Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have demonstrated that the isolated perfused rat mesenteric arterial bed (MAB) secretes peptidases capable of metabolizing bradykinin and angiotensin I. The major degradative pathway of bradykinin by enzymes found in the rat MAB perfusate was mediated by carboxypeptidase A-like activity, whereas angiotensin 1 degradation followed two main routes, one attributable to a carboxypeptidase A-like enzyme and the other to an endopeptidase. This latter enzyme seems to be a novel serine peptidase capable of releasing angiotensin II directly from both angiotensin I and renin substrate tetradecapeptide. The rat MAB perfusate was also shown to contain additional endo- and exopeptidases that might play a role in the metabolism of other vasoactive peptides. Our finding that isolated rat MAB secretes peptidases into the perfusion medium indicates that peptide processing within the microvasculature environment may be effected by enzymes besides those normally found in plasma or associated with cell membranes.
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PMID:A survey of vasoactive peptide metabolizing enzymes in the rat mesenteric arterial bed perfusate. 174 67

It has recently been claimed that there are angiotensin II (ANG II) receptors on human mononuclear cells and on platelets and this has been used for investigating the regulation of the renin-angiotensin system in hypertension. We here show the following. Binding kinetics of 125I-labelled ANG II and [3H]ANG II to mononuclear cells were slow (maximum at 90 min) and the same as for [3H]-inulin. As with [3H]inulin there was no binding at 4 degrees C. Release from the cells was slow and incomplete (about 30% after 15 min, 60% after 60 min). Binding was not saturable over a range from 10(-12) to 10(-6) mol of ANG II/l, about 8% of offered peptide being bound at all concentrations. Various inhibitors of free fluid endocytosis exhibited the same inhibition pattern of ANG II binding to mononuclear cells. Therefore uptake of ANG II into mononuclear cells displayed all the features of free fluid endocytosis. ANG II was degraded by carboxypeptidase A. When this degradation was prevented by D-phenylalanine, no binding occurred. In platelet preparations contaminated by 0.3-5% of mononuclear cells, 125I-labelled ANG II was degraded as well. Free fluid endocytosis of the degradation product strongly depended on the percentage of contaminating mononuclear cells. We conclude that there are no ANG II receptors on human mononuclear cells and that their presence on human platelets is doubtful.
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PMID:Angiotensin II binding to human mononuclear cells: receptor or free fluid endocytosis? 632 93

1. A renin-inhibitory material has been partially purified from soluble extracts of the pig kidney cortex by ammonium sulphate precipitation and diethylaminoethylcellulose (DEAE) chromatography and its properties studied. 2. It displayed competitive type kinetics. It did not inhibit cathepsin D, carboxypeptidase A, pancreatic kallikrein or trypsin. 3. Renins from dogs, rabbit and rat were inhibited, but not those from sheep or man, when assayed with pig angiotensinogen. 4. The material was inactivated by treatment with trypsin, N-ethylmaleimide or p-chloromercuribenzoate. 5. Renin-inhibitory activity was not found in plasma from peripheral blood of pigs. 6. It is concluded that the function of the renin inhibitor in the renal cortex of the pig may be restricted to the intrarenal environment.
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PMID:Properties of a renin inhibitor isolated from the pig kidney cortex. 701 9

Adenosine (Ado) is a potent vasodilator that has occasionally been shown to cause vasoconstriction. Constrictor responses are generally attributed to A1-receptor stimulation or interactions with the renin-angiotensin system. We describe a previously unreported vasoconstrictor action of Ado and inosine (Ino) in hamster cheek pouch arterioles and examine the mechanism by which these nucleosides induce constriction. Arterioles were dissected from male Golden hamster cheek pouches, transferred to a 37 degrees C tissue chamber, and cannulated at both ends. Changes of luminal diameter in response to Ado were measured to generate cumulative concentration-response curves. The concentration-response curves were biphasic: 10(-6) M Ado elicited an intense, transient constriction, and higher concentrations induced dilator responses. Pretreatment with 8(p-sulfophenyl)theophylline, an Ado receptor antagonist, inhibited the dilator responses but did not alter the constriction. Inhibition of Ado uptake with S-(4-nitrobenzyl)-6-thio-inosine eliminated the constrictor response without altering dilator responses. Similar effects were found after pretreatment with an Ado deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride. Finally, Ino, a metabolite of Ado, induced constrictions of similar magnitude to those seen with Ado, but at higher concentrations. The constrictor response was focal in nature, suggesting discrete sites of action of Ado. Methylene blue staining after Ado application revealed degranulated mast cells closely associated with the vessel wall, indicating a possible role for mast cell degranulation in the constrictor response. Supporting this idea were the observations that inhibition of degranulation by 10 microM cromolyn blocked the constrictor response, and compound 48/80 (a mast cell secretagogue) caused constriction similar to that elicited by Ado.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nucleoside-induced arteriolar constriction: a mast cell-dependent response. 820 2

