Polarizing currents increase noradrenaline-elicited accumulation of cyclic AMP in rat cerebral cortex.

Cyclic AMP accumulation elicited by noradrenaline was determined in cerebral cortical slices of rats 24 h after an application of weak anodal direct current (anodal polarization) to the surface of the sensorimotor cortex. Noradrenaline-elicited accumulation of cyclic AMP was altered regionally by the anodal polarization in relation to the duration and intensity of the polarizing current. The cyclic AMP accumulation elicited by noradrenaline was highest in the left anterior cortical region including the polarized point under polarization conditions of 0.3 microA for 1.5 h and 3.0 microA for 30 min. Under these two polarization conditions, the cyclic AMP accumulation elicited by noradrenaline was higher than that in the non-polarized control in the same cortical region. Furthermore, the beta-adrenergic antagonist propranolol almost completely reduced the elicited accumulation of cyclic AMP by noradrenaline to the control level. These results suggest that anodal polarization enhances activity of noradrenaline-sensitive cyclic AMP generating systems through beta-adrenergic mechanisms as a function of both duration and intensity in the cerebral cortex and that one polarization event has a long-lasting aftereffect on noradrenaline-sensitive cyclic AMP generating systems in the cerebral cortex.     

Adenylate cyclase activation is not sufficient to stimulate somatostatin release from dispersed cerebral cortical and diencephalic cells in glia-free cultures

Under conditions in which vasoactive intestinal peptide (VIP) induces somatostatin release from cortical and diencephalic neuronal cultures, VIP causes large increases in intracellular cyclic AMP. Both the release of somatostatin and the increase in cyclic AMP elicited by VIP require exogenous calcium, can be blocked by cobalt ion, and can be qualitatively mimicked by depolarizing concentrations of exogenous potassium ion. Direct activation of adenylate cyclase by forskolin causes large in increases in cyclic AMP content but does not induce somatostatin release. In the absence of VIP, the calcium ionophore, ionomycin, and the phorbol ester, phorbol 12-myristate-12-acetate, also stimulate somatostatin release. These results indicate that VIP-stimulation of cyclic AMP formation and VIP-stimulation of somatostatin release are calcium-dependent and that the two phenomena are dissociatable. Cyclic AMP formation is not a necessary condition for VIP-induced somatostatin release. Nucleotide formation may be a sufficient condition for release or, possibly in association with calcium influx, it may be an event unrelated to the release process.     

The postnatal development of norepinephrine-stimulated cyclic AMP accumulation in rat spinal cord

Norepinephrine (NE) stimulated cyclic adenosine 3',5'-monophosphate (cyclic AMP) accumulation in regional spinal cord and cortical tissue slices from postnatal rats demonstrated distinct developmental patterns. NE-concentration-response studies using a 10-min incubation period demonstrated minimal NE-stimulated cyclic AMP accumulation in whole spinal cord at PD 1-5 with maximal sensitivity on PD 12. Thereafter, sensitivity decreased to adult values at PD 30. Sensitivity changes were reflected in alterations in maximal response only since NE EC50s all averaged 10(-6) M. This agrees with no change in calculated Kd for NE with increased Vmax to PD 12 and a reduction thereafter. Studies on regional spinal cord and cerebral cortical cyclic AMP accumulation indicated peak NE sensitivity in cervical and thoracic cord occurred at PD 10, in lumbar cord at PD 15, and in cerebral cortex at PD 20. The fact that inhibition of phosphodiesterase (PPDE) produced the same percentage alteration in peak accumulation in spinal cord slices regardless of postnatal age suggests that PPDE is not the primary determinant of the ontogenic changes. The results indicate that the postnatal development of spinal NE receptors may be reflected in an increase in the responsiveness of the cyclic AMP system to NE.     

Anandamide and WIN 55212-2 inhibit cyclic AMP formation through G-protein-coupled receptors distinct from CB1 cannabinoid receptors in cultured astrocytes

