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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemistry, industrial usage, general toxicity, and experimental use of allylamine are briefly reviewed. This highly reactive unsaturated alkylamine has had industrial applications in a variety of organic processes, and continues to be utilized, although accurate data concerning production is not readily available. The general toxic effects of the freebase form are primarily related to irritation of the mucous membranes, whereas the relatively long history of experimental use of this chemical has emphasized its' extraordinarily deleterious effects on heart and vascular tissue. Allylamine has been given by a variety of routes to many species in attempts to cause lesions which mimic human acute vasculitis, acute myocardial necrosis, and atherosclerosis; examples of typical lesions are illustrated. More recent in vivo and in vitro experimental work concerning the cellular toxicity of allylamine are summarized, and possible mechanisms of this chemicals' toxic action are discussed.
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PMID:Allylamine cardiovascular toxicity. 355 Nov 96

Allylamine (AA, 3-aminopropene) is a specific cardiovascular toxin used experimentally to model myocardial necrosis and atherosclerosis. In these physiologic experiments, 10-day AA exposure (100 mg . kg-1 . day-1 by gavage) produced severe myocardial necrosis and increased heart rate but did not affect systolic blood pressure in rats. Mid-thoracic aortic ring segments were removed, and reactivity to contractile and relaxant agonists was tested. Aortic rings (approximately 3 mm) from AA-treated rats were contracted significantly more by high potassium (100 mM) and slightly more by norepinephrine (NE, 10 microM) than anatomically matched control aortic rings. No difference in aortic ring NE sensitivity or percentage relaxation in response to acetylcholine (1 microM) or sodium nitroprusside (100 microM) was detected between control and AA-treated rat aortic rings. Allylamine (1 microM-1 mM) induced modest, concentration-dependent contractions and tension oscillations in aortic rings from both control and AA-treated rats. Aortic rings from AA-treated rats, however, were more sensitive to AA. Vascular smooth muscle cells derived from control and AA-treated rat aortas had similar toxic sensitivity to AA in vitro using the MTT viability assay. The mechanisms by which AA exposure increased heart rate in vivo and contractility of aortic rings are unknown. These experiments support the previously proposed concept that AA-induced acute myocardial necrosis is due to coronary vasospasm and myocardial ischemia and cell injury.
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PMID:Allylamine cardiovascular toxicity: evidence for aberrant vasoreactivity in rats. 947 32

Allylamine (AA) is a cardiovascular toxin that causes lesions resembling atherosclerosis in several mammalian species. AA's toxic effects are thought to be exerted through its conversion to acrolein (AC), a potent electrophilic alkylating agent and atherogen. Semicarbazide sensitive amine oxidase (SSAO) catalyzes the oxidation of AA to AC. Glutathione S-transferases (GST) can catalyze the first step of detoxification of AC to mercapturic acid. Our previous studies suggest that the isozyme rGST8-8 is a principal defense against electrophilic stress exerted by alpha,beta-unsaturated carbonyls such as AC. In the present studies, we use cultured rat vascular smooth muscle cells (VSMC) to examine the relative roles of SSAO and rGST8-8 in the cytotoxic effects of the atherogens, AA and AC. Exposure derived AA-resistant cells (VSMC-AA) were 3.5-fold more resistant to AA when compared to VSMC and 1.8-fold more resistant to acrolein. SSAO activity was 2-fold higher in VSMC-AA than in VSMC. Consistent with the role of SSAO in biotransformation of AA, the SSAO inhibitor semicarbazide (SC; 100 microM) provided nearly complete protection from AA to both VSMC-AA and VSMC. As expected, SC did not affect the cytotoxicity of AC. Pretreatment with 100 microM sulfasalazine (SS), a GST inhibitor, potentiated AA and AC toxicity in both VSMC-AA and VSMC, indicating a protective role of GST. Catalytic efficiency (K(cat)/K(m)) of GSTs was higher toward 4-hydroxynonenal (4-HNE) (0.65 mM(-1) s(-1)) than toward 1-chloro-2, 4-dinitrobenzene (CDNB) (0.14 mM(-1) s(-1)) for VSMC. In VSMC-AA, K(cat)/K(m) was increased 4.1-fold toward CDNB (0.58 mM(-1) s(-1)) and 6-fold toward 4HNE (3.9 mM(-1) s(-1)) when compared to VSMC, indicating a preferential increase in VSMC-AA of GST isozymes which utilize alpha,beta-unsaturated carbonyls. Western blots confirmed induction of rGST8-8 in VSMC-AA. Expression of recombinant mGSTA4 (the mouse homolog of rGST8-8) in VSMC caused a 1.6-fold increase in resistance to AA and AC. This resistance was fully reversed by 50 microM SS. Our results demonstrate that GSTs are an important defense against electrophilic atherogens and that isozymes with high activity toward alpha,beta-unsaturated carbonyls are particularly important in the vascular wall.
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PMID:Role of glutathione S-transferase 8-8 in allylamine resistance of vascular smooth muscle cells in vitro. 1040 32

