cyclic-gmp and Ischemic-Attack--Transient

Post-stroke depression (PSD) is one of the psychiatric complications after stroke. Present study was conducted to elucidate the protective effect of sertraline and possible involvement of nitric oxide mechanism against transient global ischemia induced behavioral despair. Bilateral common carotid artery occlusion was given twice for 5 min at 10 min interval followed by 96 h reperfusion. Ischemia reperfusion significantly increased immobility period and decreased resistance to lateral push as compared to sham-operated group. Ischemia reperfusion caused significant oxidative damage and mitochondrial enzyme complex (I-III) dysfunction as compared to sham group. Sertraline (5 and 10mg/kg) treatment significantly reduced immobility period, increased resistance to lateral push, attenuated oxidative damage and restored mitochondrial enzyme complex activities as compared to ischemia group. L-Arginine (100mg/kg) or sildenafil (5mg/kg) pretreatment with sertraline (5mg/kg) significantly reversed the protective effect of sertraline. However, L-NAME (10mg/kg) or 7NI (10mg/kg) pretreatment with sertraline (5mg/kg) significantly potentiated their protective effect which were significant as compared to their effect alone. The present study shows that nitric oxide modulation is involved in the protective effect of sertraline.

Topics: Adult; Animals; Antidepressive Agents; Behavior, Animal; Cell Respiration; Cyclic GMP; Depression; Disease Models, Animal; Enzyme Inhibitors; Humans; Ischemic Attack, Transient; Mice; Motor Activity; Neuroprotective Agents; Neuropsychological Tests; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Oxidative Stress; Random Allocation; Reperfusion Injury; Sertraline

The present study has been designed to explore the nitric oxide mechanism in the protective effect of desipramine, venlafaxine and trazodone against I/R induced oxidative stress and mitochondrial dysfunction in mice. Vitamin E was taken as standard antioxidant. Laca mice (25-30 g) were subjected to twice BCCAO occlusion (5 min) at the interval of 10 min, followed by 96 h reperfusion. The drug treatments were started from the day of surgery and continued for the next four days. After 96 h the animals were sacrificed for biochemical (malondialdehyde, nitrite concentration, superoxidedismutase, catalase, redox ratio and GST) and mitochondrial enzyme complex (NADH dehydrogenase, succinate dehydrogenase, MTT assay and cytochrome c oxidase) estimations. Ischemia caused significant oxidative damage and mitochondrial enzyme dysfunction after 96 h of reperfusion as compared to sham operated animals. Antidepressant (desipramine, venlafaxine and trazodone) treatment significantly attenuated oxidative damage and restored mitochondrial enzyme complex activities as compared to control (I/R) group. Further, protective effects of desipramine (15 mg/kg) and/or venlafaxine (5 mg/kg) were attenuated by l-arginine (100 mg/kg) or sildenafil (5 mg/kg) pretreatment. Further, L-NAME (10 mg/kg) or 7-NI (10 mg/kg) pretreatment with desipramine (15 mg/kg) and/or venlafaxine (5 mg/kg) significantly potentiated their protective effect which was significant as compared to their effect alone. The present study highlights the involvement of nitric oxide mechanism in the protective effects of desipramine and venlafaxine against I/R induced oxidative stress and mitochondrial dysfunction in mice.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Arginine; Brain; Catalase; Cyclic GMP; Cyclohexanols; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Electron Transport Chain Complex Proteins; Enzyme Inhibitors; Glutathione; Ischemic Attack, Transient; Lipid Peroxidation; Mice; Models, Biological; Nitric Oxide; Signal Transduction; Trazodone; Venlafaxine Hydrochloride

The regional distribution of cyclic 3',5'-guanosine monophosphate was studied in the lumbosacral segments of the spinal cord of the rabbit under physiological conditions and following brief repeated sublethal ischemic insults. While the basal cGMP level in the gray matter was about 0.120 nmol cGMP/mg wet. wt., the level of cGMP in non-compartmentalized white matter was about half of this value. The highest level of cGMP in the compartmentalized gray matter was found in the dorsal horns, about 0.180 nmol cGMP/mg wet. wt., whereas the level of cGMP was greatly reduced in the ventral horns, reaching one half of the previous value. Multiple sublethal ischemic insults, repeated at 1-h intervals, caused a statistically significant decrease of cGMP in all gray matter regions. While the post-ischemic and post-reperfusion level of cGMP in the dorsal horns remained relatively high in comparison with the intermediate zone and ventral horns, the changes of cGMP level detected in the white matter columns differed considerably and resulted in a statistically significant cGMP increase in the dorsal and ventral columns and, vice versa, a statistically significant decrease of cGMP was found in the lateral columns.

