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PubMedDate not supplied

Are reactive oxygen species involved in Alzheimer's disease?

Alzheimer's disease has a multifactorial pathogenesis. Among the various factors involved, this review examines, in particular, the possibility of oxidative stress, meaning an imbalance between the formation and spread of reactive oxygen species (ROS) and the antioxidant defenses. This theory is supported by the following observations: (a) the alteration of mitochondrial function, which is likely to lead to the electron leakage in the respiratory chain and the consequent formation of superoxide radicals; (b) the unbalanced high activity of superoxide dismutase and monoamine oxidase B which causes the production of more H2O2; (c) the alteration of iron homeostasis which, in combination with the superoxide and H2O2, gives rise to the most deleterious hydroxyl radicals; (d) the increased lipid peroxidation and membrane alterations; (e) the pro-aggregating effect of ROS on beta/A4 protein and the C-terminal fragment of amyloid precursor (A4CT). Most of these changes are already present in the normal aging brain but are aggravated in AD presumably over a number of years. However, further investigations are needed to confirm these theories particularly regarding the alterations of another target of ROS, the proteins. Peroxidative stress is presumably present in the AD brain. This stress might not be a primary factor in the pathogenesis of AD, but a consequence of the tissue injury. In any case, it could contribute considerably to the pathology, in a vicious cycle of actions and reactions resulting in a critical mass of metabolic errors, responsible in the end for this disease.

Alzheimer Disease↗

PubMed1995

Pathology of the transmissible spongiform encephalopathies with special emphasis on ultrastructure.

The transmissible spongiform encephalopathies are a group of genetic and infectious disorders which are exemplified by scrapie in animals and Creutzfeldt-Jakob disease in humans. The spongiform encephalopathies are characterized by symmetrical vacuolation of neurons and neuropil. Amyloid plaque formation similar to that found in Alzheimer's disease is conspicuous in many, but not all, of these diseases. The sub-cellular pathology features of the spongiform encephalopathies have been studied by conventional transmission electron microscopy, scanning electron microscopy, freeze fracture, negative staining and most recently by application of immunogold labelling methods. Although these studies have revealed many unusual structures, convincing virus-like particles have not been demonstrated. Considerable data, including important transgenic mouse studies, now suggest that a single cellular protein, designated prion protein, is necessary for infection. Ultrastructural immunogold studies have shown that prion protein is released from the surface of neurons and neurites, diffuses through the extracellular space around infected cells where it accumulates and finally becomes aggregated as amyloid fibrils. It is likely that the accumulation of prion protein within the extracellular space is instrumental in causing nerve cell dysfunction and, ultimately, neurological disease.

Amyloid↗

PubMed1997

Hyperviscosity and microproteinuria in central obesity: relevance to cardiovascular risk.

OBJECTIVES: To investigate the role of blood rheology changes in the occurrence of glomerular proteinuria in obese patients with central fat distribution. SUBJECTS: Fifty-nine obese out-patients (31 with central and 28 with peripheral body fat distribution) and 24 healthy subjects. MEASUREMENTS: Blood and plasma viscosity (Rotational viscometer CV100 HAAKE), erythrocyte deformability (whole-blood filtration time), fibrinogen (nephelometry), urinary excretion rates of albumin, IgG, transferrin and IgA (nephelometry). RESULTS: Higher blood viscosity (at low and high shear-rates), plasma viscosity, fibrinogen, erythrocyte aggregability and lower erythrocyte deformability were found in patients with central obesity than in patients with peripheral obesity (P < 0.01) and in healthy subjects (P < 0.001). Furthermore an increased urinary excretion rate of albumin (P < 0.001), IgG (P < 0.001), transferrin (P < 0.01) and IgA (P < 0.05) was found in patients with central obesity than in the other two groups. Blood hyperviscosity (at shear-rate 1 s-1 and 1/200 ratio) significantly correlated with the amount of urinary excretion of proteins independently of the other clinical and metabolic variables. CONCLUSIONS: The data demonstrated haemorheologic disorders related to pathologic proteinuria in patients with central obesity. The interaction between these two components may increase the risk of widespread cardiovascular disease.

Adult↗

PubMed2005

Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson's disease.

