cyclic-gmp and Cerebrovascular-Disorders

Endothelial dysfunction, intended as the complex multifaced pathological product of different vasculotoxic agents or injuries, is viewed today as an attractant intermediate phenotype of cardiovascular diseases with usually long and unpredictable natural history. Furthermore, endothelial dysfunction may not only represent a vascular disease marker, but may actually play an important pathogenetic role, leading to progression of the disease and unfavourable outcomes. Among these vascular diseases, cerebrovascular accidents, namely stroke, clearly represent a paradigmatic example of the potential role of dysfunctional endothelium. In fact, in the world's growing elderly population few diseases are more dreaded than stroke. With an increasing incidence and mortality of 30%, stroke carries the threat of death or long-term disability and suffering. Endothelium produces nitric oxide (NO) under basal conditions and in response to a variety of vasoactive stimuli in large cerebral arteries and in the cerebral microcirculation. In addition to exerting a tonic dilator effect on the cerebral circulation, basal release of NO may protect cerebral endothelium by inhibiting aggregation of platelets and leukocytes. In this paper, we analyse current evidence suggesting that endothelial dysfunction can play a role in the pathogenesis of ischaemic stroke.

Topics: Animals; Calcium; Cerebrovascular Disorders; Cyclic GMP; Endothelium, Vascular; Humans; Models, Biological; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Prostaglandin-Endoperoxide Synthases; Stroke

Nitric oxide (NO) is a messenger molecule that is now a well established neurotransmitter in the central and peripheral nervous systems. NO was initially characterized as the "endothelium-derived relaxation factor" and subsequently found to mediate the elevation in cGMP following glutamatergic stimulation in the nervous system. Pharmacological and immunohistochemical data suggest numerous roles for NO throughout the body. NO knockout mice have demonstrated that NO is essential in behavioral and autonomic function. NO also appears to have neurotoxic and neuroprotective effects and may have a role in the pathogenesis of stroke and other neurodegenerative disorders.

Topics: Animals; Behavior, Animal; Cerebrovascular Disorders; Chromosome Mapping; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 7; Cyclic GMP; Humans; Long-Term Potentiation; Mice; Mice, Knockout; Nervous System Diseases; Nervous System Physiological Phenomena; Neurons; Neurotransmitter Agents; Nitric Oxide; Nitric Oxide Synthase; Phosphorylation

Evidence has steadily accumulated to indicate that the rapid fluctuations in cyclic nucleotides during primary and secondary stroke are more than epiphenomena of the disease. During acute phases of ischemia, anoxia or hypoxia cyclic AMP rapidly accumulates in cerebral tissue, cerebrospinal fluid (CSF) and venous plasma, while cyclic GMP either remains unchanged or declines. The massive release of transmitters (catecholamines and adenosine) or ionic fluxes (Na+ and K+) may account for these observations. If reflow is established through a previously occluded vessel cyclic AMP content rises even higher in conjunction with a sharp rise in cyclic GMP. It is during this reflow period subsequent to longer term stroke (30-60 min) that the synaptic membrane enzyme, adenylate cyclase, is especially vulnerable. Presumably the cause of injury to cell membrane systems results from excess lactic acid accumulation and/or Ca++ entry through the damaged blood-brain barrier. The latter initiates breakdown of membrane phospholipids with resultant synthesis of vasoactive prostaglandins and formation of free radicals causing further insult to membrane phospholipids. Thus drugs acting to inhibit formation of prostaglandins, scavenge free radicals, reduce lactate formation, inhibit Ca++ entry or stabilize cell membranes have been shown to possess varying degrees of protective action toward adenylate cyclase. Moreover, cyclic AMP has been found to reverse stroke-induced vasospasm in central vessels. Reduced cyclic AMP content in CSF has been used to monitor the severity of coma, whereas clinical improvement was associated with predictable increases in the cyclic nucleotide. Therefore, cyclic nucleotides and related membrane enzyme systems might be used as target molecules in which to develop future therapeutic strategies for prevention or treatment of stroke.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Adenosine; Adenylyl Cyclases; Animals; Brain; Brain Ischemia; Brain Neoplasms; Capillaries; Cerebrovascular Disorders; Cyclic AMP; Cyclic GMP; gamma-Aminobutyric Acid; Guanylate Cyclase; Humans; Hypoxia, Brain; In Vitro Techniques; Lactates; Lactic Acid; Norepinephrine; Phospholipids; Protein Kinases; Synaptic Membranes; Tissue Distribution

