenous injection of 2.5 mg/kg phenylephrine. Phenobarbital prevented pain-induced tachycardia (p &lt; 0.05 versus controls) but failed to prevent hemodynamic changes induced by phenylephrine. CBF remained relatively constant throughout the study. A better correlation between cerebral vascular resistance and MABP was noted in the phenobarbital group (r = 0.58, p &lt; 0.01) than in the controls (r = 0.15, p = NS), suggesting that phenobarbital potentiates the vasoconstrictor effect of catecholamines.</jats:p

Effects of Adenosine and Its Analogues on Isolated Internal Carotid Arteries from Newborn and Adult Pigs

Vasorelaxant effects of adenosine and its analogues, 5′-N-(ethylcarboxamide) adenosine (NECA), N&lt;sup&gt;6&lt;/sup&gt;-(&lt;i&gt;l&lt;/i&gt;-phenylisopropyl)-adenosine (&lt;i&gt;l&lt;/i&gt;-PIA) and N&lt;sup&gt;6&lt;/sup&gt;-cyclohexyladenosine (CHA), on isolated internal carotid arteries from newborn (1–3 days) and adult (6 months) pigs were compared. The order of vasorelaxant potencies of adenosines was: NECA &gt; &lt;i&gt;l&lt;/i&gt;-PIA &gt; adenosine &gt; CHA for the adult arteries and NECA &gt; &lt;i&gt;l&lt;/i&gt;-PIA &gt; adenosine = CHA for the newborn arteries. Sensitivities of vessels from the newborn and mature animals to CHA and &lt;i&gt;l&lt;/i&gt;-PIA did not differ. However, carotid arteries from the newborn pigs were less sensitive to NECA and adenosine than the adult arteries (p &lt; 0.05). Theophylline caused an approximately 3-fold shift to the right of the relaxant concentration-response curves to all the four adenosines on arteries from pigs of both age groups. These data suggest that adenosine is not as effective a vasodilator in the newborn as it is in the adult.</jats:p

Effect of Indomethacin on Cerebral Blood Flow Velocity of Premature Newborns

Using the Doppler technique, the effect of therapeutic doses of indomethacin on the cerebral blood flow velocity (CBFV) of anterior cerebral arteries was studied in 13 preterm infants with patent ductus arteriosus. The first intravenous injection of indomethacin (0.2 mg/kg, group 1, n = 10) induced a significant decrease in the area under the velocity curve at 15 min (––22%), which was sustained until 120 min (––28%, p &lt; 0.005). In contrast, no significant change in CBFV occurred after the third dose (group 2, n = 7). In both groups, capillary blood gases, mean arterial blood pressure, and heart rate remained stable throughout the study. In 5 mechanically ventilated infants, the increase in CBFV secondary to suctioning was significantly attenuated after the first dose of indomethacin (p &lt; 0.02) but not after the third (p = 0.56). Thus, an initial dose of indomethacin may attenuate CBFV increases secondary to clinical manipulations in the preterm newborn.</jats:p

Rapid Effects of Hypoxia on the Cerebrospinal Fluid Levels of Adenosine and Related Metabolites in Newborn and One-Month-Old Piglets

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 (PaO&lt;sub&gt;2&lt;/sub&gt; = 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 μ&lt;i&gt;M&lt;/i&gt;) and a higher concentration of hypoxanthine (4.88 ± 0.41 vs. 1.39 ± 0.60 μM) than the mature piglets (p &lt; 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 μ&lt;i&gt;M&lt;/i&gt;) than in newborn (1.55 ± 0.29 μ&lt;i&gt;M&lt;/i&gt;) piglets (p &lt; 0.05). These data might explain deficient vasodilator adaptation required for neonatal CBF regulation.</jats:p