The effects of anandamide and the cannabinoid receptor agonists WIN 55212-2 and CP 55940 on the evoked formation of cyclic AMP were compared in cultured neurons and astrocytes from the cerebral cortex and striatum of mouse embryos. The three compounds inhibited the isoproterenol-induced accumulation of cyclic AMP in neuronal cells, and these responses were blocked by the selective CB1 receptor antagonist SR 141716A. The three agonists were more potent in cortical than striatal neurons. Interestingly, WIN 55212-2, CP 55940 and anandamide also inhibited the isoproterenol-evoked accumulation of cyclic AMP in astrocytes but, in contrast to WIN 55212-2 and CP 55940, anandamide was much more potent in striatal than cortical astrocytes. Inhibition was prevented by pertussis toxin pretreatment, but not blocked by SR 141716A. Therefore, G-protein-coupled receptors, distinct from CB1 receptors, are involved in these astrocytic responses. Moreover, specific binding sites for [3H]-SR 141716A were found in neurons but not astrocytes. Furthermore, using a polyclonal CB1 receptor antibody, staining was observed in striatal and cortical neurons, but not in striatal and cortical astrocytes. Taken together, these results suggest that glial cells possess G-protein-coupled receptors activated by cannabinoids distinct from the neuronal CB1 receptor, and that glial cells responses must be taken into account when assessing central effects of cannabinoids.     

Protein kinase C activators stimulate beta-endorphin secretion from hypothalamic cells.

Relatively little is known about the regulation of secretion of hypothalamic beta-endorphin, the potent opioid that is believed to play a variety of physiological roles in brain. Previous work has shown that arginine vasopressin (AVP), which acts in brain primarily via activation of the phosphoinositol (PI) second messenger system, stimulates secretion of hypothalamic beta-endorphin. To test the hypothesis that activators of protein kinase C (PKC), which is activated following PI hydrolysis, stimulates secretion of beta-endorphins from hypothalamus, we studied the separate effects of stimulators of PKC including phorbol ester 12-myristate-13-acetate (PMA) and 1-oleolyl-2-acetyl glycerol (OAG- a diacyl glycerol analogue) on secretion of immunoreactive (IR-) beta-endorphin (measured by RIA) from dissociated fetal rat hypothalamic cell cultures. We also studied AVP and angiotensin II (Ang II), hypothalamic peptides which activate the PI second messenger pathway, and interactions of PMA and forskolin (FSK), an activator of the cyclic AMP/protein kinase A (PKA) pathway. PMA, OAG, AVP, and Ang II stimulated IR-beta-endorphin secretion. The stimulatory effect of both PMA and FSK on IR-beta-endorphin secretion was greater than that of PMA or FSK alone and was essentially additive.(ABSTRACT TRUNCATED AT 250 WORDS)     

A novel voltage-sensitive Na and Ca channel blocker, NS-7, prevents suppression of cyclic AMP-dependent protein kinase and reduces infarct area in the acute phase of cerebral ischemia in rat

Binding of cyclic AMP to the regulatory subunit of cyclic AMP-dependent protein kinase (PKA) is an essential step in cyclic AMP-mediated intracellular signal transduction. This binding is, however, rapidly inhibited in the acute phase of cerebral ischemia, indicating that the signal transduction via PKA is very vulnerable to ischemia, although this signal pathway is very important for neuronal survival in the brain. Several lines of evidence suggest that the activation of voltage-sensitive Na+ and Ca(2+) channels is an important mediator of acute ischemic brain damage. In the present study, therefore, we examined the effect of a novel Na+ and Ca(2+) channel blocker, NS-7 (4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride), on changes in the binding activity of PKA to cyclic AMP in permanent focal cerebral ischemia, which was induced by occlusion of the middle cerebral artery by the intraluminal suture method for 5 h in the rat. NS-7 (1 mg/kg) or saline was intravenously infused 5 min after occlusion. The binding activity of PKA to cyclic AMP and local cerebral blood flow were assessed by the in vitro [(3)H]cyclic AMP binding and the [(14)C]iodoantipyrine methods, respectively. NS-7 significantly suppressed inhibition of the binding activity of PKA to cyclic AMP in the ischemic regions such as the frontal and parietal cortices and the medial region of the caudate-putamen without affecting cerebral blood flow or arterial blood pressure. Infarct area measured in the brain slices stained with cresyl violet was significantly smaller in animals treated with NS-7 than in those treated with saline. Blockade of voltage-sensitive Na+ and Ca(2+) channels by NS-7 was expected to reduce ischemia-induced depolarization and thus prevent a massive formation of free radicals, which is known to inhibit the binding activity of PKA to cyclic AMP. These data clearly indicate that NS-7 provides very efficient neuroprotection in the acute phase of cerebral ischemia, and sustains the normal function of PKA.     

