Intracranial pressure monitoring: modeling cerebrovascular pressure transmission.

OBJECTIVES: To examine changes in cerebrovascular pressure transmission derived from arterial blood pressure (ABP) and intracranial pressure (ICP) recordings by autoregressive moving average modeling technique. METHODS: Digitized ICP and ABP recordings were obtained from patients with brain injury. Two groups were defined: Group A with 4 patients who demonstrated plateau waves, and Group B with 4 intracranial hypertensive, hypoperfused patients. For each 16.5 s interval, mean values of ICP, ABP, cerebral perfusion pressure (CPP), and corresponding highest modal frequency (HMF) of cerebrovascular pressure transmission were computed. RESULTS: Mean values of CPP and HMF of 56.2 mmHg and 2.0 Hz for Group A were significantly higher (p < 0.005) than corresponding mean values of 31.9 mmHg and 0.744 Hz for Group B. The mean value of the slope of the regression line between HMF and CPP for group A of -0.034 Hz/mmHg was significantly different (p < 0.025) than the mean value of 0.0077 Hz/mmHg for Group B. Computations of HMF, pressure reactivity, and correlation pressure reactivity index on continuous pressure recordings are illustrated. CONCLUSIONS: Values of HMF of cerebrovascular pressure transmission are inversely related to CPP when pressure regulation is thought to be intact, and directly related when regulation is likely lost.

Plateau waves: changes of cerebrovascular pressure transmission.

OBJECTIVE: To test the validity of the hypothesis that active vasodilatation and vasoconstriction underlie the occurrence of intracranial pressure (ICP) plateau waves by evaluating corresponding changes of cerebrovascular pressure transmission of arterial blood pressure (ABP) to ICP. METHODS: Digitized recordings of ICP and ABP sampled at 30 Hz were obtained from nine patients with traumatic brain injury. For each 16.5 s recording interval mean values of ICP, ABP, cerebral perfusion pressure (CPP), and the corresponding highest modal frequency (HMF) of cerebrovascular pressure transmission were calculated. RESULTS: Mean ICP and HMF significantly increased (P < 0.003) and mean CPP decreased significantly (P < 0.00036) at onset of the wave. Conversely at termination, mean ICP and HMF significantly decreased (P < 0.026) and mean CPP significantly increased (P < 0.028). In addition, the strong negative correlations between mean ICP and mean CPP (r = -0.87) and mean HMF and CPP (r = -0.87) were demonstrated. CONCLUSION: The findings that HMF increased at onset and decreased at the termination of plateau wave support the validity of the vasodilatatory/constriction cascade model that postulates active vasodilation at the onset and active vasoconstriction of the cerebrovascular bed at the termination of a plateau wave.

Comparison of PGE2, prostacyclin and leptin release by human adipocytes versus explants of adipose tissue in primary culture.

The present studies were designed to investigate the sites of PGE(2), prostacyclin and leptin formation in human adipose tissue. Most of the PGE(2) and prostacyclin formation by adipose tissue explants from obese humans after 48 h in primary culture was due to blood vessels and other tissues not digested by collagenase. However, there was appreciable PGE(2) formation by adipocytes over a 48 h incubation and leptin formation was only seen in adipocytes. An increase in COX-2 immunoreactive protein was also seen after incubation of isolated human adipocytes for 48 h. The release of PGE(2) by adipocytes incubated for 48 h was about 4% that by intact adipose tissue explants while the release of prostacyclin was about 1.5% that by tissue. However, in a different experimental design where PGE(2) formation was measured over 2 h in the presence of 20 microM arachidonic acid the formation of PGE(2) by adipocytes after 48 h prior incubation in primary culture was 38% of that by tissue explants. Dexamethasone enhanced leptin release by adipocytes while inhibiting PGE(2) release and COX-2 up-regulation. The mechanisms involved in up-regulation of COX-2 activity during primary culture of adipocytes and the inhibition of this by dexamethasone do not appear to involve p38 MAPK or p42-44 MAPK. Interleukin I(beta) further enhanced PGE(2) formation by adipocytes but did not affect leptin formation. In conclusion, these data indicate that leptin release is exclusively a function of adipocytes while prostanoids are made by both adipocytes and the other cells present in human adipose tissue

Cyclic variation of cerebral pial arteriolar diameter synchronized with positive-pressure inhalation.