Topics: Animals; Brain; Cerebrovascular Circulation; Cerebrovascular Disorders; Cyclic GMP; Dogs; Glucose; Humans; Mice; Oxygen Consumption; Rats; Vasodilator Agents; Vinca Alkaloids

Topics: Acidosis; Animals; Biological Transport, Active; Brain Ischemia; Calcium; Cell Membrane; Cerebrovascular Disorders; Cyclic GMP; Electrophysiology; Energy Metabolism; Epilepsy; Fatty Acids, Nonesterified; Free Radicals; Glutathione; Hypoglycemia; Hypoxia, Brain; Ions; Lactates; Lactic Acid; Microscopy, Electron; Mitochondria; Neuroglia; Neurons; Phospholipids; Time Factors

We investigated the role of the NO/cGMP system in the vasodilatory response to hypercapnia after cortical spreading depression (CSD) in barbiturate anesthetized rats in vivo. Regional cerebral blood flow (rCBF) was measured by laser Doppler flowmetry (LDF). Hypercapnia (arterial pCO2 50-60 mm Hg) increased rCBF by 2.8+/-1.0%/mm Hg (n = 34). Fifteen minutes after CSD, resting rCBF was reduced to 87%, and rCBF response to hypercapnia was abolished (p < 0.001, n = 28). Within 1 h after CSD, only little restoration of vascular reactivity occurred. Topical application of the NO-donors S-nitroso-N-acetylpenicillamine (SNAP), 3-morpholinosydnonimine (SIN1), or spermine/NO complex (Sperm/NO), or of the cell permeable guanosine 3',5'-cyclic monophosphate (cGMP) analogue 8-Br-cGMP reestablished resting rCBF to values measured before CSD, and reversed CSD-induced attenuation of the cerebrovascular response to hypercapnia. Restoration of resting rCBF to pre-CSD level by the NO-independent vasodilator papaverine had no effect on the attenuated hypercapnic response. In conclusion, we have shown that the compromised vascular reactivity to hypercapnia after CSD can be reversed to normal reactivity by restoration of the basal NO or cGMP concentration in the cortex, suggesting a reduction of the cerebrovascular NO or cGMP concentration following CSD.

Topics: Analysis of Variance; Animals; Cerebral Cortex; Cerebrovascular Circulation; Cerebrovascular Disorders; Cortical Spreading Depression; Cyclic GMP; Drug Interactions; Hypercapnia; Laser-Doppler Flowmetry; Male; Molsidomine; Nitric Oxide; Nitric Oxide Donors; Penicillamine; Rats; Rats, Wistar; Spermine; Thionucleotides; Time Factors