Topics: Animals; Anterior Horn Cells; Cyclic GMP; Ischemic Attack, Transient; Male; Posterior Horn Cells; Rabbits; Recurrence; Reperfusion; Spinal Cord; Time Factors

The authors investigated the changes and the potential of cyclic nucleotide-dependent signal transduction, which induces smooth muscle relaxation, in the basilar artery with severe vasospasm in dogs with double experimental subarachnoid hemorrhage (SAH) to explore at which biochemical level the arterial dilative capability was impaired. The amount of cyclic adenosine and guanosine monophosphates (cAMP and cGMP) decreased significantly in the basilar artery after SAH. The activities of adenylate and guanylate cyclases also were decreased significantly in the smooth muscle cells of the basilar artery 4 days after SAH. In addition to the failure of the pathways to produce cyclic nucleotides, the activities of cAMP- and cGMP-dependent protein kinases, which are representative actual enzymes that amplify the signal for vascular dilation, also significantly decreased together with the almost total loss of activation by cyclic nucleotides in the same basilar artery after SAH. It was revealed that the system for smooth muscle relaxation was impaired severely in the cerebral arteries with severe vasospasm after SAH, on the biochemical basis of significantly less vasodilative capability and in several of the steps to produce the cyclic nucleotides of intracellular signal transduction.

Topics: Adenylyl Cyclases; Animals; Basilar Artery; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Dogs; Female; Guanylate Cyclase; Ischemic Attack, Transient; Kinetics; Male; Muscle, Smooth, Vascular; Signal Transduction; Subarachnoid Hemorrhage; Vasodilation

We hypothesize that the interaction between protein kinase C (PKC) and nitric oxide (NO) plays a role in the modulation of cerebral vascular tone, and the disturbance of this interaction following subarachnoid hemorrhage (SAH) results in vasospasm. To prove this hypothesis with direct evidence, PKC activities of smooth muscle cells of canine basilar arteries in the control and in the SAH groups were measured by an enzyme immunoassay method. N omega-nitro-L arginine (L-NA), an inhibitor of NO production, enhanced PKC activity. This enhancement was inhibited neither by 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) nor SIN-1, a NO releasing agent. PKC activity in the SAH was significantly higher than in the control; however, no further enhancement was produced with L-NA. In the SAH, PKC activity was not inhibited either by 8-bromo-cGMP or SIN-1. We conclude that NO maintains an appropriate vascular tone through inactivation of PKC, and that this effect is disturbed following SAH, resulting in PKC-dependent vascular contraction, such as vasospasm. On the other hand, once PKC has been activated, NO precursors do not inhibit PKC. These facts indicate NO inactivates PKC through the inhibition of phosphatidylinositol breakdown.

Topics: Animals; Basilar Artery; Cyclic GMP; Dogs; Enzyme Activation; Enzyme Inhibitors; Female; Immunoenzyme Techniques; Ischemic Attack, Transient; Male; Molsidomine; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Protein Kinase C; Reference Values; Subarachnoid Hemorrhage

While nitric oxide (NO) has been implicated as a mediator of glutamate excitotoxicity after cerebral ischemia/reperfusion, melatonin has been reported to inhibit brain NO production by suppressing nitric oxide synthase. The purpose of the present studies was to determine the effect of exogenous melatonin administration on NO-induced changes during brain ischemia/reperfusion. Indicators of cerebral cortical and cerebellar NO production [nitrite/nitrate levels and cyclic guanosine monophosphate (cGMP)] were used to estimate neural changes after transient bilateral carotid artery ligation followed by reperfusion in adult Mongolian gerbils (Meriones unguiculatus). Results show for the first time that melatonin prevents the increases in NO and cGMP production after transient ischemia/reperfusion in frontal cerebral cortex and cerebellum of Mongolian gerbils. The inhibitory effect of melatonin on NO production and its ability to scavenge free radicals and the peroxynitrite anion may be responsible for the protective effect of melatonin on neuronal structures during transient ischemia followed by reperfusion.