Cardiac mast cells have been recently isolated and characterized in humans, however canine cardiac mast cells have not been investigated. The objective of this study is to describe the histological and morphological characteristics of canine cardiac mast cells and examine the potential usefulness of canine models in investigating the role of mast cells in cardiovascular pathology. Canine cardiac mast cells could be easily identified by staining with Toluidine Blue or FITC-avidin. Using Toluidine Blue staining, we demonstrated fewer mast cells in formalin-fixed samples than in specimens fixed in Carnoy's, thus identifying a formalin-sensitive mast cell population in the canine heart. Mast cells were equally distributed in atria and ventricles with approximately 50% showing a perivascular location. Using enzyme-histochemical techniques, we detected tryptase and chymase activity in canine cardiac mast cells. Ultrastructural studies identified mast cells as granular cells with an eccentric non-segmented nucleus. Immunohistochemistry with the macrophage specific antibody AM-3K demonstrated that resident cardiac macrophages were 1.9 times more numerous than mast cells, also showing a predominantly perivascular (60%) location. Perivascular macrophages were more often periarteriolar, whereas perivascular mast cells were more often located along small veins and capillaries. Due to their ability to release cytokines and growth factors and their strategic perivascular location, resident cardiac inflammatory cells, such as mast cells and macrophages, may be important in pathological processes causing myocardial inflammation and fibrosis. Furthermore, mast cell-derived chymase, an important angiotensin II-forming enzyme may have a significant role in regulating the cardiac renin-angiotensin system.
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PMID:Histochemical and morphological characteristics of canine cardiac mast cells. 1044 63

It has been discussed in several studies that non-immunologic factors, such as renin angiotensin aldosterone system (RAAS) may play a role in the pathophysiology of anaphylaxis. This study aimed to determine whether RAAS plays a part in the fall in blood pressure during drug reactions or not. Twenty patients who experienced hypotension during drug reaction and 15 healthy volunteers were enrolled in this study. None of the patients in the study or control groups were under treatment with any drug that was capable of influencing to RAAS. Serum levels of angiotensin-I (A-I), angiotensin-II (A-II), angiotensin converting enzyme (ACE) and aldosterone were measured in both study and control groups. The Mann-Whitney U test was used to compare the results of the groups. There were no statistically significant differences between the groups with respect to A-I, A-II, ACE and aldosterone levels. It was concluded that a fall in blood pressure during drug reaction must be the result of mast cell mediator effects on the vascular wall rather than RAAS impairment.
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PMID:Renin angiotensin aldosterone system and drug allergies complicated with hypotension. 1092 19

Various psychosocial factors have been implicated in the etiology and pathogenesis of certain cardiovascular diseases such as atherosclerosis, now considered to be the result of a chronic inflammatory process. In this article, we review the evidence that repeated episodes of acute psychological stress, or chronic psychologic stress, may induce a chronic inflammatory process culminating in atherosclerosis. These inflammatory events, caused by stress, may account for the approximately 40% of atherosclerotic patients with no other known risk factors. Stress, by activating the sympathetic nervous system, the hypothalamic-pituitary axis, and the renin-angiotensin system, causes the release of various stress hormones such as catecholamines, corticosteroids, glucagon, growth hormone, and renin, and elevated levels of homocysteine, which induce a heightened state of cardiovascular activity, injured endothelium, and induction of adhesion molecules on endothelial cells to which recruited inflammatory cells adhere and translocate to the arterial wall. An acute phase response (APR), similar to that associated with inflammation, is also engendered, which is characterized by macrophage activation, the production of cytokines, other inflammatory mediators, acute phase proteins (APPs), and mast cell activation, all of which promote the inflammatory process. Stress also induces an atherosclerotic lipid profile with oxidation of lipids and, if chronic, a hypercoagulable state that may result in arterial thromboses. Shedding of adhesion molecules and the appearance of cytokines, and APPs in the blood are early indicators of a stress-induced APR, may appear in the blood of asymptomatic people, and be predictors of future cardiovascular disease. The inflammatory response is contained within the stress response, which evolved later and is adaptive in that an animal may be better able to react to an organism introduced during combat. The argument is made that humans reacting to stressors, which are not life-threatening but are "perceived" as such, mount similar stress/inflammatory responses in the arteries, and which, if repetitive or chronic, may culminate in atherosclerosis.
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PMID:Stress, inflammation and cardiovascular disease. 1180 Dec 60

