Possible obligatory functions of cyclic nucleotides in hypercapnia-induced cerebral vasodilation in adult rats.

Current evidence suggests that nitric oxide (NO) and vasodilating prostanoids, possibly via the actions of cGMP and cAMP, play permissive roles in hypercapnic cerebral vasodilation. The present study examined whether cGMP and cAMP have obligatory functions in hypercapnia. Using a closed cranial window in adult rats, we measured pial arteriolar diameters and periarachnoid cerebrospinal fluid (pCSF) cyclic nucleotide levels during normo- and hypercapnia and in the presence or absence of inhibitors of neuronal NO synthase (nNOS) or cyclooxygenase (COX). Also, we measured cGMP and cAMP contents in primary neuronal and astrocyte cultures, at different levels of CO2. Hypercapnia (arterial PCO2 65 mmHg)-induced pial arteriolar dilation was accompanied by 70-80% elevations in pCSF cGMP and cAMP. Inhibition of nNOS with 7-nitroindazole (7-NI) significantly reduced both the CO2-induced arteriolar dilation (by 77%) and the pCSF cGMP and cAMP increases (by 60-70%). Inhibition of COX with indomethacin reduced arteriolar CO2 reactivity (by 83%) and pCSF cyclic nucleotide increases (by 80-100%). In neuronal cultures a transient NO-dependent increase in cGMP, but not cAMP, was seen when the CO2 level was raised from 5 to 14%. No changes were seen in astrocytes. The 7-NI and indomethacin-inhibitable increases in pial arteriolar diameter and cyclic nucleotide production during hypercapnia suggest a link between these two responses. One possible, although not exclusive, interpretation of these findings is that the cyclic nucleotides have an obligatory function in the CO2 response. The large overlap in the abilities of nNOS and COX inhibitors to elicit those effects further implies interactions ("cross talk") between the cGMP and cAMP vasodilating pathways. The in vitro data suggest that hypercapnia stimulates NO production in neurons.

Role of nitric oxide and cAMP in prostaglandin-induced pial arterial vasodilation.

The present study was designed to investigate the role of nitric oxide (NO), guanosine 3',5'-cyclic monophosphate (cGMP), and adenosine 3',5'-cyclic monophosphate (cAMP) in the vasodilator response to prostaglandin (PG)I2 and PGE2 in newborn pigs equipped with a closed cranial window. PGI2 (1-100 ng/ml) produced pial arterial dilation that was blunted by nitro-L-arginine (L-NNA, 10(-6) M), an NO synthase inhibitor (9 +/- 1 vs. 2 +/- 1%, 21 +/- 1 vs. 5 +/- 3% for 1 and 100 ng/ml PGI2 respectively, n = 6; means +/- SE). PGI2-induced vasodilation was associated with increased cortical periarachnoid cerebrospinal fluid (CSF) cGMP, and these changes in cGMP were blocked by L-NNA (386 +/- 8 and 1,054 +/- 30 fmol/ml vs. 266 +/- 6 and 274 +/- 4 fmol/ml for control and PGI2 100 ng/ml before and after L-NNA respectively, n = 6). In contrast, PGI2-associated changes in CSF cAMP were unchanged by L-NNA (1,021 +/- 25 and 2,703 +/- 129 fmol/ml vs. 980 +/- 23 and 2,636 +/- 193 fmol/ml for control, PGI2 100 ng/ml before and after L-NNA, respectively, n = 6). PGE2 elicited similar changes in pial artery diameter and cyclic nucleotides; vasodilation and changes in CSF cGMP also being similarly inhibited by L-NNA. After L-NNA, topical administration of the NO donor sodium nitroprusside (SNP, 10(-9) M) increased pial artery diameter up to the resting level before L-NNA and partially restored the vasodilation elicited by PGI2 and PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)

CO2 and cerebral circulation in newborn pigs: cyclic nucleotides and prostanoids in vascular regulation.

The role of cyclic nucleotides and prostanoids in cerebrovascular reactivity to increased carbon dioxide was investigated in anesthetized and artificially ventilated newborn pigs equipped with closed cranial windows. Pial arteriolar diameter was measured, and cortical periarachnoid cerebrospinal fluid (CSF) was collected from beneath the cranial window for determination of adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), and prostanoids. Progressively increasing arterial PCO2 (PaCO2) from normocapnia (33 +/- 1 mmHg) to hypercapnia (final PaCO2, 83 +/- 2 mmHg) resulted in dose-dependent pial arteriolar dilation and concomitant increases in cAMP, cGMP, and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in cortical CSF. N omega-methyl-L-arginine, N omega-nitro-L-arginine, N omega-nitro-L-arginine methyl ester, methylene blue, and LY 83583 did not inhibit cerebral vasodilation or the increases in cortical cAMP/cGMP induced by hypercapnia. Indomethacin abolished the vasodilatory response to hypercapnia and attenuated the hypercapnia-induced increases in cAMP and cGMP. Prostacyclin analogues increased both cAMP and cGMP levels in cortical CSF and induced pial arteriolar dilation (iloprost > carbaprostacyclin). The present data suggest that in newborn pigs cyclic nucleotides are involved in cerebral vasodilation in response to hypercapnia via a prostanoid-dependent mechanism.