Kallikrein gene delivery has been shown to attenuate hypertension, cardiac hypertrophy, and renal injury in hypertensive animal models. The aim of this study was to investigate the potential protective effects of kallikrein gene delivery in salt-induced stroke and cerebrovascular disorders.. Adenovirus harboring the human tissue kallikrein gene (AdCMV-cHK) was delivered intravenously into Dahl salt-sensitive (DS) rats after 4 weeks of high salt loading, and blood pressure was monitored weekly for 9 weeks.. A single injection of AdCMV-cHK caused a significant reduction of systolic blood pressure compared with that in control rats, with or without an injection of adenovirus carrying the LacZ (control) gene (AdCMV-LacZ). A maximal blood pressure reduction of 21 mm Hg was observed 2 weeks after gene delivery. The stroke mortality rate of DS rats (AdCMV-LacZ group versus the AdCMV-cHK group) was significantly decreased: 38% versus 9% at 3 weeks and 54% versus 27% at 5 weeks after gene delivery. Kallikrein gene delivery significantly attenuated salt-induced aortic hypertrophy, as evidenced by reduced thickness of the aortic wall. Recombinant human tissue kallikrein was detected in rat serum and urine after gene transfer. Kinin-releasing activities in the brain as well as urinary kinin and cGMP levels were significantly increased in rats receiving the kallikrein gene.. This is the first study to demonstrate the protective effect of kallikrein gene delivery in reducing salt-induced stroke mortality and vascular dysfunction.

Topics: Adenoviridae; Animals; Aorta; Blood Pressure; Brain; Cerebrovascular Disorders; Cyclic GMP; Gene Transfer Techniques; Humans; Hypertrophy; Injections, Intravenous; Kallikreins; Kinins; Male; Rats; Rats, Inbred Dahl; Recombinant Proteins; Sodium Chloride; Time Factors

In the present study we tested the hypothesis whether an angiotensin AT2 receptor-mediated stimulation of the bradykinin (BK)/nitric oxide (NO) system can account for the effects of AT1 receptor antagonism on aortic cGMP described previously in SHRSP. Adult SHRSP were treated for 4 hours with angiotensin II (ANG II) (30 ng/kg per min IV) or vehicle (0.9% NaCl I.V.). Animals were pretreated with vehicle, losartan (100 mg/kg P.O.), PD 123319 (30 mg/kg I.V.), losartan plus PD 123319, icatibant (500 microg/kg I.V.), N(G)-nitro-L-arginine methyl ester (L-NAME; 1 mg/kg I.V.), or minoxidil (3 mg/kg I.V.). Mean arterial blood pressure (MAP) was continuously monitored over the 4-hour experimental period, and plasma ANG II and aortic cGMP were measured by RIA at the end of the study. ANG II infusion over 4 hours raised MAP by about 20 mm Hg. Losartan alone or losartan plus ANG II as well as minoxidil plus ANG II markedly reduced blood pressure when compared to vehicle-treated or ANG II-treated animals, respectively. Plasma levels of ANG II were increased 2-fold by ANG II infusion alone or by ANG II in combination with icatibant, L-NAME, or minoxidil. The increase in plasma ANG II levels was even more pronounced after losartan treatment. Aortic cGMP content was significantly increased by ANG II, losartan, losartan plus ANG II, and minoxidil plus ANG II by 60%, 45%, 68%, and 52%, respectively (P<.05). The effects of ANG II and of losartan plus ANG II on aortic cGMP content were both blocked by cotreatment with the AT2 receptor antagonist PD 123319. Icatibant and L-NAME abolished the effects of ANG II on aortic cGMP. Our results demonstrate the following: (1) ANG II increases aortic cGMP by an AT2 receptor-mediated action because the effect could be prevented by an AT2 receptor antagonist; (2) the effect of ANG II was not secondary to blood pressure increase because it remained under reduction of MAP with minoxidil; (3) losartan increased aortic cGMP most likely by increasing plasma ANG II levels with a subsequent stimulation of AT2 receptors; and (4) the effects of AT2 receptor stimulation are mediated by BK and, subsequently, NO because they were abolished by B2 receptor blockade as well as by NO synthase inhibition.