PD (Parkinson's disease) is an aetiologically heterogeneous disorder characterized by a clinical phenotype consisting of resting tremor, rigidity and bradykinesia. Motor symptoms are associated with a progressive loss of dopaminergic neurons, with Lewy body inclusions within surviving neurons. Although heritability studies have shown evidence of familial aggregation, twin studies have provided limited support for a genetic aetiology. Nevertheless, classical linkage methods have nominated 11 regions of the genome and pathogenic mutations have been identified in several genes, including alpha-synuclein, parkin, ubiquitin C-terminal hydrolase L1, oncogene DJ-1, PTEN-induced protein kinase 1 and microtubule-associated protein tau. Most recently, heterozygous mutations in LRRK2 (leucine-rich repeat kinase 2) were found to cause late-onset, autosomal-dominant PD. Despite their consistent clinical phenotype, family members with LRRK2 mutations can have variable alpha-synuclein and tau pathologies. Lrrk2 is a member of the Roc (Ras of complex proteins) family, with Ras GTPase and MAPKKK (mitogen-activated protein kinase kinase kinase) catalytic domains. Thus its discovery highlights vesicle dynamics and secondary-messenger signalling in disease pathophysiology. To diagnose a disease accurately and effectively treat it, requires an understanding of its molecular pathogenesis. Herein, we provide an overview of the genetics of PD, how these discoveries are revolutionizing long-held beliefs and more importantly how this knowledge may be translated into patient therapy.

Humans↗

PubMed1995

Grumose or foamy spheroid bodies involving astrocytes in the human brain.

Grumose or foamy spheroid bodies (GFSB), which correspond to the classical pathological description, 'grumose degeneration', are described. By light microscopy, GFSB are faintly eosinophilic and spheroidal structures with a foamy appearance in haematoxylin and eosin stains; they vary from 10 to 50 microns in diameter and contain amorphous debris-like material. Some GFSB, however, contain a varying amount of eosinophilic grumose aggregates, some of which are randomly stained with periodic acid Schiff (PAS), Schmorl, Berlin blue, Grimelius or silver methods. The Gallyas stain, on the other hand, usually stains the contents of GFSB black or brown. Immunohistochemically, most GFSB are ubiquitin-positive. Characteristically glial fibrillary acidic protein is associated with some GFSB giving a foamy appearance. Ultrastructurally, GFSB consist of dense bodies of various sizes and configuration. Glial fibrillary bundles and astrocytic punctate adhesions are occasionally observed associated with GFSB. Anatomically, GFSB are observed preferentially in the rostroventral parts of both the substantia nigra pars reticulata and the globus pallidus in a number of human neurodegenerative diseases and aged brains. GFSB, however, appear outside the above regions in various circumstances such as trauma, infarction and astrocytomas. In conclusion, GFSB are ubiquitinated structures closely related to astrocytes in their formation and with a preferred location in the deep regions of the basal ganglia.

Astrocytes↗

PubMed1995

[An autopsy case of intravascular malignant lymphomatosis with intracranial lymphomatous mass lesions].

A 50-year-old man was admitted to our hospital, because of weakness in his right leg. On admission, he had generalized hyperreflexia and positive Babinski signs bilaterally. After admission, weakness in his left leg and confusion developed. A cerebrospinal fluid examination revealed increases in cell counts and protein but was negative for malignant cells. Blood chemistry was normal except for elevated LDH. A bone marrow biopsy yielded lymphoma cells. Successive T2-weighted cranial MRI showed a progressively expanding high signal area in the right parieto-occipital lobe. His confusional state improved after chemotherapy; however, two months later another cranial CT showed multiple enhanced mass lesions. The patient died 20 months after the onset of illness. Postmortem examination revealed widespread intravascular aggregates of malignant lymphomatous cells in the cerebrum, lungs and kidney, as well as multiple infarcts without atherosclerosis in the cerebrum. These pathological findings are compatible with those of intravascular malignant lymphomatosis. In addition, extravascularly expanding tumor cells formed multiple nodular lesions in the cerebral hemisphere. An immunohistochemical study showed that the tumor cells were positive for B-cell marker L26. Intracranial lymphomatous mass lesion rarely occurs in cases of intravascular malignant lymphomatosis. In the present case, tumor cells were presumably restricted to intravascular spaces, occluded them and resulted in ischemic lesions in the cerebrum in the early phase, but they expanded extravascularly and developed mass lesions in the terminal stages. In conclusion, intravascular malignant lymphomatosis is considered to be phenotypes of malignant lymphoma. This is the first case of intravascular malignant lymphomatosis associated with intracranial lymphomatous mass lesions in Japan.