Topics: Animals; Brain; Carotid Arteries; Cerebellum; Cerebral Cortex; Constriction; Cyclic GMP; Frontal Lobe; Gerbillinae; Ischemic Attack, Transient; Male; Melatonin; Nitric Oxide

This study was undertaken to investigate how protein kinase C (PKC) and nitric oxide (NO) interact to regulate the vascular tone, and how their interaction contributes to the development of vasospasm after subarachnoid hemorrhage (SAH). For these purposes, vasospasm was conducted with a canine model. We investigated the following subjects with arteries from intact animals and those from the SAH model, and compared the results between the two; tension at rest of isometric tension study, the effect of PKC inhibitors and of an inhibitor of NO synthesis on the tension at rest, and levels of guanosine 3',5'-cyclic monophosphate (cGMP) as an indicator of NO production. The tension at rest was enhanced in the artery from the SAH model compared to that from intact animals, and it was PKC-dependent. Arteries from intact animals but not those from the SAH model developed tonic tensions by NO inhibitors, and these tonic tensions were suppressed by PKC inhibitors, and also by cGMP. An enzyme immunoassay revealed a decreased cGMP level in the SAH model. The evidence indicates that NO exerts a negative feedback control on PKC activation. Subarachnoid hemorrhage interferes with this feedback control, resulting in PKC-dependent enhanced vascular tone and vasospasm.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Alkaloids; Animals; Basilar Artery; Cyclic GMP; Dogs; Enzyme Inhibitors; Female; In Vitro Techniques; Ischemic Attack, Transient; Isometric Contraction; Isoquinolines; Male; Models, Cardiovascular; Muscle Tonus; Muscle, Smooth, Vascular; Nitric Oxide; Piperazines; Protein Kinase C; Staurosporine; Subarachnoid Hemorrhage

Nitroglycerin, as well as nitric oxide, causes hyperpolarization and cGMP elevation in vascular smooth muscle cells. It is unknown whether nitroglycerin ameliorates vasospasm by an increase in cGMP levels after subarachnoid hemorrhage (SAH). The purpose of the present study was to measure the levels of both cGMP and cAMP in the cerebral arteries and parietal cerebral cortices in a primate model and to determine the effect of nitroglycerin on vasospasm after SAH.. Chronic vasospasm was induced by clot placement around the right middle cerebral artery (MCA). Seven days after the surgery, angiography was repeated and either nitroglycerin (3 micrograms/kg per hour) or saline was administered intravenously. Angiography and regional cerebral blood flow (rCBF) measurements in the bilateral parietal cortices were performed before and after each treatment. Both cGMP and cAMP levels were measured in the cerebral arteries and bilateral parietal cortices.. A significant vasospasm occurred in the cerebral arteries on both sides, more prominently on the right side. Concomitantly, rCBF on the right side was significantly decreased (P < .05). In the right MCA, cGMP levels were significantly lower than in the normal MCA (P < .05). After the administration of nitroglycerin for 3 hours, the cerebral vessels were significantly dilated on both sides (P < .05), and rCBF was significantly increased on the right side (P < .05) but not on the left side. Although depressed cGMP levels in the right MCA were not recovered by nitroglycerin, a significant increase in cGMP levels was observed in the basilar artery (P < .05). In both parietal cortices, cGMP levels were significantly decreased after SAH (P < .05) and unchanged after nitroglycerin treatment. There were no significant changes in cAMP levels in SAH and after nitroglycerin treatment.. The vasodilator effect of nitroglycerin in spastic MCA may not be mediated by an increase in cGMP levels, suggesting an involvement of hyperpolarization of the smooth muscle cells. Given the increase in rCBF, nitroglycerin may be therapeutic for the treatment of vasospasm.

Topics: Animals; Blood Pressure; Cerebral Angiography; Cerebral Arteries; Cerebral Cortex; Cerebrovascular Circulation; Cyclic GMP; Heart Rate; Ischemic Attack, Transient; Macaca; Macaca fascicularis; Nervous System; Nitroglycerin; Nucleotides, Cyclic; Regional Blood Flow; Subarachnoid Hemorrhage; Vasodilator Agents

Topics: Animals; Biological Assay; Carotid Stenosis; Cell Line; Cerebral Infarction; Cyclic GMP; Female; Fibroblasts; Humans; Ischemic Attack, Transient; Male; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Nitric Oxide; Rats