Role of protein kinase C in glial cell proliferation

Phorbol 12-myristate 13-acetate (PMA) has been shown to stimulate DNA synthesis and cell proliferation in a population of glial cells isolated from newborn rat brain. The non-tumor promoter 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), on the other hand, was without an effect. The cultures treated with PMA displayed an extensive process formation and an increase in cell content. The tumor promoter-induced [3H]thymidine incorporation into acid-precipitable material was completely blocked by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a potent inhibitor of protein kinase C (PKC), thereby suggesting a role for PKC in the control of DNA synthesis in glial cells. Subcellular fractionation and in vitro assay of PKC activity revealed a translocation of the enzyme from cytosol to particulate fraction in PMA-treated cultures.     

Somatostatin pretreatment desensitizes somatostatin receptors linked to adenylate cyclase and facilitates the stimulation of cyclic adenosine 3':5'-monophosphate accumulation in anterior pituitary tumor cells

Somatostatin-14 (SRIF) inhibits both hormone- and forskolin-stimulated cyclic adenosine 3':5'-monophosphate (cyclic AMP) formation in tumor cells of the mouse anterior pituitary (AtT-20/D16-16). However, long-term pretreatment of cells with SRIF modifies the responsiveness of this system in two ways: The response of adenylate cyclase to stimulatory agents is enhanced, whereas the ability of SRIF to inhibit stimulated cyclic AMP formation is reduced. The supersensitive adenylate cyclase response and the SRIF desensitization were dependent on the concentration and duration of SRIF pretreatment. Enhancement of forskolin-stimulated cyclic AMP formation occurred within 4 hr, whereas that of corticotropin-releasing-factor-, (-)-isoproterenol-, and vasoactive intestinal peptide-induced cyclic AMP accumulation required 16 hr of pretreatment. The elevated responses to each of these stimulants were due to increases in their maximal ability to stimulate cyclic AMP formation. Cycloheximide treatment blocked the enhanced cyclic AMP response induced by SRIF pretreatment, suggesting a requirement for protein synthesis. In membrane preparations, SRIF pretreatment facilitated activation of adenylate cyclase by forskolin, sodium fluoride, and guanosine 5'-(beta,tau-imido)-triphosphate without affecting basal activity. These results suggest that desensitization of an inhibitory input to adenylate cyclase is accompanied by a supersensitivity of adenylate cyclase to stimulatory agents through a process requiring protein synthesis.     

PACAP-induced formation of cyclic AMP in the chicken brain: regional variations and the effect of melatonin

We have studied the effects of pituitary adenylate cyclase-activating polypeptide (PACAP27 and PACAP38) on cyclic AMP formation in chick brain, and the action of melatonin upon the PACAP-evoked effects. PACAP stimulated cyclic AMP production in the hypothalamus>cerebral cortex>pineal gland>optic lobes. In the hypothalamus and cerebral cortex, the rank-order of both PACAP forms and VIP in evoking the cyclic AMP response was: PACAP38 approximately PACAP27>VIP, suggesting the presence in the tested tissues of PAC1 receptors. Melatonin suppressed (IC50=19.8 nM) the PACAP27 (0.1 microM)-induced cyclic AMP response in the hypothalamus, but not in the cerebral cortex. Melatonin also suppressed the hypothalamal cyclic AMP synthesis stimulated by forskolin, but not that evoked by histamine or isoprenaline. Our observations show that PACAP is capable of potently stimulating cyclic AMP formation in some regions of the chick brain, and suggest that the hypothalamus may be a site for a functional interaction between PACAP and the pineal hormone melatonin.     

Augmentation of neurotransmitter receptor-stimulated cyclic AMP accumulation in rat brain: differentiation between the effects of baclofen and phorbol esters

The augmentation of isoproterenol or vasoactive intestinal peptide (VIP)-stimulated cyclic AMP accumulation in rat brain slices by the GABAB agonist baclofen was compared to that mediated by tumor-promoting phorbol esters. The protein kinase C inhibitor H7 and desensitization of protein kinase C reduced the cyclic AMP augmenting effect of the phorbol ester, but not baclofen. Incubation of brain slices in the presence of both baclofen and a phorbol ester amplified the cyclic AMP response to isoproterenol or VIP to a greater degree than that found with either baclofen or the phorbol ester alone, with the increased augmentation appearing to be additive. These findings indicate that although stimulation of GABAB receptors or protein kinase C activation by phorbol esters have similar effects on transmitter-stimulated cyclic AMP production in brain, these augmenting actions appear to be independently mediated.     