Brain↗

PubMed2004

Redox-active metals, oxidative stress, and Alzheimer's disease pathology.

Considerable evidence is mounting that dyshomeostasis of the redox-active biometals, Cu and Fe, and oxidative stress contribute to the neuropathology of Alzheimer's disease (AD). Present data suggest that metals can interact directly with Abeta peptide, the principal component of beta-amyloid that is one of the primary lesions in AD. The binding of metals to Abeta modulates several physiochemical properties of Abeta that are thought to be central to the pathogenicity of the peptide. First, we and others have shown that metals can promote the in vitro aggregation into tinctorial Abeta amyloid. Studies have confirmed that insoluble amyloid plaques in postmortem AD brain are abnormally enriched in Cu, Fe, and Zn. Conversely, metal chelators dissolve these proteinaceous deposits from postmortem AD brain tissue and attenuate cerebral Abeta amyloid burden in APP transgenic mouse models of AD. Second, we have demonstrated that redox-active Cu(II) and, to a lesser extent, Fe(III) are reduced in the presence of Abeta with concomitant production of reactive oxygen species (ROS), hydrogen peroxide (H(2)O(2)) and hydroxyl radical (OH*). These Abeta/metal redox reactions, which are silenced by redox-inert Zn(II), but exacerbated by biological reducing agents, may lead directly to the widespread oxidation damages observed in AD brains. Moreover, studies have also shown that H(2)O(2) mediates Abeta cellular toxicity and increases the production of both Abeta and amyloid precursor protein (APP). Third, the 5' untranslated region (5'UTR) of APP mRNA has a functional iron-response element (IRE), which is consistent with biochemical evidence that APP is a redox-active metalloprotein. Hence, the redox interactions between Abeta, APP, and metals may be at the heart of a pathological positive feedback system wherein Abeta amyloidosis and oxidative stress promote each other. The emergence of redox-active metals as key players in AD pathogenesis strongly argues that amyloid-specific metal-complexing agents and antioxidants be investigated as possible disease-modifying agents for treating this horrible disease.

Alzheimer Disease↗

PubMed1987

[Morphological approach to characterizing the heterogeneity of blood plasma lipoproteins in different types of pathology].

Heterogeneity of lipoprotein particles of the main classes is shown in primary and secondary hyperlipidemias. It displays biochemical, physical and chemical impairments in the system of lipid transport. Aggregation is one of lipoprotein heterogeneity manifestation. Morphological electron microscopic characteristic is one of the main methods in lipoprotein abnormal heterogeneity diagnosis.

Animal Nutritional Physiological Phenomena↗

PubMed2005

Temporal profiles of neuronal degeneration, glial proliferation, and cell death in hNFL(+/+) and NFL(-/-) mice.

Neurofilament (NF) aggregate formation within motor neurons is a pathological hallmark of both the sporadic and familial forms of amyotrophic lateral sclerosis (ALS). The relationship between aggregate formation and both microglial and astrocytic proliferation, as well as additional neuropathological features of ALS, is unknown. To examine this, we have used transgenic mice that develop NF aggregates, through either a lack of the low-molecular-weight NF subunit [NFL (-/-)] or the overexpression of human NFL [hNFL (+/+)]. Transgenic and wild-type C57bl/6 mice were examined from 1 month to 18 months of age, and the temporal pattern of motor neuron degeneration, microglial and astrocytic proliferation, and heat shock protein-70 (HSP-70) expression characterized. We observed three overlapping phases in both transgenic mice, including transient aggregate formation, reactive microgliosis, and progressive motor neuron loss. However, only NFL (-/-) mice demonstrated significant astrogliosis and HSP-70 upregulation in both motor neurons and astrocytes. These in vivo models suggest that the development of NF aggregates in motor neurons leads to motor neuron death, but that the interaction between the degenerating motor neurons and the adjacent non-neuronal cells may differ significantly depending on the etiology of the NF aggregate itself.

Amyotrophic Lateral Sclerosis↗

PubMed1988

Cathepsin G is a strong platelet agonist released by neutrophils.