Laboratory observations have noted that during normocapnia and intact vascular tone, changes in the intracranial pressure (ICP) and arterial blood pressure (ABP) recordings are not similar. The purpose of the present study was to determine whether: 1) the diameter of cerebral pial arterioles synchronously increases during positive pressure inhalation and decreases during the expiration phase of ventilation; and 2) the variation in arteriolar diameter is greater when vascular tone is intact than when arterioles are maximally dilated. Severe hypercapnia was induced by prolonged ventilation with gas mixture of 20% O2, 10% CO2, and 70% N2 in 8 piglets. S-VHS recordings of 3600X magnification of nine pial arterioles were obtained during conditions of normal vascular tone and severe hypercapnia and digitally analyzed by an image-averaging method. Variation of the amplitude of arteriolar diameter over the ventilation cycle was computed and found to synchronously increase during positive pressure inhalation and to decrease to a steady state baseline during passive expiration. Mean amplitude of variation in diameter (+/- S.D.) during normal tone and hypercapnia was computed as 1.63 (+/- 0.693) microns and 1.012 (+/- 0.869) microns respectively and found to be significantly greater during the condition of normal vascular tone than during hypercapnia (p < .006). These results suggest that a cyclic variation of arteriolar blood volume is one causal factor related to the low frequency variation of the baseline of ICP associated with positive pressure ventilation.

Spectral characteristics of B-waves and other low-frequency activity.

Low frequency oscillations of intracranial pressure (ICP) between 0.5 to 2.0 cycles/min have been termed B-waves. While such low frequency activity may be generated by cerebral vasomotor activity, activity in the B-wave band may also be related to other causes. The objective of this study is to: 1) describe the low frequency characteristics of ICP and arterial blood pressure (ABP) recordings with a mathematical model based on ventilator-induced intrathoracic pressure (ITP) modulation of arterial blood pressure; and 2) use the model to eliminate low frequency activity within the B-wave range unrelated to vasomotor activity. The model describes the frequency locations of spectra associated with ventilation about both the principal and first harmonic cardiac frequency to within 1% error. Spectra within the B-wave range harmonically related to the ventilator frequency were classified as caused by patient-ventilator interaction. Of 11 patients with severe head-injury, 64% (7/11) demonstrated B-wave activity, and 4 patients demonstrated the activity solely in the ICP recording. Variation of heart rate did not correspond to the occurrence of B-waves. The proposed model describes the low frequency spectra found within ABP and ICP recordings and can be used to eliminate spectra with the B-wave range related to ventilation.

Variation of proposed correlation indices of cerebrovascular reactivity with change of arteriolar diameter.

The purpose of this study was to examine the relationship between proposed correlation indices of cerebrovascular reserve and corresponding changes of cerebrovascular reserve as measured by changes of pial arteriolar diameter. Mild and severe physiologic challenge was produced in piglets by appropriate ventilation with foreign gas mixture and altered alveolar ventilation. Intracranial pressure (ICP), arterial blood pressure (ABP), and video micrometer recordings of pial arteriolar diameter were made. Serial values of ICP and ABP were used to compute the Correlation Coefficient index (Corrx) and the Pressure Reactivity Index (PrX). For the 10 mild physiologic challenge experiments, correlations between percent change index (% delta Corrx and % delta PrX) and percent change of pial arteriolar diameter (% delta dia.) induced by mild challenges (n = 40) were 0.51 (p < .005) and 0.097 (p n.s.) respectively. For 8 asphyxia experiments, serial values with respect to time of the correlation indices were correlated with % delta dia. obtained before, during induction and recovery. The grand mean (n = 8) correlation values (+/- S.D.) of the Corrx and PrX were 0.76 (+/- 0.18, p < .025) and 0.21 (+/- 0.38, p n.s.) respectively. In contrast to the PrX index, changes of the Corrx index significantly correlated with changes of pial arteriolar diameter. However, Corrx and PrX were simultaneously high only during a state of maximum dilation. These findings suggest that sudden salient increases of the Corrx and PrX indices induced by physiologic challenge are indicative of vigorous dilatory response of the cerebral arterioles and loss of cerebrovascular reserve.