The present study was undertaken to determine whether oxyhemoglobin (OxyHb) is responsible for the functional alterations in the cerebral arteries observed during chronic vasospasm after subarachnoid hemorrhage. Vascular strips of canine basilar arteries were kept in organ culture for 3 days with or without repetitive exposure to OxyHb (OxyHb-treated and control strips). Contractions elicited by high levels of potassium (80 mM) and uridine 5'-triphosphate (3 x 10(-4) M) were reduced in the OxyHb-treated group in a concentration-dependent manner. The relaxations evoked by nitric oxide and 8-bromo-cyclic guanosine monophosphate (8-bromo-cGMP) were not affected. Relaxations elicited by the calcium channel blocker, diltiazem, were attenuated in the OxyHb-treated rings. When the extracellular calcium concentration ([Ca2+]e) was changed from a concentration in the external solution of 10(-8) M to 10(-3) M, myogenic tension developed. Myogenic tension, expressed as a percentage of the maximum contraction in each segment, was augmented in the OxyHb-treated group at [Ca2+]e of 10(-5) M and 10(-4) M. There were no significant differences in passive compliance of the arterial wall between the two groups. These results demonstrated that prolonged exposure to OxyHb in vitro results in a decrease in contractile capacity and an increase in sensitivity to [Ca2+]e, in agreement with previous findings in spastic arteries. By contrast, impairment of the 8-bromo-cGMP-mediated relaxation pathway and increased stiffness of the arterial wall, which have been reported to occur in spastic arteries, were not induced by prolonged exposure to OxyHb in vitro.

Topics: Analysis of Variance; Animals; Basilar Artery; Calcium; Calcium Channel Blockers; Compliance; Cyclic GMP; Diltiazem; Dogs; Female; Ischemic Attack, Transient; Male; Muscle Contraction; Nitric Oxide; Organ Culture Techniques; Oxyhemoglobins; Potassium; Subarachnoid Hemorrhage; Uridine Triphosphate; Vasoconstriction; Vasodilation

We hypothesized that nitric oxide exerts a negative feedback control on protein kinase C (PKC) activation, and the disturbance of the feedback control after subarachnoid hemorrhage results in vasospasm due to PKC activation. This study was undertaken to verify this hypothesis.. Different dogs were prepared for three separate experiments: measurement of the angiographic diameter of the basilar artery and determination of cGMP and PKC activity in vascular smooth muscle cells. In each experiment, two models were used: the single-hemorrhage model for mild vasospasm and the two-hemorrhage model for severe vasospasm. In both models, chronological changes of these three parameters were examined from day 1 until day 7.. In the single-hemorrhage model, mild vasospasm and a slight decrease of the cGMP level were noted on day 4, then both returned to the baseline levels on day 7. PKC activity was slightly enhanced throughout the study period. In the two-hemorrhage model, severe vasospasm and a significant decrease of the cGMP level were observed on day 5 and persisted until day 7. PKC activity was remarkably enhanced from day 5 until day 7. The differences between the two models with regard to the three parameters were statistically significant.. The decrease of cGMP level and the enhancement of PKC activity were obviously associated with the development of severe vasospasm. We conclude that subarachnoid hemorrhage disturbed the feedback control exerted by nitric oxide on PKC activation, leading to PKC-dependent vasospasm.

Topics: Animals; Basilar Artery; Cerebellum; Cerebral Angiography; Cyclic GMP; Disease Models, Animal; Dogs; Enzyme Activation; Feedback; Female; Ischemic Attack, Transient; Male; Muscle, Smooth, Vascular; Nitric Oxide; Protein Kinase C; Subarachnoid Hemorrhage; Time Factors

Calcitonin gene-related peptide (CGRP) is a potent vasodilator and a primary signaling molecule in neurovascular communication. In the present study, the authors examined cerebrovascular responses to CGRP and its related second messenger systems during cerebral vasospasm induced by subarachnoid hemorrhage (SAH). Tension measurements were performed in vitro on ring strips of basilar arteries obtained from rabbits subjected to artificial SAH and from control (non-SAH) animals. In vessels from SAH animals, which were preconstricted with serotonin, the vasorelaxant response to CGRP was attenuated. Because it has been suggested that vasodilation elicited by CGRP is mediated by cyclic 3',5'-adenosine monophosphate (cAMP) and/or cyclic 3',5'-guanosine monophosphate (cGMP), the vascular effects of directly activating these second messenger systems were also examined. The relaxant effect of forskolin, which activates adenylate cyclase directly, was slightly enhanced after SAH. In contrast, the relaxant effect of nitroglycerin (GTN), which activates soluble guanylate cyclase directly, was unchanged after SAH. The attenuation of CGRP-induced vasorelaxation could be the result of a modification in its ability to stimulate the production of second messengers. Experiments testing the capacity of CGRP to elevate cAMP levels showed no significant differences between vessels from non-SAH and SAH animals. Similarly, the resting levels of cAMP and the forskolin-induced elevations of cAMP did not differ between non-SAH and SAH animals. In contrast, cGMP levels were lower in resting and CGRP-treated vessels from SAH animals than in those from non-SAH animals. No significant differences in the levels of cGMP were observed between non-SAH and SAH vessels treated with GTN. This study indicates that CGRP-induced vasodilation is attenuated during vasospasm in a rabbit model of SAH. The findings also demonstrate that vasodilatory responses mediated by cAMP and cGMP are intact, although the levels of cGMP in SAH vessels are reduced. Together, these observations suggest that an attenuation in the capacity of vessels to dilate in response to CGRP occurs during cerebral vasospasm, and this change in CGRP vasoactivity is a result of modifications prior to, or independent of, the elevation of cyclic nucleotide second messengers.