The present studies were undertaken to characterize a serine protease released by N-formyl-L-Met-L-Leu-L-Phe (fMet-Leu-Phe)-stimulated neutrophils that rapidly induces platelet calcium mobilization, secretion and aggregation. The biological activity associated with this protease was unaffected by leupeptin, was only weakly diminished by N-p-tosyl-L-Lys-chloromethane, but was strongly inhibited by alpha 1-antitrypsin, soyabean trypsin inhibitor, N-tosyl-L-Phe-chloromethane and benzoyloxycarbonyl-Gly-Leu-Phe-chloromethane (Z-Gly-Leu-PheCH2Cl). These observations indicated that the biological activity of neutrophil supernatants could be attributed to a chymotrypsin-like enzyme such as cathepsin G. Furthermore, platelet aggregation and 5-hydroxytryptamine release induced by cell-free supernatants from fMet-Leu-Phe-stimulated neutrophils were found to be blocked by antiserum to cathepsin G in a concentration-dependent manner but were unaffected by antiserum to elastase. The biological activity present in neutrophil supernatants co-purified with enzymic activity for cathepsin G during sequential Aprotinin-Sepharose affinity chromatography and carboxymethyl-Sephadex chromatography. SDS/polyacrylamide-gel electrophoresis of the reduced, purified protein, demonstrated three polypeptides with apparent Mr values of 31,500, 29,000 and 28,000 and four polypeptides were resolved on acid-gel electrophoresis. Purified cathepsin G from neutrophils cross-reacted with anti-(cathepsin G) serum in a double immunodiffusion assay and elicited platelet calcium mobilization, 5-hydroxytryptamine secretion and aggregation. Calcium mobilization and secretion induced by low concentrations of cathepsin G were partially dependent on arachidonic acid metabolites and ADP, while stimulation by higher enzyme concentrations was independent of amplification pathways, indicating that cathepsin G is a strong platelet agonist. These results suggest that pathological processes which stimulate neutrophils and release cathepsin G can in turn result in the recruitment and activation of platelets.

Blood Platelets↗

PubMed2006

Dual binding site acetylcholinesterase inhibitors: potential new disease-modifying agents for AD.

The therapeutic potential of acetylcholinesterase (AChE) inhibitors has been strengthened recently by evidence showing that besides their role in cognitive function, they might contribute to slow down the neurodegeneration in Alzheimer's disease (AD) patients. It is known that AChE exerts secondary noncholinergic functions, related to its peripheral anionic site, in cell adhesion and differentiation, and recent findings also support its role in mediating the processing and deposition of beta-amyloid (Abeta) peptide. AChE is one of the proteins that colocalizes with Abeta peptide deposits in the brain of AD patients and promotes Abeta fibrillogenesis by forming stable AChEA beta complexes. Additionally, it has also been postulated that AChE binds through its peripheral site to the Abeta nonamyloidogenic form and acts as a pathological chaperone inducing a conformational transition to the amyloidogenic form (Inestrosa et al., 1996; Bartolini et al., 2003). Anew series of dual binding site AChE inhibitors has been designed and synthesized as new potent AChE inhibitors, which might simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting Abeta peptide aggregation through binding to both catalytic and peripheral sites of the enzyme.

Acetylcholinesterase↗

PubMed1977

Immunochemical studies on the nature of the serum component (SAA) related to secondary amyloidosis.

The relative occurrence of the amyloid-related serum protein SAA in various disease states and in healthy subjects has been compared by both solid phase radioimmunoassay ((RIA) and immunodiffusion techniques which employ antibodies to purified amyloid fibril proten AA of hemogeneous size and charge. SAA levels were elevated above normal in certain categories of neoplastic, inflammatory, and infectious diseases as well as in secondary amyloidosis. The lowest median value, 8 ng./ml., was observed for approximately 150 normal sera, with no age-related increase in subjects ranging in age from 16 to 70 years. The results are consistent with several recent observations that SAA is normal acute phase reactant, and hence the RIA for SAA has no prognostic or diagnostic significance for secondary amyloidosis. The sensitivity of RIA for the detection of SAA is lower than would be expected when AA cross-reactivity values for sera are correlated with their reaction with anti-AA antibodies in immunodiffusion. This observation, along with others reported elsewhere suggests that those determinants which cross-react with anti-AA antibodies are relatively hidden in native SAA. Myeloma sera were less reactive than other groups of pathologic sera in immunodiffusion, although they were similar to other patients' sera when analyzed by RIA. Antibodies to highly purified AA were also used to investigate the structue of SAA by a double-antibody immunoprecipitation method. Precipitated SAA was partially dissociated during sodium dodecyl sulfate-urea-polyacrylamide gel electrophoresis to a 12,500 molecular weight moiety designated, SAAL. Multiple radiolabeled species of molecular weight intermidiate to SAA and SAAL were also detected and appeared to represent imcompletely dissociated SAA. The results suggest the SAA is an aggregate of several SAAL chains.