Wnt genes define distinct boundaries in the developing human brain: implications for human forebrain patterning

Understanding the factors that govern human forebrain regionalization along the dorsal-ventral and left-right (L-R) axes is likely to be relevant to a wide variety of neurodevelopmental and neuropsychiatric conditions. Recent work in lower vertebrates has identified several critical signaling molecules involved in embryonic patterning along these axes. Among these are the Wingless-Int (WNT) proteins, involved in the formation of dorsal central nervous system (CNS) structures, as well as in visceral L-R asymmetry. We examined the expression of WNT2b and WNT7b in the human brain, because these genes have highly distinctive expression patterns in the embryonic mouse forebrain. In the human fetal telencephalon, WNT2b expression appears to define the cortical hem, a dorsal signaling center previously characterized in mouse, which is also confirmed by BMP7 expression. In diencephalon, WNT2b expression is restricted to medial dorsal structures, including the developing pineal gland and habenular nucleus, both implicated in CNS L-R asymmetry in lower organisms. At 5 weeks gestation, WNT7b is expressed in cerebral cortical and diencephalic progenitor cells. As the cortical plate develops, WNT7b expression shifts, demarcating deep layer neurons of the neocortex and the hippocampal formation. Spatial and temporal expression patterns show startling similarity between human and mouse, suggesting that the developmental roles of these WNT genes may be highly conserved, despite the far greater size and complexity of the human forebrain.     

Role of the cAMP-dependent protein kinase and protein kinase C in regulating the morphological differentiation of PC12 cells

The cell line A126-1B2 is a PC12-derived mutant that is resistant to the toxic effects of dibutyryladenosine 3':5'-cyclic monophosphate (dbcAMP) and is deficient in adenosine 3':5'-cyclic monophosphate (cAMP)-dependent protein kinase II (PKAII). This mutant formed neurites in response to nerve growth factor (NGF), but not in response to dbcAMP; and dbcAMP did not increase the rate of NGF-dependent neurite formation. Thus, while PKAII is essential for process formation in response to agents that act through the cAMP-dependent pathway, activation of PKAII is not essential for NGF-dependent neurite formation. Unexpectedly, NGF and phorbol 12-myristate 13-acetate (PMA; 10-1,000 nM) synergistically stimulated the formation of short processes that were apparent within 30 min of NGF addition in 85% of these mutant cells. These processes were similar, but not identical, in appearance to the NGF-dependent neurites that formed only after a period of 24-48 hr. This effect is dependent on the activation of protein kinase C (PKC) because an inactive phorbol ester was without effect. In contrast, there was only a small effect of NGF and/or PMA on process formation in wild type cells within the first few hours. The effect of PMA is not augmented by dbcAMP in the A126-1B2 mutant cells. After several hours, PMA caused a concentration-dependent decrease in cell adhesion; and higher concentrations of PMA resulted in a transient detachment of the cells and a loss of neurites. These experiments suggest a role for PKC in the regulation of process formation.     

Heterochronous maturation of regional brain astroglia: neuronal modulation of striatal glial cells differentiation ex vivo

Subcultured astroglial cells from striatum, cerebral cortex and ventral mesencephalon obtained from primary cultures of fetal (E14, E17 and E21) or postnatal (days 5-6) rats showed different regional, age-dependent morphological response (stellation) to cyclic AMP. While most of the cerebral cortex and ventral mesencephalic astroglial cell population was responsive at all ages tested, striatal cells at E14 and E17 were not. At age E21 striatal astroglia showed a significant shift toward a mature-like type of response to cyclic AMP. Postnatal striatal astroglia responded to cyclic AMP as the cortical and ventral mesencephalic astroglia did, with generalized stellation. Prenatal striatal astroglia was characterized immunocytochemically as A2B5+, fibronectin+, vimentin+, S-100+ and GFAP-. Failure of early prenatal (E14, E17) striatal astroglia to differentiate in response to cyclic AMP, was overcome by previous (5-7 days) co-culture with primary cell dissociates from postnatal-, but not from prenatal donors, from all brain regions tested including a non-target region for striatal cells, such as septum. This effect was duplicated when striatal astroglia was co-cultured with cell populations enriched in neurons through Percoll gradients. Only cell-to-cell contact co-cultures were able to induce a change in the studied response. Dead neuron-enriched populations obtained following various types of physical treatments were also able to change significantly striatal cell response toward cyclic AMP. Enriched astroglial populations from postnatal donors did not change striatal astroglial response toward cyclic AMP, except for ventral mesencephalic astroglia which induced a comparatively reduced but significant increase in striatal cell responsiveness. It is concluded that astroglial maturation and potential for phenotype expression during brain development proceeds with regional heterochrony. Also, that maturation of prenatal striatal astroglia responsiveness toward cyclic AMP is inducible by non-diffusible factors, probably of neuronal origin, expressed in live or dead primary cultures from various, homotopic and heterotopic, postnatal brain regions. It is further suggested that striatal afferents and/or mature local striatal neurons express membrane associated molecules that regulate responsiveness for phenotype expression of striatal glial cells, thus reinforcing the concept of a highly interactive, continuous neuron-glial developmental process that takes place during brain organization.     