Plasma cyclic nucleotide levels in acute leukemia patients.

To verify the clinical usefulness of extracellular cyclic nucleotide determination as a tumor marker, plasma cyclic AMP (cAMP) and cyclic GMP (cGMP) levels were measured in 70 normal subjects and 173 acute leukemia patients studied in different stages of their disease. Mean plasma cAMP levels were similar in leukemic and normal subjects, although in 48 patients in the active stage of the disease, first diagnosis, or relapse, the cAMP values were below the normal range, and most of these patients failed to respond to chemotherapy. Plasma cGMP levels were markedly elevated in untreated patients, normalized in all patients who attained complete remission, and increased promptly to pretreatment values in patients who relapsed, suggesting that their determination may be useful to monitor the patients' response to treatment.

Catecholamine metabolites and cyclic nucleotides in cerebrospinal fluid in dementia of Alzheimer type.

Three, 4-dihydroxyphenylacetic acid (DOPAC); 3-methoxy, 4-hydroxyphenylacetic acid (HVA); 3-methoxy; 4-hydroxyphenylglycol (MHPG); adenosine 3', 5'-cyclic monophosphate (cyclic AMP); and guanosine 3', 5'-cyclic monophosphate (cyclic GMP) were measured in cerebrospinal fluid (CSF) of patients with dementia of Alzheimer type (DAT) and controls. DOPAC levels were lower and HVA levels were higher in DAT patients than in controls. In the most rostral fractions of CSF from DAT patients there was a negative correlation between DOPAC and cyclic AMP levels. In addition, patients with onset of DAT symptoms before the age of 65 had lower DOPAC levels, a higher HVA/DOPAC ratio, and higher cyclic nucleotide levels than patients with late onset of DAT. By combining DOPAC and cyclic AMP levels, we could clearly distinguish these two groups.

[Markers of brain tumors]. / I marker dei tumori cerebrali.

Biological markers of tumors are compounds or enzymatic activities measurable in body fluids. Their presence or concentration must be linked to tumoral growth. The markers of the central nervous system tumors are detected in CSF. Alpha-feto-protein, carcinoembryonic antigen, human chorionic gonadotropin, adenohypophyseal peptide hormones, enzymes, etc., have found some application in the early diagnosis of leptomeningeal metastasis. Other applications involve the early detection and recurrency of primary brain tumors, as well as the evaluation of efficacy of their therapy. The tests based on the CSF content of desmosterol and polyamines have been studied extensively. Their rationale is discussed and specificity, sensitivity, efficiency and predictive value are considered. Experimental results concerning a new possible biochemical marker, based on CSF concentration of cyclic adenosine monophosphate, are reported.

Noradrenergic overactivity in chronic schizophrenia: evidence based on cerebrospinal fluid noradrenaline and cyclic nucleotide concentrations.

Concentrations of noradrenaline (NA), homovanillic acid, 5-hydroxyindoleacetic acid and cyclic nucleotides were determined in lumbar cerebrospinal fluid (CSF) from acute and chronic schizophrenics and various groups of psychiatric and non-psychiatric control subjects. Statistically significant increases in NA and cyclic adenosine monophosphate were found in CSF from chronic schizophrenics compared to all other groups. These results were shown by statistical analyses to be unrelated to medication. They may be interpreted as evidence for noradrenergic overactivity as a possible primary abnormality in chronic schizophrenia.

Probenecid-induced accumulation of cyclic nucleotides, 5-hydroxyindoleacetic acid, and homovanillic acid in cisternal spinal fluid of genetically nervous dogs.

These studies have been conducted on 40 dogs, twenty each of a genetically nervous strain and of a normal strain of short-haired pointers. The nervous strain after about age 3 months displays extreme hypervigilance, timidity, human avoidance, and often shows catatonic-like muscle rigidity when in the presence of humans or novel stimuli. Measurements of probenecid-induced accumulation of acid metabolites in cisternal cerebrospinal fluid (CSF) have been carried out. Among the compounds measured at from 1.5 hr to 6.0 hr after probenecid treatment, homovanillic acid (HVA) was similar for the two strains, 5-hydroxy-indoleacetic acid (5-HIAA) was lower, but cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) were higher for the nervous strain when compared with age- and sex-matched behaviorally normal dogs. Probenecid levels in CSF were similar at all points in time from 1.5 to 6.0 hr after its intravenous administration in a dose of 50 mg/kg body weight. These findings coupled with previously observed differences in the two strains suggest that hyperresponsiveness of the central nervous system (CNS) noradrenergic and cholinergic systems and a hyporesponsiveness of the serotoninergic system are related to the genetically expressed aberrant behavior.