Adolescent↗

PubMed2004

Orexin loss in Huntington's disease.

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded CAG repeat in the gene encoding huntingtin, a protein of unknown function. Mutant huntingtin forms intracellular aggregates and is associated with neuronal death in select brain regions. The most studied mouse model (R6/2) of HD replicates many features of the disease, but has been reported to exhibit only very little neuronal death. We describe for the first time a dramatic atrophy and loss of orexin neurons in the lateral hypothalamus of R6/2 mice. Importantly, we also found a significant atrophy and loss of orexin neurons in Huntington patients. Like animal models and patients with impaired orexin function, the R6/2 mice were narcoleptic. Both the number of orexin neurons in the lateral hypothalamus and the levels of orexin in the cerebrospinal fluid were reduced by 72% in end-stage R6/2 mice compared with wild-type littermates, suggesting that orexin could be used as a biomarker reflecting neurodegeneration. Our results show that the loss of orexin is a novel and potentially very important pathology in HD.

Animals↗

PubMed2003

Part II: alpha-synuclein and its molecular pathophysiological role in neurodegenerative disease.

Alpha-synuclein (alphaSN) brain pathology is a conspicuous feature of several neurodegenerative diseases. These include prevalent conditions such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and the Lewy body variant of Alzheimer's disease (LBVAD), as well as rarer conditions including multiple systems atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1). Common in these diseases, some referred to as alpha-synucleinopathies, are microscopic proteinaceous insoluble inclusions in neurons and glia that are composed largely of fibrillar aggregates of alphaSN. This molecular form of alphaSN contrasts sharply with normal alphaSN, which is an abundant soluble presynaptic protein in brain neurons. alphaSN is a highly conserved protein in vertebrates and only seven of its 140 amino acids differ between human and mouse. Flies lack an alphaSN gene. Implicated in neurotoxicity are two alphaSN mutants (A53T and A30P) that cause extremely rare familial forms of PD, alphaSN fibrils and protofibrils, soluble protein complexes of alphaSN with 14-3-3 protein, and phosphorylated, nitrosylated, and ubiquitylated alphaSN species. Unlike rare forms of fPD caused by mutations in alphaSN, disease mechanisms in most alpha-synucleinopathies implicate wildtype alphaSN and seem to converge around oxidative damage and impairments in protein catabolism. It is not known whether these causalities involve alphaSN from the beginning, but defects in the handling of this protein seem to contribute to disease progression because accumulation of toxic alphaSN forms damage neurons. Here, we summarize the main structural features of alphaSN and its functions, and discuss the molecular alphaSN species implicated in human disease and transgenic animal models of alpha-synucleinopathy in fly and rodents.

Alzheimer Disease↗

PubMed2004

Parkinson's disease transgenic mitochondrial cybrids generate Lewy inclusion bodies.

Many models of Parkinson's disease (PD) have succeeded in replicating dopaminergic neuron loss or alpha-synuclein aggregation but not the formation of classical Lewy bodies, the pathological hallmark of PD. Our cybrid model of sporadic PD was created by introducing the mitochondrial genes from PD patients into neuroblastoma cells that lack mitochondrial DNA. Previous studies using cybrids have shown that information encoded by mitochondrial DNA in patients contributes to many pathogenic features of sporadic PD. In this paper, we report the generation of fibrillar and vesicular inclusions in a long-term cybrid cell culture model that replicates the essential antigenic and structural features of Lewy bodies in PD brain without the need for exogenous protein expression or inhibition of mitochondrial or proteasomal function. The inclusions generated by PD cybrid cells stained with eosin, thioflavin S, and antibodies to alpha-synuclein, ubiquitin, parkin, synphilin-1, neurofilament, beta-tubulin, the proteasome, nitrotyrosine, and cytochrome c. Future studies of these cybrids will enable us to better understand how Lewy bodies form and what role they play in the pathogenesis of PD.