Use of resistance-area product derived from Doppler MCA velocity to estimate the range of active cerebrovascular regulation.

The purpose of the present study was to explore the development of a method to estimate the range of active cerebrovascular regulation using resistance-area product (RAP) derived from transcranial Doppler ultrasound recordings of middle cerebral artery blood velocity (MCAV) obtained before and after physiologic challenge. Intracranial pressure (ICP), arterial blood pressure (ABP), and MCAV were monitored on 9 patients before and after challenges with either Noradrenlin or CO2 inhalation. One patient was monitored at 24, 48, 72, and 96 hrs. For each cardiac cycle a value of RAP was computed from the inverse of the slope of the regression line of paired values of aligned MCAV and ABP recordings. Mean values of percent change of difference of RAP (% delta RAP) versus change of cerebral perfusion pressure (CPP) were computed. Theoretical values of % delta RAP were derived from reported lab values of percent change diameter of arterioles versus ABP. Of the nine patients, 22% (2/9) demonstrated either impaired dilation and/or constriction. Furthermore, the correlation between theoretical and experimental values of % delta RAP and CPP (n = 34) was strong (r = .86, p < .005). The serially-monitored patient failed to dilate during all CO2 challenges and to fully constrict to the Noradrenlin challenge at 72 hrs. % delta RAP associated with corresponding changes of CPP may have value as a clinical method to estimate the range of active cerebrovascular regulation.

An estimated compliance index derived from intracranial pressure recording.

The purpose of this study is to test the validity of a proposed compliance index, percent change of compliance per mmHg of intracranial pressure (%CC/mmHg), by comparison of values of the index with corresponding experimentally derived values of compliance. The derivation of %CC/mmHg is based on two assumptions: 1) the pressure-volume characteristic of the craniospinal sac can be linearized for small perturbations about an equilibrium; and 2) during a brief interval in which these perturbations occur the pathophysiologic state of the sac does not significantly change. By rapid infusion of 0.2 ml of mock cerebrospinal fluid (CSF) experimental values of compliance (n = 44) were obtained from 10 piglets during monitoring of intracranial pressure (ICP). A strong correlation (r = 0.89, p < .001, n = 44) was obtained between values of %CC/mmHg and corresponding values of experimentally derived compliance (ml/mmHg). The value of the proposed index of compliance, %CC/mmHg, needs to be evaluated in the clinical setting. However, from the view of validation of ICP instrumentation, high values of both mean ICP and mean %CC/mmHg are contradictory and indicative of the occurrence of instrumentation error due to electronic direct current drift.

Compensatory role of NO in cerebral circulation of piglets chronically treated with indomethacin.