Topics: Analysis of Variance; Animals; Basilar Artery; Calcitonin Gene-Related Peptide; Colforsin; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; In Vitro Techniques; Ischemic Attack, Transient; Isometric Contraction; Male; Nitroglycerin; Potassium; Rabbits; Serotonin; Subarachnoid Hemorrhage; Vasodilation

Using microdialysis, we evaluated temporal changes in striatal extracellular cGMP level following ischemia and its relationship to nitric oxide (NO) production. In untreated animals, significant elevation of cGMP was observed during ischemia and during 4 h of recirculation. In animals treated with L-NAME ischemia induced a modest increase in the cGMP level, but this level was significantly lower than that observed in the untreated animals. These results demonstrate first, that the microdialysis technique can be used to detect changes in extracellular cGMP levels during ischemia and second, that ischemia and recirculation induce a rise in cGMP which is diminished by nitric oxide synthase inhibition, suggesting a linkage to NO production.

Topics: Analysis of Variance; Animals; Corpus Striatum; Cyclic GMP; Ischemic Attack, Transient; Male; Microdialysis; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar

We hypothesized that a decrease in cyclic GMP, a second messenger in the glutamate-nitric oxide pathway, would reduce oxygen consumption and improve O2 balance in the ischaemic cerebral cortex. To test this hypothesis, a study was performed in unilateral middle cerebral artery occluded rats which were assigned to either a control or methylene blue (10(-3) M) group. Regional cerebral blood flow was determined using 14C-iodoantipyrine and regional arterial and venous O2 saturations were determined by microspectrophotometry (n = 6). Cyclic GMP level was measured by radioimmunoassay (n = 8). Guanylate cyclase and cyclic GMP-phosphodiesterase activities were determined in an additional set of control rats (n = 10). The cyclic GMP levels were not different between the ischaemic and contralateral areas in the control group. Compared to the cyclic GMP in the control ischaemic cortex, topical methylene blue significantly decreased the cyclic GMP level by 56% in the ischaemic cortex of the methylene blue group. Ischaemia did not alter the activities of guanylate cyclase but mildly decreased cyclic GMP-phosphodiesterase. The regional cerebral blood flow and O2 consumption in the control group were 50% and 32% lower than those in corresponding contralateral cortex. Topical methylene blue did not alter regional cerebral blood flow and O2 consumption in the ischaemic cortex. Our data showed that cyclic GMP is not a major controller on O2 supply or O2 consumption in the ischaemic brain.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Topical; Analysis of Variance; Animals; Blood Pressure; Brain; Carbon Dioxide; Cerebral Cortex; Cerebrovascular Circulation; Cyclic GMP; Guanylate Cyclase; Heart Rate; Hemodynamics; Hemoglobins; Ischemic Attack, Transient; Male; Methylene Blue; Oxygen Consumption; Partial Pressure; Pons; Rats; Regional Blood Flow

In the canine basilar artery during chronic vasospasm following subarachnoid hemorrhage, endothelium-dependent relaxations were diminished. Release of endothelium-derived relaxing factor (EDRF), as measured by a bioassay method, was unchanged. Relaxation to nitric oxide (NO) in preparations without endothelium was smaller in the spastic arteries. Production of cyclic GMP, measured by radioimmunoassay, was reduced in the spastic arteries; the impaired production was accompanied by decrease in GTP, the substrate for the production of cyclic nucleotide. The contents of other high-energy phosphates, such as creatine phosphate and ATP were also markedly reduced. Close temporal correlation between the metabolic failure and development of vasospasm was observed. Sarcolemmal regulation of intracellular calcium concentration was impaired in the pathological condition, suggesting a link between the metabolic failure and the pathological protracted contractions. Metabolic changes, and resultant affected viability of smooth muscle cells are likely to be an important factor in the pathogenesis of chronic vasospasm.