Aged↗

PubMed1990

The platelet aggregating factor(s) of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura is characterized by disseminated platelet aggregates throughout the microcirculation and a large body of clinical, experimental and pathological evidence implicates in vivo platelet aggregation as being pivotal in the disease. For this reason considerable energy has been spent by many investigators to identify a platelet aggregating factor. The understated reason for these studies is that the characterization of such a factor could lead to the subsequent identification of a medication or a plasma factor that could neutralize the aggregating factor. Although a platelet aggregating factor has been suspected to play a causal role in TTP for almost 50 years, only in recent years have investigators systematically attempted to identify such a factor. One group has identified a 37 kD protein in the plasma of TTP patients which can initiate platelet aggregation through a unique pathway of aggregation and this factor can be inhibited by normal IgG. The other group of workers (ourselves) have provided evidence that the platelet aggregating factor of TTP is calpain. Thus, the very nature of the aggregating factor, and by implication its inhibitors, is very different for the two groups, and it may take other investigators to resolve whether there are multiple platelet aggregating factors of TTP. Nonetheless, it is apparent that recent research has dramatically improved our understanding of this uncommon but important disorder and it is possible that such investigations will lead to more successful treatments of this condition.

Blood Coagulation Factors↗

PubMed2001

alpha-Synuclein implicated in Parkinson's disease catalyses the formation of hydrogen peroxide in vitro.

Some rare inherited forms of Parkinson's disease (PD) are due to mutations in the gene encoding a 140-amino acid presynaptic protein called alpha-synuclein. In PD, and some other related disorders such as dementia with Lewy bodies, alpha-synuclein accumulates in the brain in the form of fibrillar aggregates, which are found inside the neuronal cytoplasmic inclusions known as Lewy bodies. By means of an electron spin resonance (ESR) spin trapping method, we show here that solutions of full-length alpha-synuclein, and a synthetic peptide fragment of alpha-synuclein corresponding to residues 61-95 (the so-called non-Abeta component or NAC), both liberate hydroxyl radicals upon incubation in vitro followed by the addition of Fe(II). We did not observe this property for the related beta- and gamma-synucleins, which are not found in Lewy bodies, and are not linked genetically to any neurodegenerative disorder. There is abundant evidence for the involvement of free radicals and oxidative stress in the pathogenesis of nigral damage in PD. Our new data suggest that the fundamental molecular mechanism underlying this pathological process could be the production of hydrogen peroxide by alpha-synuclein.

Cell Death↗

PubMed1992

Soluble guanylate cyclase of platelets: function and regulation in normal and pathological states.

Chromatography of 105,000 x g supernatants of human and rat platelets on DEAE-cellulose yielded identical elution profiles containing 2 protein fractions (peaks I and II). Only peak II was found to possess guanylate cyclase activity. In the spectrum of the 105,000 x g supernatant of human platelets the absorption maximum was specified at 410 nm (the Soret band) which disappeared from the spectrum of the active protein fraction (peak II) but was detected in the nonactive fraction (peak I). The enzyme preparation was obtained in the heme-deficient form. In the experiments with rat platelets, the Soret band was absent from the corresponding spectra and the enzyme was not activated by sodium nitroprusside; i.e., in soluble guanylate cyclase of rat platelets, unlike the generally accepted notion, the heme is not a prosthetic group of the enzyme. It was shown that carnosine (beta-alanyl-L-histidine), a water-soluble antioxidant, inhibits guanylate cyclase activation by sodium nitroprusside. This inhibitory effect is caused by the interaction of carnosine with the guanylate cyclase heme and can be used for evaluating the degree of saturation of the enzyme with the heme. ADP-induced aggregation of human platelets (donors) is accompanied by a fall in the basal guanylate cyclase activity (with Mg2+) and the enhancement of the enzyme stimulation with sodium nitroprusside, protoporphyrin IX, arachidonic acid and L-arginine with simultaneous cGMP elevation in platelets. A hypothetic scheme of the regulatory role of cGMP in platelet aggregation is proposed. In the experiments with the acute myocardial ischemia of rats, 15 min after the surgery a sharp fall in the platelet guanylate cyclase activity accompanied by a decrease in the enzyme activity in the ischemic zone of the left ventricle of heart took place. The results provided evidence of the high sensitivity of platelet guanylate cyclase to pathological changes occurring in the myocardium at the earliest stages of the development of pathology.

Adenosine Diphosphate↗