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by exuberant inflammation and fibrosis, a process believed to contribute to progressive loss of normal renal function. Despite early-onset hypertension and intrarenal renin/angiotensin II (AngII) activation, angiotensin-converting enzyme (ACE) inhibition does not consistently confer renal protection in ADPKD. The hypothesis was that mast cells within the inflammatory interstitium release chymase, an enzyme capable of efficient conversion of AngI to AngII, providing an ACE-independent route of AngII generation. End-stage ADPKD renal tissue extracts and cyst fluids were assayed for time-dependent, chymostatin-inhibitable conversion of (125)I-AngI to (125)I-AngII under conditions of ACE and aminopeptidase inhibition by means of HPLC. Thirteen of 14 ADPKD kidney extracts exhibited chymase-like AngII-generating capacity; calculated initial reaction rates averaged 3.9 +/- 2.9 fmol AngII/min/ micro g protein with a mean maximal conversion of 55% +/- 30% of added substrate. AngII-generating activity was both protein and substrate dependent. All five cyst fluid samples were negative. Chymase-like activity was detectable in only three of six non-ADPKD kidney extracts. Immunoreactive chymase protein was present in/around mast cells within the fibrotic renal interstitium in all samples. Findings demonstrate for the first time the presence of mast cells, mast cell-associated immunoreactive chymase protein, and chymase-like AngII generating capacity in ADPKD cystic kidneys. Results support the potential for ACE-independent AngII generation and for mast cell-initiated inflammatory processes in ADPKD, each with therapeutic implications for ADPKD renal progression.
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PMID:Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease. 1474 98

In addition to the traditional renin-angiotensin system, a great deal of evidence favors the existence of numerous independent tissue-specific renin-angiotensin systems. We report that mast cells are an additional source of renin and constitute a unique extrarenal renin-angiotensin system. We use renin-specific antibodies to demonstrate that cardiac mast cells contain renin. Extending this observation to the human mast cell line HMC-1, we show that these mast cells also express renin. The HMC-1 renin RT-PCR product is 100% homologous to Homo sapiens renin. HMC-1 cells also contain renin protein, as demonstrated both by immunoblot and immunocytochemical analyses. Renin released from HMC-1 cells is active; furthermore, HMC-1 cells are able to synthesize renin. It is known that, in the heart, mast cells are found in the interstitium in close proximity to nerves and myocytes, which both express angiotensin II receptors. Inasmuch as myocardial interstitium contains angiotensinogen and angiotensin-converting enzyme, and because we were able to detect renin only in mast cells, we postulate that the release of renin from cardiac mast cells is the pivotal event triggering local formation of angiotensin II. Because of the ubiquity of mast cells, our results represent a unique paradigm for understanding local renin-angiotensin systems, not just in the heart, but in all tissues. Our findings provide a rationale for targeting mast cells in conjunction with renin-angiotensin system inhibitors in the management of angiotensin II-related dysfunctions.
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PMID:Mast cells: a unique source of renin. 1534 8

The renin-angiotensin system is a key target for drugs combating cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor type-1 (AT1 receptor) blockers are well known. However, angiotensin peptides can be generated through a number of pathways besides the classic system. This review outlines some of these pathways, their relation to the classic system and the likely effect of inhibiting them. Renin is still the key enzyme in angiotensin peptide generation and seems to be the only route to angiotensin I formation in vivo. Renin inhibitors may have some advantages in terms of specificity. Also, by blocking angiotensin I generation, the production of downstream bioactive angiotensin I metabolites should also be blocked. Chymase, a mast cell serine protease, cleaves angiotensin I to produce angiotensin II and may be important at sites of inflammation such as atherosclerotic plaque. Angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase structurally related to ACE but resistant to ACE inhibitors, has a protective effect on cardiac function. Neutral endopeptidase 24.11 breaks down both atrial natriuretic peptide and angiotensin II. Inhibiting it potentiates the action of endogenous atrial peptide but only affects circulating angiotensin II when basal levels are above normal. Dual inhibitors of ACE and endopeptidase 24.11 may be of value where there is both sodium retention and increased angiotensin II. Targeting the renin-angiotensin system by gene therapy or antibody treatment may provide a longer-term treatment for hypertension.
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PMID:Targeting the renin-angiotensin system: what's new? 1563 41


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