S. L. Zuckerman

Tumor necrosis factor-α induces pial arteriolar dilation in newborn pigs

Abstract The present study in piglets was designed to examine cerebrovascular effects of tumor necrosis factor-α (TNFα) and potential mechanisms involved. Anesthetized newborn pigs with closed cranial windows implanted were used. Effects of nitric oxide synthase (NOS) inhibitors, N G -nitro- l -arginine ( l -NNA) and aminoguanidine, and a prostaglandin H synthase inhibitor, indomethacin, on pial arteriolar responses to TNFα were determined. In addition, cortical cerebrospinal fluid (CSF) prostanoids (PGE 2 and 6-keto-PGF 1α ) and cyclic nucleotides (cAMP and cGMP) were examined as indices of local cerebral production. Diameters of pial arterioles were recorded every 5 min for 30 min following topical infusion of TNFα under the window. CSF was sampled at the end of the 30-min recordings. TNFα (10 −8 and 10 −7 M) caused dilation of pial arterioles and increased CSF prostanoids and cyclic nucleotides. Indomethacin blocked TNFα-induced vasodilation and the increase of prostanoids and cAMP, but not of cGMP. l -NNA and aminoguanidine blocked TNFα-induced vasodilation. Both inhibitors attenuated TNFα-induced prostanoid increase. Aminoguanidine blocked TNFα-induced increased cGMP and attenuated the increase in cAMP. These results are consistent with the hypothesis that TNFα increases cAMP via prostnoid synthesis. They also suggest that TNFα increases cGMP through nitric oxide synthesis, which, in addition, may promote production of prostanoids and, thus, cAMP.

Effects of indomethacin on cerebral vasodilator responses to arachidonic acid and hypercapnia in newborn pigs.

ABSTRACT: Responses of pial arterioles to topically applied arachidonic acid, conversion of exogenous arachidonic acid to prostanoids, and pial arteriolar dilation to hypercapnia were examined before and at progressive times after treatment with indomethacin (5 mg/kg i.v.) in chlor-alose-anesthetized newborn pigs with closed cranial windows. Before treatment with indomethacin, arachidonic acid and hypercapnia dilated pial arterioles and increased cortical periarachnoid cerebrospinal fluid concentrations of 6-keto-prostaglandin (PG) F1α and PGE2. One h after indomethacin treatment, the dilations and prostanoid synthesis were blocked. By 2 h after indomethacin treatment, hypercapnia produced significant dilation of pial arterioles, and dilation to both stimuli had returned to preindometha-cin levels by 3 h. Inhibition of conversion of exogenous arachidonic acid to prostanoids as monitored by increases in 6-keto-PGF1α and PGE2 in cerebrospinal fluid under the window also was reversed by 3 h after treatment with indomethacin. Repeated indomethacin treatment again blocked dilations and conversion of arachidonic acid to prostanoids on the brain surface. The possibility of short duration of vascular effectiveness of indomethacin when it is administered systemically needs to be considered, both when it is used as a probe for understanding contributions of PGH synthase products to control of cerebral circulation and when it is used therapeutically in attempts to alter the newborn cerebral circulation.

Pituitary adenylate cyclase-activating polypeptide dilates cerebral arterioles of newborn pigs.

Abstract The actions of the 38- and 27-amino acid forms of synthetic pituitary adenylate cyclase-activating polypeptide (PACAP-38 and PACAP-27) on cerebral arterioles were tested in anesthetized newborn pigs equipped with closed cranial windows. The diameter changes of pial arterioles to topical PACAP were measured and cortical periarach-noid cerebrospinal fluid samples were collected for measurement of cAMP. The 38- and 27-amino acid forms of PACAP produced similar dose-dependent vasodilations. The increases of pial arteriolar diameter produced by PACAP-38 were 6 ± 1%, 15 ± 2%, 23 ± 3%, and 38 ± 3%, and those produced by PACAP-27 were 6 ± 1%, 15 ± 2%, 27 ± 5%, and 38 ± 8% at 10−9, 10−8, 10−7, and 10−6 <M, respectively. Arteriolar diameter began to increase 1-2 min and reached a maximum 6-8 min after topical application of PACAP. Vasoactive concentrations of PACAP-38 and PACAP-27 increased cerebrospinal fluid cAMP levels dose dependently. Thus, PACAP-38 and PACAP-27 appear to stimulate cerebral adenylate cyclase and are potent dilators of newborn pigs pial arterioles.

The influence of opioids on local cerebral glucose utilization in the newborn pig

Topical methionine enkephalin, leucine enkephalin, and dynorphin (10(-6)M) previously have been observed to produce prominent pial arteriolar dilation. Dilation to these opioids could be caused directly by opioids acting on vascular receptors, or indirectly, as a consequence of increased metabolism. Therefore, we examined this possibility by determining the influence of opioids on cerebral glucose utilization in piglets with closed cranial windows using the [14C]deoxyglucose method. Qualitatively, the autoradiographic images expressed as a change in relative optical density from vehicle were unchanged by these opioids. Quantitatively, the opioids similarly had no effect on cerebral glucose utilization (53 +/- 5, 70 +/- 8, 63 +/- 5, and 52 +/- 3, mumol.100 g-1.min-1 for vehicle, methionine enkephalin, leucine enkephalin, and dynorphin, respectively). In contrast, topical glutamate (10(-3) M) produced similar dilation but increased cerebral glucose utilization (41 +/- 3 vs 89 +/- 8 mumol.100 g-1.min-1 for vehicle and glutamate, respectively). Therefore, these opioids do not appear to produce vascular effects through a change in cerebral metabolic utilization of glucose.