Topics: Adenosine Triphosphate; Animals; Basilar Artery; Calcium Channels; Cell Membrane Permeability; Chronic Disease; Cyclic GMP; Dogs; Guanosine Triphosphate; Ischemic Attack, Transient; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide

Nitric oxide has been implicated as a mediator of glutamate excitotoxicity in primary neuronal cultures.. A number of indicators of brain nitric oxide production (nitric and cyclic guanosine monophosphate [cGMP] concentrations and nitric oxide synthase activity) were examined after bilateral carotid ligation and right middle cerebral artery occlusion in adult rats.. Brain nitrite was significantly increased in the right versus left cortex 5, 10, and 20 minutes after middle cerebral artery occlusion (P < .05), with a return to baseline at 60 minutes. There were no significant changes in cerebellar concentrations. Cortical levels of cGMP were increased at 10, 20, and 60 minutes after occlusion, with significant right-to-left differences (P < .05). Cerebellar concentrations of cGMP were also increased but without significant side-to-side differences. Nitric oxide synthase activity increased approximately 10-fold from baseline 10 minutes after occlusion in the right cortex but decreased markedly by 60 minutes from its peak at 10 minutes. The right-to-left difference in nitric oxide synthase activity was significant at 20 minutes (P < .05). Pretreatment of rats with NG-nitro-L-arginine, a nitric oxide synthase inhibitor, abolished the rise in nitrite and cGMP.. These results suggest that a sharp transient increase in the activity of nitric oxide synthase occurs during the first hour of cerebral ischemia, which leads to a burst in nitric oxide production and activation of guanylate cyclase.

Topics: Amino Acid Oxidoreductases; Analysis of Variance; Animals; Arginine; Arterial Occlusive Diseases; Brain; Cerebellum; Cerebral Arterial Diseases; Cerebral Cortex; Cyclic GMP; Functional Laterality; Ischemic Attack, Transient; Male; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Nitroarginine; Rats; Rats, Wistar

The vasoactive effects of substance P (SP), as well as the content of cyclic guanine monophosphate (cGMP), were determined in the rabbit basilar artery after subarachnoid haemorrhage (SAH). Out of 47 rabbits, 24 were subjected to a SAH, induced by injecting 5 ml of autologous arterial blood into the cisterna magna; 23 were used as controls. In 20 animals (10 SAH and 10 controls), isometric tension recording of isolated rings of the basilar artery--dissected 2 days after SAH--was employed to assess the dose-dependent vasodilatation to SP (10(-10) to 10(-6) M) after precontraction with serotonin (10(-8) to 10(-5) M). In 15 animals (8 SAH and 7 controls), the basal cGMP content was measured in the basilar artery 2 days after SAH. In the other 12 animals (6 SAH and 6 controls), the increase in cGMP content was measured in the basilar artery after a 10-minute incubation with SP (10(-6) M). SP caused significantly less dilatation in animals subjected to SAH than in controls, especially for concentrations between 10(-9) and 10(-6) M (p < 0.001). The cGMP content in the arteries 2 days after SAH was significantly lower than in control arteries (31.5 +/- 7.3 against 57.3 +/- 4.3 pmoles/g tissue). In the preparations incubated with SP, the increase of cGMP was 440 +/- 115% in the control arteries, and only 97 +/- 30% in the arteries after SAH. It is concluded that the vasodilator activity of SP is significantly impaired after SAH.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Basilar Artery; Cyclic GMP; Dose-Response Relationship, Drug; Ischemic Attack, Transient; Male; Nitric Oxide; Rabbits; Subarachnoid Hemorrhage; Substance P; Vasoconstriction; Vasodilation