We hypothesize that inhibitory effects exist between prostanoids and nitric oxide (NO) in their contributions to cerebral circulation. Piglets (1-4 days old) were divided into three chronically treated (6-8 days) groups: control piglets, piglets treated with indomethacin (75 mg/day), and piglets treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg x kg(-1) x day(-1)). Pial arterioles dilated in response to hypercapnia similarly among the three groups (41 +/- 4, 40 +/- 6, and 45 +/- 11%). Cerebrospinal fluid cAMP increased in control piglets, while cGMP increased in indomethacin-treated piglets. L-NAME, but not 7-nitroindazole, inhibited the response to hypercapnia only in indomethacin-treated piglets (40 +/- 6 vs. 17 +/- 5%). Topical sodium nitroprusside or iloprost restored dilation in response to hypercapnia. Similar results were obtained when the dilator was bradykinin. Pial arterioles of control and L-NAME-treated piglets constricted in response to ACh (-24 +/- 3%). However, those of indomethacin-treated piglets dilated in response to ACh (15 +/- 2%). This dilation was inhibited by L-NAME. NO synthase activity, but not endothelial NO synthase expression, increased after chronic indomethacin treatment. These data suggest that chronic inhibition of cyclooxygenase can increase the contribution of NO to cerebrovascular circulatory control in piglets.

Endothelial NO and prostanoid involvement in newborn and juvenile pig pial arteriolar vasomotor responses.

Specific cerebrovascular dilatory responses in newborn piglets are entirely prostanoid dependent, but require both nitric oxide (NO) and prostanoids in juveniles. We examined endothelial dependency and mechanisms of NO- and prostanoid-mediated cerebrovascular responses in anesthetized newborn and juvenile pigs implanted with closed cranial windows. Light/dye endothelial injury inhibited newborn and juvenile hypercapnic and bradykinin (BK) responses and inhibited dilation to acetylcholine in juveniles. Iloprost and NO act permissively in restoring light/dye inhibited newborn and juvenile responses, respectively. Differences in sensitivity to iloprost and sodium nitroprusside were not observed. Juvenile (not newborn) hypercapnic and BK cerebrovascular responses were sensitive to soluble guanylyl cyclase inhibition. Pial arteriolar diameter and cortical production of prostacyclin, cAMP, and cGMP in response to BK were measured under control conditions, after treatment with indomethacin and/or N(omega)-nitro-L-arginine methyl ester (L-NAME). Indomethacin inhibited BK responses in newborns. Juvenile responses were inhibited by L-NAME, and mildly by indomethacin. Cortical 6-keto-PGF(1 alpha), cAMP, and cGMP increased in response to BK in both age groups. Newborn cerebrovascular responses are largely NO independent, but NO becomes more important with maturation.

Cerebral vascular endothelial heme oxygenase: expression, localization, and activation by glutamate.

Endogenous carbon monoxide (CO) contributes to vasodilator responses of cerebral microvessels in newborn pigs. We investigated the expression, intracellular localization, and activity of heme oxygenase (HO), the key enzyme in CO production, in quiescent cerebral microvascular endothelial cells (CMVEC) from newborn pigs. HO-1 and HO-2 isoforms were detected by RT-PCR, immunoblotting, and immunofluorescence. HO-1 and HO-2 are membrane-bound proteins that have a strong preference for the nuclear envelope and perinuclear area of the cytoplasm. Betamethasone (10(-6) to 10(-4) M for 48 h) was associated with upregulation of HO-2 protein by approximately 50% and inhibition of Cox-2 but did not alter HO-1 or endothelial nitric oxide synthase expression in CMVEC. In vivo betamethasone treatment of newborn pigs (0.2 and 5.0 mg/kg im for 48 h) upregulated HO-2 in cerebral microvessels by 30-60%. HO activity as (14)CO production from [(14)C]glycine-labeled endogenous heme was inhibited by chromium mesoporphyrin (10(-6) to 10(-4) M). L-Glutamate (0.3-1.0 mM) stimulated HO activity 1.5-fold. High-affinity specific binding sites for L-[(3)H]glutamate suggestive of the glutamate receptors were detected in CMVEC. Altogether, these data suggest that, in cerebral circulation of newborn pigs, endothelium-derived CO may contribute to basal vascular tone and to responses that involve glutamate receptor activation.

Mechanism of permissive prostacyclin action in cerebrovascular smooth muscle.