Topics: Angiotensin II; Animals; Aorta; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cerebrovascular Disorders; Cyclic GMP; Hypertension; Imidazoles; Losartan; Male; Minoxidil; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Pyridines; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Reference Values

We have previously shown that a locus on rat chromosome 5, termed STR 2, co-localizes with the genes encoding atrial natriuretic and brain natriuretic peptides, and is closely linked to the development of strokes in rats of a F2 hybrid cohort obtained by crossing stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats. We also demonstrated that there are significant differences in vascular functioning that are co-segregated with stroke latency of stroke-prone spontaneously hypertensive rats.. To investigate the vascular responses to natriuretic peptides in the stroke-prone phenotype of spontaneously hypertensive rats.. In view of the important vasoactive properties of natriuretic peptides, we tested the vascular responses to 10(-11)-10(-9) mol/l atrial natriuretic peptide and to 10(-11)-10(-7) mol/l brain natriuretic peptide in isolated rings of aortas and internal carotid arteries obtained from stroke-prone and stroke-resistant spontaneously hypertensive rats. The 6-week-old rats were exposed for 4 weeks either to their regular diet (n = 15 of both strains) or to the stroke-permissive Japanese-style diet (n = 14 of both strains). A group of 14 normotensive, age-matched and sex-matched Wistar-Kyoto rats was also studied.. Systolic blood pressures in stroke-prone and stroke-resistant spontaneously hypertensive rats were similar, and were significantly higher than those in Wistar-Kyoto rats. Vascular responses to nitroglycerin, atrial natriuretic peptide, and brain natriuretic peptide in rats of the two hypertensive strains and in Wistar-Kyoto rats fed their regular diet were comparable. In contrast, the vasorelaxant responses to atrial natriuretic peptide in stroke-prone spontaneously hypertensive rats fed Japanese diet were lower both in aortas and in internal carotid arteries than were those in spontaneously hypertensive rats (both P < 0.05 by analysis of variance) and in Wistar-Kyoto rats (both P < 0.05). Similarly, vasorelaxant responses to brain natriuretic peptide were lower both in aortas and in internal carotid arteries of stroke-prone spontaneously hypertensive rats than they were in spontaneously hypertensive rats (both P < 0.05) and in Wistar-Kyoto rats (P < 0.05). The responses to nitroglycerin in the stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats fed Japanese-style diet were also similar.. The vasorelaxant effects of natriuretic peptides are impaired in stroke-prone spontaneously hypertensive rats. This abnormality could play a role in the pathogenesis of stroke incidence in this hypertensive model.

Topics: Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Carotid Artery, Internal; Cerebrovascular Disorders; Cyclic GMP; Hypertension; In Vitro Techniques; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Nitroglycerin; Phenotype; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasodilation

These studies were designed to investigate the protective effects of the new angiotensin II receptors antagonist BAY 10-6734 (6-n-butyl-4-methoxycarbonyl-2-oxo-1[(2'-(1H-tetrazol-5-yl) -3-fluorobiphenyl-4-yl)methyl] 1,2-dihydropyridine, CAS 156001-18-2) on haemodynamic, hormonal, renal, and structural parameters in renin transgenic rats (TGR(mRen2)27), salt-loaded Dahl S and R rats, and salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) in long-term trials. Study 1: In SHR-SP the development of blood pressure, cardiac hypertrophy, and the deleterious effects of salt loading on kidney structure and kidney function was prevented by BAY 10-6734. Study 2: In salt-loaded Dahl S rats with a suppressed plasma renin activity treatment with BAY 10-6734 did not delay the increase in blood pressure but prevented cardiac hypertrophy and the increase in plasma ANP (Atrial natriuretic peptide). Study 3: TGR develop malignant hypertension associated with cardiac hypertrophy, elevated left-ventricular end-diastolic pressure and increased plasma ANP. After 6 weeks of treatment with BAY 10-6734 (30 mg/kg p.o. bid) cardiac pump function was improved and cardiac hypertrophy was reversed in this angiotension dependent form of hypertension. The beneficial effects of BAY 10-6734 in these different animal hypertension models are also emphasized by a reduction in mortality.