The authors have investigated the hypothesis that loss of endothelium-derived relaxing factor (EDRF) activity contributes to cerebral vasospasm after subarachnoid hemorrhage. Adventitial exposure to hemoglobin was studied angiographically by injecting purified hemoglobin solution or autologous whole blood into the cisterna magna of anesthetized pigs. Both interventions induced intra- but not extracerebral vasoconstriction, which persisted for 2 and 7 days, respectively. Cyclic guanosine monophosphate (cGMP) levels were measured in isolated buffer-perfused pig intrathecal arteries to quantify inhibition of basal EDRF activity by hemoglobin. Adventitial exposure was less effective than intimal exposure, 10 microM hemoglobin applied adventitially for 30 minutes having an effect equivalent to that of 1 microM applied intraluminally for 5 minutes. The depression of cGMP levels by hemoglobin was reversible and equivalent to the effect of endothelial denudation or incubation with NG-nitro-L-arginine methyl ester, so that the effects of hemoglobin can be attributed to a specific action on EDRF rather than interaction with a nitric oxide-like substance produced by vascular smooth muscle or adventitial nerves. Cyclic GMP levels in isolated arteries were unchanged after in vivo exposure to hemoglobin for either 2 or 7 days or to whole blood for 2 days, and were reduced by intraluminal perfusion with 1 microM hemoglobin. In contrast, after 7 days of in vivo exposure to whole blood, cGMP levels were already depressed, and not further reduced by intraluminal perfusion with 1 microM hemoglobin. The findings support the view that adventitially applied hemoglobin can inhibit basal EDRF activity and that in vivo adventitial exposure to whole blood leads to a reduction in basal cGMP levels in association with vasoconstriction of intrathecal arteries. Both mechanisms could contribute to the clinical syndrome of cerebral vasospasm after subarachnoid hemorrhage.

Topics: Animals; Cerebral Arteries; Chronic Disease; Cyclic GMP; Hemoglobins; Ischemic Attack, Transient; Nitric Oxide; Subarachnoid Hemorrhage; Subarachnoid Space; Swine; Time Factors; Vasoconstriction

Topics: Acetylcholine; Animals; Calcium; Cerebral Arteries; Coronary Vasospasm; Coronary Vessels; Cyclic GMP; Humans; Ischemic Attack, Transient; Nitric Oxide; Oxyhemoglobins

Opipramol, a potent sigma ligand and a tricyclic antidepressant compound, provided significant neuronal protection (P less than 0.0001) against ischemia-induced neuronal cell loss in the hippocampus in Mongolian gerbils, at a dose of 50 mg/kg (30 min pretreatment). However, opipramol did not offer protection when given 60 min after the ischemic insult. Opipramol decreased basal levels of cGMP in the cerebellum of the mouse and harmaline-induced increases in levels of cGMP, with approximate ED50 values of 4 and 27 mg/kg. Opipramol antagonized methamphetamine- and pentylenetetrazol-induced increases in levels of cGMP. Parenteral administration of opipramol also antagonized the increases in levels of cGMP in the cerebellum of the mouse after the local administration of D-serine, an agonist at the N-methyl-D-aspartate (NMDA)-associated, strychnine-insensitive glycine receptor. These results indicate that opipramol attenuates responses mediated through the NMDA receptor complex. These results further support the functional modulation of the NMDA receptor complex by sigma ligands and provide a neurochemical correlate for the observed anti-ischemic properties of opipramol.

Topics: Animals; Cerebellum; Cyclic GMP; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Ligands; Male; Methamphetamine; Mice; Neurons; Opipramol; Pentylenetetrazole; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, sigma

The present study was an extension of earlier work regarding the role of cyclic nucleotides and related enzymes during cerebral ischemia in the gerbil. Following unilateral carotid occlusion, levels of cyclic AMP and cyclic GMP were measured in four rapidly inactivated brain regions at 3, 6, and 24 hr after permanent occlusion and at 2 hr of occlusion plus 1 hr of reflow. An analysis of variance indicated significant minor fluctuations in the steady-state levels of the two cyclic nucleotides within the frontal cortex, the hippocampus, the striatum, and especially the olfactory tubercle with respect to occlusion time (3 and 24 hr) but not when comparing control vs ischemic hemispheres (except at 3 hr). Changes occurred only in animals developing neurological symptoms of ischemia. At 24 hr postocclusion the specific activity of the low-Km form of cyclic AMP phosphodiesterase was elevated especially on the ischemic side when determined in homogenates of the four brain regions. Alternatively, the high-Km form of the enzyme in the presence or absence of Ca2+-calmodulin was unchanged. Guanylate cyclase activity in tissue homogenates was not influenced by the conditions of ischemia until 24 hr had elapsed, an event likewise unique to symptomatic gerbils. The sensitivity of the enzyme to hematin-catalase was decreased in the ischemic hemispheres of the hippocampus, striatum, and olfactory tubercle. In addition, further activation of the hematin-catalase response by NaN3 was depressed in the ischemic side of the hippocampus and striatum. Taken together these and previous studies indicate that fluctuations in the steady-state levels of cyclic nucleotides that occur rather prominently during acute and to a lesser degree during prolonged ischemia are not correlated with associated changes in enzymes responsible for their synthesis and/or degradation.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Brain; Cyclic AMP; Cyclic GMP; Female; Gerbillinae; Guanylate Cyclase; Ischemic Attack, Transient; Kinetics; Organ Specificity