A biochemical and morphological study of the altered growth pattern of central catecholamine neurons following 6-hydroxydopamine

The ability of a series of adrenergic agents to displace the binding to brain membranes of [3H]WB 4101, a potent alpha-adrenergic antagonist (WB 4101 = 2-[2-(2,6-dimethoxyphenoxy)ethylaminomethyl]-1,4-benzodioxane hydrochloride), has been compared with the potency of these agents in stimulating or inhibiting the alpha-adrenergic component of cyclic AMP accumulation in rat cerebral cortex slices. [3H]WB 4101 rapidly bound to a high affinity site (KD = 2.7 nM) in membranes from cerebral cortex. Binding came to equilibrium by 2 min at 37 degrees C and was rapidly reversed in the presence of phentolamine. The potencies of adrenergic agents (WB 4101 greater than phentolamine greater than naphazoline) in displacing binding of [3H]WB 4101 were comparable to the potencies of these agents as inhibitors of the alpha-adrenergic component of norepinephrine-stimulated cyclic AMP accumulations. Phenoxybenzamine, clonidine, chlorpromazine and haloperidol were about 10--30 times more potent in inhibiting cyclic AMP accumulation than in displacing [3H]WB 4101 binding. The potency of classical alpha-adrenergic agonists in displacing WB 4101 (epinephrine greater than norepinephrine greater than methoxamine) correlated with the ability of these agonists to increase cyclic AMP levels. Overall a significant correlation (r = 0.87, P less than 0.005) was found between WB 4101 binding and alpha-adrenergically mediated cyclic AMP accumulation in brain. Several ligands bind to specific sites in brain membranes with alpha-adrenergic receptor properties. The identification of these binding sites as receptors depends on a correlation of binding with a known alpha-adrenergic receptor-mediated response in brain. These data demonstrating that WB 4101 correlates with norepinephrine-stimulated cyclic AMP accumulation suggest that WB 4101 may bind to the membrane receptor sites mediating the alpha-adrenergic accumulation of cyclic AMP in rat cerebral cortex.     

Effect of opioid peptides onl-noradrenaline-stimulated cyclic AMP formation in homogenates of rat cerebral cortex and hypothalamus

Morphine and the opioid peptides leucine-enkephalin (leu-enk), methionine-enkephalin (met-enk) and beta-endorphin had no effect on basal cyclic AMP levels in rat cerebral cortex and hypothalamus, but each inhibited noradrenaline (NA)-stimulated cyclic AMP formation in both brain regions. This inhibition was reversed by naloxone. Naloxone did not reverse phentolamine- or propranolol-induced inhibition of NA-stimulated cyclic AMP formation. The increase in cyclic AMP formation induced by NaF or MnCl2 was unaffected by met-enk or morphine. These data suggest that in rat cerebral cortex and hypothalamus opiates bind to opiate receptors and that the opiate-receptor complex interferes with noradrenergic receptor activity.     

Exaggerated cyclic AMP accumulation and glial cell reaction in the cerebellum during Purkinje cell degeneration in pcd mutant mice