Repeated cycles of oxidative injury by allylamine induce proliferative rat vascular smooth muscle cell (vSMC) phenotypes characterized by enhanced secretion of osteopontin (OPN). The present study was designed to evaluate the role of extracellular matrix (ECM) interactions in the induction of proliferative phenotypes in this model of oxidant injury. Because OPN is involved in ECM/integrin signaling, and may participate in proliferative control, the proliferation profiles of control and allylamine vSMCs seeded on different matrices were compared. Allylamine cells exhibited a proliferative advantage over controls when seeded on plastic, Pronectin, or fibronectin, but not type I collagen. Addition of GRGDS peptide selectively enhanced [3H]-thymidine incorporation in allylamine vSMCs, while anti-OPN antibodies nullified their proliferative advantage. Allylamine cells exhibited altered expression of alpha1, alpha5 and beta3 integrin subunits and enhanced downstream integrin-coupled increases in focal adhesion kinase, AP-1 and NF-kappaB binding activity. Inhibition of NF-kappaB by pyrrolidine dithiocarbamate selectively compromised proliferation of allylamine vSMCs, while seeding on a non-permissive collagen matrix ablated enhancement of NF-kappaB inducibility. These results implicate ECM interactions in the deregulation of vSMC proliferation following repeated cycles of oxidative chemical injury.
Atherosclerosis 2002 Jun
PMID:Collagen suppresses the proliferative phenotype of allylamine-injured vascular smooth muscle cells. 1199 48

Increased risk of vasospasm, a spontaneous hyperconstriction, is associated with atherosclerosis, cigarette smoking, and hypertension-all conditions involving oxidative stress, lipid peroxidation, and inflammation. To test the role of the lipid peroxidation- and inflammation-derived aldehyde, acrolein, in human vasospasm, we developed an ex vivo model using human coronary artery bypass graft (CABG) blood vessels and a demonstrated acrolein precursor, allylamine. Allylamine induces hypercontraction in isolated rat coronary artery in a semicarbazide-sensitive amine oxidase activity (SSAO) dependent manner. Isolated human CABG blood vessels (internal mammary artery, radial artery, saphenous vein) were used to determine: (1) vessel responses and sensitivity to acrolein, allylamine, and H(2)O(2) exposure (1 microM-1 mM), (2) SSAO dependence of allylamine-induced effects using SSAO inhibitors (semicarbazide, 1 mM; MDL 72274-E, active isomer; MDL 72274-Z, inactive isomer; 100 microM), (3) the vasoactive effects of two other SSAO amine substrates, benzylamine and methylamine, and (4) the contribution of extracellular Ca(2+) to hypercontraction. Acrolein or allylamine but not H(2)O(2), benzylamine, or methylamine stimulated spontaneous and pharmacologically intractable hypercontraction in CABG blood vessels that was similar to clinical vasospasm. Allylamine-induced hypercontraction and blood vessel SSAO activity were abolished by pretreatment with semicarbazide or MDL 72274-E but not by MDL 72274-Z. Allylamine-induced hypercontraction also was significantly attenuated in Ca(2+)-free buffer. In isolated aorta of spontaneously hypertensive rat, allylamine-induced an SSAO-dependent contraction and enhanced norepinephrine sensitivity but not in Sprague-Dawley rat aorta. We conclude that acrolein generation in the blood vessel wall increases human susceptibility to vasospasm, an event that is enhanced in hypertension.
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PMID:Acrolein generation stimulates hypercontraction in isolated human blood vessels. 1709 30