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged

Ischemia of the rat brain was induced for 15 min, 2 and 4 hrs, 1 and 3 days. The studies were performed during the ischemia as well as within 15 min and 2 hrs after cerebral blood flow restoration. The same experiments were carried out in animals with removed upper cervical sympathetic ganglia. During ischemia phasic changes of the energy metabolism were revealed (dissociation of oxydation and phosphorylation) as well as of activity of cerebral enzymes and water content in the brain tissue (ischemic and postischemic oedema). Changes of cAMP and cGMP contents corresponded to the above changes which reflected the adren- and cholinergic phases of adaptation. Sympathectomy led to similar though less obvious changes of the metabolism. The ischemia in desympathized animals led to greater changes of metabolism spreading beyond the adaptive shifts to an overtension of adrenergic compensatory mechanisms, increasing the mortality rate from 45 to 70%. The adaptive-trophic effect of the sympathetic innervation seems to tell on the optimal relations between adren- and cholinergic phases of compensation in the brain ischemia. Desympathization makes the effects of brain ischemia more grave.

Topics: Adaptation, Physiological; Animals; Body Water; Brain; Cyclic AMP; Cyclic GMP; Energy Metabolism; Female; Ischemic Attack, Transient; Male; Rats; Sodium-Potassium-Exchanging ATPase; Sympathectomy; Sympathetic Nervous System; Time Factors

The effects of global cerebral ischemia on neurochemical parameters in the brain were examined in rats. Global cerebral ischemia was produced by temporary occlusion of the bilateral common carotid arteries 24 hr after the permanent electrocauterization of the bilateral vertebral arteries. In 10-min cerebral ischemic rats, the brain levels of monoamine were unaltered. The brain levels of gamma-aminobutyric acid (GABA), which increased about 1.5-fold just before recirculation, almost recovered to the levels of the sham operated group (sham ope. levels) within 5 min after recirculation. The brain levels of cyclic AMP (cAMP), although they altered a little just before recirculation, increased about 6-fold 1 min after recirculation, and they recovered to the sham ope. levels 3-5 min later. In 30-min cerebral ischemic rats, the brain levels of monoamine decreased to about 40% of the sham ope. levels just before recirculation, and norepinephrine (NE) and 5-hydroxytryptamine (5-HT) levels did not recover within 30 min after recirculation in the telencephalon. The brain GABA levels which increased about 2-fold just before recirculation, recovered to the sham ope. levels in all brain regions by 30-min recirculation except for the levels in cerebral cortex and cerebellum. The brain cAMP levels which increased about 3.5-fold 10 min after recirculation, almost recovered 20 min later. However, the cAMP levels in the telencephalon decreased to levels lower than the sham ope. levels 30 min after recirculation. It is suggested that the changes of these neurochemical parameters in the telencephalon are related in part to the abnormalities of behavior and EEG activity which have been already reported.

Topics: Acetylcholinesterase; Animals; Biogenic Amines; Brain; Choline; Choline O-Acetyltransferase; Cyclic AMP; Cyclic GMP; gamma-Aminobutyric Acid; Ischemic Attack, Transient; Male; Neurotransmitter Agents; Rats; Rats, Inbred Strains; Time Factors

Topics: Animals; Cerebral Cortex; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Energy Metabolism; Gerbillinae; Ischemic Attack, Transient

An understanding of the physiology of vascular smooth muscle and knowledge of the reaction of such muscle to certain drugs are essential for the development of a means of treating cerebral arterial spasm. The role of cyclic nucleotides in vascular smooth muscle activity is reviewed and possible therapeutic approaches are listed. Probably the safest and most effective treatment would be 1) stimulation of the adenyl cyclase-cyclic adenosine monophosphate system by a beta(2)-adrenergic drug combined with 2) inhibition of the phosphodiesterase system.

Topics: Adenylyl Cyclases; Animals; Blood Vessels; Cyclic AMP; Cyclic GMP; Guanylate Cyclase; Ischemic Attack, Transient; Isoproterenol; Muscle, Smooth; Nitroprusside; Phosphodiesterase Inhibitors