The Purkinje cell degeneration mutant (pcd) is characterized by a complete loss of cerebellar Purkinje cells. Norepinephrine causes an accumulation of cyclic AMP in the cerebellum of pcd that is far greater than in normal mice. Experiments were conducted 1) to correlated changes in the cyclic-nucleotide response with a histologic examination of the cerebellum during neuronal loss and 2) to examine the role of cyclic AMP catabolism and adenosine receptor interactions in the phenomenon. The greatest elevation in cyclic AMP occurred between 30 and 128 days of age when a severe astrocytic response was demonstrated throughout the cerebellar cortex. Purkinje cells had degenerated by 45 days of age. Norepinephrine elicited a smaller increase in cyclic AMP from 155-day-old mice than at earlier ages, and the response continued to decrease with age; at 270 days, equal accumulation, and at 365 days. lower accumulation of cyclic AMP was detected in pcd cerebella. During this time, the Purkinje cell debris had been removed, the granule cell layer was depleted of granule cells, and the molecular layer was deprived of a large number of parallel fibers. However, although phagocytosis of neuronal debris was completed, large numbers of astrocytic processes were still seen in the neuropil. Biochemical experiments in vitro established that the exaggerated accumulation of cyclic AMP in the presence of norepinephrine was not due to lower catabolism of cyclic AMP, a synergistic interaction with adenosine, or a result of lower protein in the pcd cerebellum. The correlates of heightened norepinephrine-stimulated accumulation of cyclic AMP with neuronal loss and the glial cell reaction might indicate that cyclic nucleotides play a role in controlling some glial cell functions, ie, proliferation, migration, and phagocytosis.     

Cyclic AMP-generating systems: regional differences in activation by adrenergic receptors in rat brain

Catecholamine, histamine, and adenosine-mediated accumulations of radioactive cyclic AMP were assessed in adenine-labeled slices from eight rat brain regions. 2-Fluoronorepinephrine, a selective beta-adrenergic agonist, elicited an an accumulation of cyclic AMP in cerebral cortex, cerebellum, hippocampus, striatum, superior colliculi, thalamus, hypothalamus, and medulla-pons. In cerebral cortex and most other brain regions, the beta-adrenergic-mediated response appeared to involve primarily beta 1-adrenergic receptors, while in cerebellum, there was a significant involvement of beta 2-adrenergic receptors. 6-Fluoronorepinephrine, a selective alpha-adrenergic agonist, elicited accumulations of cyclic AMP in all regions except cerebellum. Combinations of the two fluoro derivatives afforded in all brain regions an accumulation of cyclic AMP identical with that elicited by norepinephrine. In hypothalamus, the alpha- and beta-adrenergic responses were significantly greater than additive. In cerebral cortex, the alpha-adrenergic receptor-mediated response appeared to involve alpha 1-adrenergic receptors and to be nearly completely dependent on adenosine, while in other brain regions, the dependence of the alpha-adrenergic response on adenosine was less or absent. Combinations of 6-fluoronorepinephrine and histamine had greater than additive effects in cortex and hippocampus. The results indicate that the interactive control of cyclic AMP-generating systems by alpha-adrenergic, beta-adrenergic, adenosine, and histamine receptors differs significantly among rat brain regions.     

Vasoactive intestinal peptide stimulates cyclic AMP metabolism in choroid plexus epithelial cells

Some peptides of the glucagon-secretin family were found to stimulate intracellular cyclic AMP accumulation in cultured bovine choroid plexus epithelial cells. Vasointestinal peptide and porcine intestinal peptide at concentrations of 30 and 300 nM, respectively, evoked 50-fold elevations of cyclic AMP; half-maximal responses were obtained with concentrations of 15 and 102 nM for the two peptides, respectively. Secretin and glucagon each produced 25- to 50-fold elevations of cyclic AMP at 330 microM, but showed no effect below 3 microM. Gastric inhibitory peptide and prealbumin had little or no response at any concentration tested. Experiments measuring the cellular cyclic AMP accumulation in response to pairs of peptides suggested that vasointestinal peptide, porcine intestinal peptide and secretin act through a common receptor. Studies with antagonists to isoproterenol and histamine indicated that this receptor is distinct from the beta-adrenergic and H2-histamine receptors known to exist on choroidal cells.     

Evidence for disordered cyclic amp metabolism in patients with cerebral infarction.

Systemic blood cyclic AMP levels were elevated but urinary excretion was unaltered in patients with recent cerebral infarction. Cerebral venous levels for cyclic AMP were significantly higher than arterial levels. CSF cyclic AMP levels were also elevated. After intravenous 10% glycerol, CSF cyclic AMP levels decreased and cerebral A-V differences were reduced. Elevation of cyclic AMP levels in plasma may be due to alteration of neuroendocrinal function after cerebral infraction and contributed to in part by release from infarcted brain. Cyclic AMP release into cerebral venous blood and CSF suggests (1) blood brain barrier damage and (2) extracellular cyclic AMP accumulation in infarcted brain secondary to abnormal neurotransmitter release and/or impaired cellular function which appears to be partially reversed by glycerol.