Prostacyclin permissively allows increased cAMP and cerebral vasodilation to hypercapnia in piglets. The prostacyclin receptor (IP) is coupled to phospholipase C (PLC) in piglet cerebral microvascular smooth muscle cells (SMC). We hypothesize that inhibition of PLC blocks the permissive action of IP receptor agonist, iloprost, and direct activation of PKC substitutes for the IP receptor agonist in SMC. SMC cAMP production was measured at normal pHi/pHo and with reduced pHi/pHo in the absence and presence of iloprost (100 pM). Half of the cells were pretreated with U73122, the PLC inhibitor, which decreased the basal IP3 and blocked the increase in IP3 caused by iloprost. Without iloprost, decreasing pHi/pHo increased cAMP production (40%). With iloprost, the cAMP response to acidosis increased to over 80%. U73122 prevented accentuation of the cAMP response by iloprost. Phorbol myristate acetate augmented the response to acidosis similarly to iloprost. These data suggest IP agonists augment the cAMP response to acidosis via coupling through PLC to activate PKC.

Stimulation of leptin release by arachidonic acid and prostaglandin E(2) in adipose tissue from obese humans.

The purpose of this study was to examine the effect of arachidonic acid and its metabolites on leptin formation by explants of human adipose tissue over a 48-hour incubation in primary culture. We found that arachidonic acid or prostaglandin E(2) (PGE(2)) stimulated leptin release by explants of subcutaneous adipose tissue from obese humans. The stimulatory effect of arachidonic acid on leptin formation was blocked by NS-398, a cyclooxygenase-2 (COX-2) inhibitor. There was appreciable release of PGE(2) to the medium over 48 hours, and this was inhibited by 99% in the presence of 200 nmol/L dexamethasone or 5 micromol/L NS-398. The increase in PGE(2) release correlated with induction of COX-2 activity during the 48-hour incubation. The increase in COX-2 activity was blocked by 200nmol/L dexamethasone. The level of leptin mRNA at 48 hours was reduced by 28% if PGE(2) was added in the absence of dexamethasone, while in the presence of dexamethasone, the amount of leptin mRNA was enhanced by 156%. These data suggest that when upregulation of COX-2 is blocked by dexamethasone, exogenous PGE(2) enhances both leptin release and leptin mRNA accumulation by explants of human adipose tissue in primary culture.

Dynamics of nuclear localization sites for COX-2 in vascular endothelial cells.

We investigated the relationships among expression, activity, and spatial organization of cyclooxygenase (COX-1 and COX-2) in endothelial cells from porcine and human cerebral microvessels and from human umbilical vein. In quiescent cells, COX-1 was detected in the perinuclear zone and the cytoplasm, while COX-2 was mainly a nuclear resident possibly connected with the nuclear matrix. COX-2 immunogold labeling was situated in the nuclear envelope, at the nuclear pores, and in connection with the perichromatin regions of the nucleus, considered to be the sites of active transcription. In human endothelial cells transcriptionally activated by interleukin (IL)-1beta, the nucleus remained a major COX-2 localization site during the first 12 h of stimulation, when COX-2 expression was maximally induced. The continuous rise in prostanoid synthesis at 17-23 h of stimulation was associated with COX-2 relocation from the nucleus to the nuclear envelope and the cytoplasm. IL-1beta did not affect COX-1 expression, activity, and localization. COX-2 nuclear localization sites and trafficking between the nucleus and the cytoplasm in endothelial cells may indicate a novel function of COX-2 in regulating gene expression.

Contributions of prostacyclin and nitric oxide to carbon monoxide-induced cerebrovascular dilation in piglets.