Cerebral vasoconstriction in response to hypocapnia is maintained after ischemia/reperfusion injury in newborn pigs.

Background and Purpose: Hypocapnic cerebral vasoconstriction is used therapeutically to reduce elevated intracranial pressure caused by cerebral edema. Because cerebral ischemia/reperfusion injury causes a selective loss of prostanoid-dependent responses, including vasodilation to hypercapnia, we designed these experiments to examine the effect of ischemia/reperfusion on hypocapnic cerebral vasoconstriction. Methods: Microvascular responses were studied in 10 newborn pigs (closed cranial window) in response to hyperventilation-induced hypocapnia (Paco2, 22±2 mm Hg) both before and 45 minutes after 20 minutes of global cerebral ischemia. Responses to hypercapnia (PaCO2, 63±3 mm Hg), topical isoproterenol (10−7 M), and norepinephrine (10−4 M) were also studied before and after ischemia in the same animals for comparison. Results: Before ischemia/reperfusion, pial arterioles vasoconstricted to hypocapnia (−17±2%) and norepinephrine (−35±4%) and vasodilated to COj2 (37±7%) and isoproterenol (25±2%). After ischemia/ reperfusion, the constriction of pial arterioles to hypocapnia (−19±2%) was similar to that before ischemia. This is in contrast to the loss of dilation to hypercapnia. Dilation to isoproterenol and constriction to norepinephrine were not affected by ischemia. Conclusions: Hypocapnic cerebral vasoconstriction is maintained after ischemia/reperfusion. Since prostanoid-dependent responses, such as hypercapnic dilation, are lost following cerebral ischemia, these data suggest that hypocapnic constriction is not dependent on an intact prostanoid system and that cerebral vascular responses to CO2 involve multiple mechanisms, depending on whether CO2 is increasing or decreasing from baseline.

Recent advances and controversies in cerebrovascular physiology in the newborn

Important differences exist between adult and newborn responses to different cerebrovascular influences. This review discusses the important influence that the prostanoid system has in newborn cerebral hemodynamics. Activated oxygen species and their generation through different cerebral insults are discussed. The role of several radical scavengers as modes of therapy is reviewed. The endo-thelium-derived relaxing factor system and its major influence in the adult is compared with its lesser role in the newborn. Finally, the pathophysiology of the alterations in newborn cerebral hemodynamics seen with experimentally induced seizures is reviewed.

Chronic Inhibition of Prostanoid Generation Produces an Increased Role of Nitric Oxide in the Newborn. 218

Hypercapnia-induced cerebral vasodilation is a prostanoid associated response in the piglet, but a nitric oxide (NO) associated response in many adult models. While NO does not appear to play a major role in the maintenance of cerebral vascular tone in the newborn (NB), hypercapnia-induced cerebral vasodilation is both NO and prostanoid associated in the juvenile pig. We hypothesized that chronic inhibition of cyclooxygenase (COX) in the piglet would increase the role of the NO system in cerebrovascular responses. The closed cranial window technique was used in piglets anesthetized withα-chloralose to determine pial arteriolar response. Chronic indomethacin(75mg SR po BID) treated NB animals dilated in response to CO2 similarly to control NB animals (40.8±36% vs 46.0±4.6%). Topical LNA (10-3M) attenuates CO2 induced dilation in chronic indomethacin treated animals (14.3±4.4% vs 40.8±3.6%; p<0.001). Neither indomethacin nor LNA altered response to isoproterenol. We conclude that with chronic COX inhibition, there develops a significant hypercapnia-induced cerebral vasodilation in which NO has an important role. The chronic inhibition of the NBs principal dilator system accelerates the role of the constitutive NO system in NB cerebral hemodynamics.

Permissive Role of Prostanoids in Cerebrovascular Dilation Induced by Estrogens in the Newborn. † 1121

Estrogens have vascular protective effects in addition to their anti-lipid effects. Estrogens enhance endothelium-dependent vasodilation in the adult. While estrogens increase constitutive nitric oxide (NO) synthase activity, NO does not have a major role in maintenance of vasomotor tone in the newborn. We hypothesized that if estrogens altered vascular tone in the newborn, it would be via a dilator system other than NO. Using the closed cranial window technique, pial arterial vessel diameter was quantified in response to topically administered ovarian steroids in piglets anesthetized withα-chloralose. 17β-estradiol (10-5M) produced pial vasodilation that was not altered by topical LNA (10-3M) and was attenuated by indomethacin (5mg/kg iv): 36.1±1.6% vs 27.3±6.1% vs 6.4±2.6% respectively. 17α-estradiol (10-5M) produced pial vasodilation that was not altered by topical LNA and was attenuated by indomethacin: 34.6±2.2% vs 26.2±4.2% vs 3.3±4.2% respectively. Carbacyclin (6·10M-11), a prostacyclin analogue in a concentration not sufficient to alter pial diameter, was able to restore the dilator response to β-estradiol attenuated by indomethacin. We conclude that in the newborn the estradiols produce a prostanoid associated pial vasodilation with no major role for NO, and that the prostanoids play a permissive role in the response.