Topics: Aldosterone; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Antihypertensive Agents; Atrial Natriuretic Factor; Body Weight; Cerebrovascular Disorders; Cyclic GMP; Dihydropyridines; Hemodynamics; Hormones; Hypertension; Kidney; Rats; Rats, Inbred SHR; Renin; Tetrazoles

Patients with atrial fibrillation have been reported to exhibit abnormal hemostasis. Since nitric oxide (NO) exerts antithrombotic effects and attenuates platelet function, we evaluated two indicators of plasma NO levels, the plasma levels of nitrite and nitrate (NOx), and the levels of cGMP in platelets. We also examined whether indicators of plasma NO levels were associated with abnormalities in parameters related to platelet function, blood coagulation, and fibrinolysis. We evaluated 45 patients with chronic sustained atrial fibrillation (33 men and 12 women, age range 63 +/- 2 years) compared with 45 sex- and age- (+/- 2 years) matched nonhospitalized subjects with sinus rhythm. There were no significant differences between the two groups in the incidence of risk factors for stroke except for ischemic heart disease or in echocardiographic parameters. Plasma levels of NOx measured using the Greiss reagent (mean [interquartile range]: 15.6 [9.5 to 25.7] versus 24.1 [14.2 to 40.8] mumol/L, n = 45) and the platelet cGMP levels (0.33 [0.16 to 0.67] versus 0.63 [0.31 to 1.29] pmol/10(9) platelets, n = 9) were significantly (P < .05) lower in the patients with atrial fibrillation than in the control subjects. Plasma levels of D-dimer, beta-thromboglobulin, and fibrinogen were significantly (P < .05) higher in the patients with atrial fibrillation. The two groups did not differ as to the plasma levels of tissue plasminogen activator or plasminogen activator inhibitor-1. Our findings suggest that a decrease in plasma NO levels may account for the hemostatic abnormalities observed in patients with atrial fibrillation.

Topics: Aged; Atrial Fibrillation; beta-Thromboglobulin; Blood Platelets; Blood Proteins; Cerebrovascular Disorders; Comorbidity; Cyclic GMP; Diabetes Mellitus; Echocardiography; Female; Fibrinogen; Hemodynamics; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Myocardial Ischemia; Nitrates; Nitric Oxide; Nitrites; Risk Factors; Smoking; Thrombophilia

We investigated the effect of chronic angiotensin-covering enzyme (ACE) inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRsp). Animals were treated prenatally and, subsequently, up to the age of 20 weeks with the ACE inhibitor perindopril (0.01 and 1 mg/kg per day). The contribution of endogenous bradykinin potentiation to the actions of the ACE inhibitor was assessed by co-treatment with the bradykinin B2-receptor antagonist, icatibant (500 micrograms/kg/day s.c.), from 6 to 20 weeks of age and by measurement of myocardial prostacyclin and cyclic guanosine monophosphate (GMP) concentrations. Chronic high-dose treatment with perindopril attenuated the development of hypertension and left ventricular hypertrophy while low-dose perindopril treatment had no effect on these parameters. However, low-dose perindopril improved cardiac function of isolated perfused hearts as demonstrated by an increasing left ventricular pressure and dp/dtmax without change in heart rate. Low-dose perindopril further reduced lactate concentrations and the enzymatic activities of lactate dehydrogenase and creatine kinase in the coronary venous effluent and increased tissue concentrations of glycogen, adenosine triphosphate, and creatine kinase in the myocardium. Concomitant chronic bradykinin receptor blockade abolished all ACE inhibitor-induced effects on cardiac function and metabolism. Cardiac prostacylin concentrations were 3-fold elevated in perindopril-treated animals when compared to vehicle-treated controls, while cardiac cyclic GMP concentrations remained unchanged. Our data demonstrate that chronic ACE inhibitor treatment can improve cardiac function and metabolism independently of the antihypertensive and antihypertrophic drug actions by potentiation of endogenous bradykinin.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cerebrovascular Disorders; Cyclic GMP; Epoprostenol; Heart; Hypertension; Hypertrophy, Left Ventricular; Indoles; Myocardium; Perindopril; Rats; Rats, Inbred SHR; Ventricular Pressure