Carbon monoxide (CO) is an endogenous dilator in the newborn cerebral microcirculation. Other dilators include prostanoids and nitric oxide (NO), and interactions among the systems are likely. Experiments on anesthetized piglets with cranial windows address the hypothesis that CO-induced dilation of pial arterioles involves interaction with the prostanoid and NO systems. Topical application of CO or the heme oxygenase substrate heme-L-lysinate (HLL) produced dilation. Indomethacin, N(omega)-nitro-L-arginine (L-NNA), and either iberiotoxin or tetraethylammonium chloride (TEA) were used to inhibit prostanoids, NO, and Ca(2+)-activated K(+) (K(Ca)) channels, respectively. Indomethacin, L-NNA, iberiotoxin, or TEA blocked cerebral vasodilation to CO and HLL. Vasodilations to both CO and HLL were returned to indomethacin-treated piglets by topical application of iloprost. Vasodilations to both CO and HLL were returned to L-NNA-treated piglets by sodium nitroprusside but not iloprost. In iberiotoxin- or TEA-treated piglets, dilations to CO and HLL could not be restored by either iloprost or sodium nitroprusside. The dilator actions of CO involve prostacyclin and NO as permissive enablers. The permissive actions of prostacyclin and NO may alter the K(Ca) channel response to CO because neither iloprost nor sodium nitroprusside could restore dilation to CO when these channels were blocked.

Regulation of leptin release and lipolysis by PGE2 in rat adipose tissue.

The role of eicosanoids formed by adipose tissue from rats was examined in the presence of the specific cyclooxygenase-2 inhibitor NS-398. This agent totally blocked the release of prostaglandin E2 (PGE2) by rat adipose tissue over a 24-h incubation in primary culture. The final concentration of PGE2 after 24 h was 12 nM, and half-maximal inhibition of PGE2 formation required 35 nM NS-398. While inhibition of PGE2 formation by NS-398 had no effect on basal leptin release or lipolysis, it enhanced the lipolytic action of 10 nM isoproterenol by 36%. The in vivo administration of PGE2 doubled serum leptin. PGE2 also directly stimulated leptin release by rat adipose tissue incubated in the presence of 25 nM dexamethasone, which inhibited endogenous PGE2 formation by 94%. The inhibition of lipolysis as well as the stimulation of leptin release by PGE2 were mimicked by N6-cyclopentyladenosine (CPA). These data indicate that exogenous PGE2 can stimulate leptin release by adipose tissue when the basal formation of PGE2 is blocked by dexamethasone. However, while the endogenous formation of PGE2 does not appear to regulate basal lipolysis or leptin release, it may play a role in the activation of lipolysis by catecholamines.

Eicosanoids as endogenous regulators of leptin release and lipolysis by mouse adipose tissue in primary culture.

Prostaglandin E(2) (PGE(2)) stimulated leptin release over a 24-h incubation of mouse adipose tissue in primary culture. The maximal stimulation of leptin release was seen with 100 nm PGE(2). The role of endogenous eicosanoids in the regulation of lipolysis and leptin formation was examined in the presence of NS-398, a selective cyclooxygenase-2 inhibitor. NS-398 at a concentration of 5 microm enhanced lipolysis by 30% and lowered leptin release by 24%. This concentration of NS-398 almost completely inhibited PGE(2) formation. An inhibition of basal lipolysis by PGE(2) or N(6)-cyclopentyladenosine (CPA) was seen in the presence but not in the absence of NS-398. CPA, whose receptor, like that of PGE(2) inhibits cyclic AMP accumulation in adipose tissue, also enhanced leptin release. These data indicate that PGE2 can stimulate leptin release and suggest that endogenous eicosanoids affect both lipolysis and leptin formation by mouse adipose tissue.

Preservation of cerebrovascular tone and reactivity by sodium channel inhibition in experimental prolonged asphyxia in piglets.