Angiotensin-converting enzyme (ACE) inhibitors can improve cardiac function independent of their blood pressure (BP)-lowering actions. We investigated the effect of chronic subantihypertensive ACE inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRSP). Animals were treated in utero and subsequently to age 20 weeks with the ACE inhibitor perindopril (0.01 mg/kg/day). The contribution of endogenous bradykinin (BK) potentiation to the actions of the ACE inhibitor was assessed by cotreatment with the BK beta 2-receptor antagonist Hoe 140 (500 micrograms/kg/day subcutaneously, s.c.) from age 6 to 20 weeks and by measurement of myocardial prostacyclin and cyclic GMP concentrations. Chronic low-dose perindopril treatment had no effect on development of hypertension and left ventricular hypertrophy (LVH), but perindopril improved cardiac function, as demonstrated by increased LV pressure (LVP) (19.4%) and LVdp/dtmax (27.8%) but no change in heart rate (HR). The activities of lactate dehydrogenase (LDH) and creatine kinase (CK) as well as lactate concentrations in the coronary venous effluent were reduced by 39.3, 50, and 60.6%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and CK were increased by 16.3, 33.1, and 28.2%, respectively. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by concomitant chronic BK receptor blockade. Cardiac prostacyclin concentrations were threefold elevated in perindopril-treated animals whereas cardiac cyclic GMP concentration remained unchanged as compared with that of controls. Our data demonstrate that chronic low-dose ACE inhibitor treatment can improve cardiac function and metabolism by potentiating endogenous BK.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cerebrovascular Disorders; Coronary Circulation; Creatine Kinase; Cyclic GMP; Disease Models, Animal; Glycogen; Heart; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Indoles; L-Lactate Dehydrogenase; Myocardium; Perindopril; Rats; Rats, Inbred SHR

The localization and distribution of catecholamines, selected neuropeptides, and the cyclic nucleotide second messengers has been determined in the superior cervical ganglion of the stroke-prone variant of the spontaneously hypertensive rat (SHR) and its normotensive Wistar-kyoto (WKY) control. Significant alteration in the frequency of occurrence of dopaminergic small intensely fluorescent cell clusters was seen in the stroke-prone variant of the SHR. The immunofluorescent localization of cyclic AMP (cAMP) and cyclic GMP (cGMP) were also changed in the stroke-prone variant, as was the immunofluorescent staining quantity of the neuropeptides somatostatin and substance P. The morphological pattern of staining for the various compounds in the normotensive control (WKY) was equivalent to the Sprague-Dawley rat strain. The implications of the altered neurochemistry in the superior cervical ganglion on the high blood pressure, and the predisposition for stroke in this strain are discussed.

Topics: Animals; Catecholamines; Cerebrovascular Disorders; Cyclic AMP; Cyclic GMP; Ganglia, Sympathetic; Hypertension; Neuropeptides; Nucleotides, Cyclic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Somatostatin; Substance P

Topics: Adolescent; Adult; Cerebrovascular Disorders; Coronary Disease; Cyclic AMP; Cyclic GMP; Female; Humans; Hypertension; Male; Middle Aged; Vascular Diseases

Cyclic guanosine monophosphate (cGMP) levels have been measured in the cerebrospinal fluid of patients with various neurological diseases. The subjects with epilepsy or cerebrovascular diseases do not show any difference from the controls. Moreover, in the CSF of patients having cerebral tumors the levels of cGMP are markedly increased. This change is in line with previous in vitro studies on the increase of cGMP during cell growth and cell proliferation showing that the role of the nucleotide is important for the control of the life cycle of the cell.

Topics: Adolescent; Adult; Aged; Alzheimer Disease; Brain Neoplasms; Cerebrovascular Disorders; Cyclic GMP; Epilepsy; Female; Humans; Hydrocephalus, Normal Pressure; Male; Middle Aged; Multiple Sclerosis