Sodium channels using cAMP as a second messenger play a role in the regulation of cerebral circulation and metabolism. Cerebrospinal fluid (CSF) cAMP levels have been shown to correlate with the degree and duration of hypoxic injury and outcome and to be an indicator of cerebral vascular reactivity. We hypothesize that sodium channel inhibition either before or at termination of experimental asphyxia will attenuate cerebrovascular alterations and maintain CSF cAMP levels. Three groups of piglets with closed cranial windows were studied: asphyxia or group 1 (n = 5) and two treatment groups. Pigs were treated with 50 mg/kg of sodium channel blocker before asphyxia (group 2, n = 6) and after the termination of asphyxia and start of reventilation (group 3, n = 6). Asphyxia was sustained over 60 min by ventilating piglets with 10% O2 gas mixture and decreasing minute ventilation followed by 60 min of reventilation with room air. Every 10 min, pial arterial diameters were measured, and CSF samples were collected for cAMP determination. Vascular reactivity to topically applied isoproterenol (10(-4) M) was evaluated 60 min after recovery. During asphyxia, cAMP levels in group 2 peaked and declined at a later time with mean values remaining significantly higher than those of groups 1 and 3. During reventilation, CSF cAMP concentrations were highest in group 3 and lowest in group 1. Pial arteriolar dilation occurred during asphyxia in all three groups but to a lesser degree in the pretreated group compared with groups 1 and 3. Pial arteriolar reactivity to isoproterenol postasphyxia was preserved in both groups 2 and 3. In summary, in newborn pigs, pretreatment with sodium channel blocker resulted in higher CSF cAMP levels and a lesser degree of pial arteriolar dilation during prolonged asphyxia. Pretreatment or treatment at reventilation restored vascular tone and reactivity.

Developmental changes in endothelium-derived vasorelaxant factors in cerebral circulation.

Endothelium-derived prostanoids are predominant vasorelaxant factors in the cerebral circulation of newborn pigs in vivo, whereas in older pigs nitric oxide (NO)-mediated responses also contribute to the regulation of cerebral vascular tone. We compared the expression and activities of NO synthase and cyclooxygenase in the cerebral microcirculation of newborn and adult pigs. In adult animals, expression and activity of endothelial NO synthase in cerebral microvessels and in cultured cerebral endothelial cells is two- to threefold higher than in newborn pigs; acetylcholine and bradykinin cause a greater increase in NO production in adult pigs. Expression and activity of cyclooxygenase in cerebral microvascular endothelial cells is similar in newborn and adult pigs; acetylcholine and bradykinin stimulated dilator prostanoid production to the same degree in both age groups. Endothelial prostanoid synthesis in cerebral microvessels and cultured endothelial cells was inhibited 30-70% by NS-398, reflecting a large contribution of COX-2 in both newborn and adult animals. These data indicate that in the cerebral circulation of pigs, NO synthase is age-dependently upregulated, whereas endothelial cyclooxygenase is not altered during postnatal development.

Enhanced pial arteriolar sensitivity to bioactive agents following exposure to endothelin-1.

Effects of prior exposure of pial arterioles to endothelin-1 (ET-1) (10(-9) M) on the constriction induced by the by-products of hemolyzed blood (5-HT, LTC4, LPA, and thromboxane analog U-46619) were examined. Piglets (age: 1-3 d) anesthetized with a mixture of ketamine hydrochloride and acepromazine were implanted with cranial windows, and anesthesia was maintained with alpha-chloralose. Topical applications of the by-products of hemolyzed blood mildly constricted pial arterioles. Following prior exposure of the microvessels to ET-1, application of the by-products of hemolyzed blood produced significantly potentiated and long-lasting constrictions compared to the controls. In another experiment, pretreatment of pial arterioles with U-46619 (10(-8) M) also potentiated the constriction induced by ET-1. The constriction produced was fast and longer-lasting. Thus, these data show that by-products of hemolyzed blood, though not potent vasoconstrictors per se, potently constricted pial arterioles in the presence of ET-1. The same agents in the CSF can also potentiate constriction induced by ET-1. Hence, by-products of hemolyzed blood may play a significant role in the initiation and maintenance of cerebral arterial narrowing observed following intracranial bleeding.