Complex formation of allylamine with pyridoxal phosphate and inhibiton of GO-T and GP-T of human serum and rat liver by allylamine.
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Alanine Transaminase↗
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Altered protein secretion and extracellular matrix deposition is associated with the proliferative phenotype induced by allylamine in aortic smooth muscle cells.
Repeated cycles of allylamine-induced aortic injury in vivo modulate the proliferative potential of smooth muscle cells (SMCs) during serial propagation in vitro. This modulation may be partly mediated by disturbances in polyphosphoinositide metabolism which afford allylamine-treated cells a growth advantage over control cells [Cox, Murphy and Ramos (1990) Exp. Mol. Pathol. 53, 52-63]. The present studies were conducted to further evaluate the mechanisms which mediate the enhanced proliferative potential of allylamine cells. Cellular growth and/or [3H]thymidine incorporation into DNA were evaluated in control and allylamine cells seeded on plastic culture dishes or glass coverslips in the presence of 0.1, 1 or 10% fetal bovine serum (FBS). On either substrate, incubation in 0.1% FBS for 48 h inhibited DNA synthesis in cultures of both cell types, but the inhibitory response was more pronounced in allylamine cells. Subsequent challenge with 10% FBS increased thymidine incorporation to a greater extent in allylamine cells. Interestingly, enhanced DNA synthesis of allylamine cells was associated with increased cell numbers only when seeded on a glass surface. The enhanced growth rate on glass was not due to increased plating efficiency since comparable attachment rates were observed for both cell types. Reseeding of control cells on glass substrates pre-coated by allylamine cells afforded control cells a growth advantage comparable with that observed for allylamine cultures. Conditioned media from growth-arrested, as well as cycling cultures, of allylamine cells stimulated DNA synthesis in cultures of either cell type to a greater extent than conditioned media from control counterparts. In addition, the responsiveness of allylamine cells to secreted products was enhanced relative to that of control cells. Metabolic labelling studies revealed that the synthesis and/or secretion of 52, 46, 33 and 28 kDa proteins was enhanced in allylamine cultures relative to controls, and that the expression of two proteins of 30 and 31 kDa only occurred in allylamine cultures. We conclude that the enhanced growth response of allylamine cells is associated with both altered protein secretion and differential extracellular matrix deposition.
Allylamine↗
Comparative toxicity of allylamine and acrolein in cultured myocytes and fibroblasts from neonatal rat heart.
Allylamine is toxic to the cardiovascular system causing aortic, valvular and myocardial lesions. Acute toxicity is believed to involve metabolism of allylamine to highly reactive acrolein. Comparative toxicity of allylamine and acrolein was evaluated in cardiac fibroblasts and myocytes, which were obtained from neonatal rat hearts by a differential plating technique. Allylamine and acrolein were added directly to serum supplemented culture media (M199). Toxicity was assessed by measuring lactate dehydrogenase (LDH) release as an indicator of cell lysis. Spontaneous beating activity of myocytes, and adenosine 5' triphosphate (ATP) levels of myocytes and fibroblasts were also assessed. Cell lysis occurred 4 h after treatment of myocytes with 0.5 mM allylamine, whereas 20 mM allylamine was required to lyse fibroblasts. Acrolein, at a concentration of 0.05 mM, was equally toxic to fibroblasts and myocytes. Semicarbazide, a benzylamine oxidase inhibitor, protected myocytes from allylamine toxicity, but clorgyline, a monoamine oxidase inhibitor, was ineffective. Semicarbazide was ineffective against acrolein toxicity. Beating activity of myocytes was arrested by 0.05 mM acrolein and 0.5 mM allylamine, although 0.05-0.1 mM allylamine reduced beating activity. Myocyte ATP levels were reduced 4 h after exposure to 0.01 mM acrolein. Allylamine at 0.05 mM reduced ATP in myocytes, but 10 mM allylamine was required to reduce ATP in fibroblasts. ATP levels remained normal in myocytes exposed to 1 mM allylamine in the presence of 0.1 mM semicarbazide. The findings support the hypothesis that the toxicity of allylamine in cultured myocytes is dependent on its metabolism to acrolein, and that cytotoxicity may result from interference with energy production.
Acrolein↗
Differential processing of osteopontin characterizes the proliferative vascular smooth muscle cell phenotype induced by allylamine.
Repeated cycles of vascular injury by allylamine induce vascular lesions similar to those seen in atherosclerotic vessels, or following balloon catheterization. Vascular (aortic) smooth muscle cells harvested from allylamine-treated animals (i.e., allylamine cells) acquire a proliferative advantage relative to control counterparts that is associated with differential secretion and extracellular matrix sequestration of several proteins. In the present study, we have characterized two of these proteins (M(r) 52 and 36 kDa; pl 5.6 and 5.2, respectively) and their putative role in the expression of a proliferative phenotype. Because the physical properties of these proteins were comparable to those of osteopontin (OPN) and its thrombin-generated fragment(s), initial experiments were conducted to examine the expression and processing of OPN in this cell system. OPN mRNA expression was enhanced during early G1 cell cycle progression in allylamine cells relative to control counterparts. However, comparable amounts of OPN (M(r) 56, 52, and 50 kDa) were detected by Western analysis in media conditioned by both cell types using the OP-199 or B77-Rat1 antibodies to OPN. Allylamine cells, however, produced increased amounts of a 36 kDa protein recognized by the OP-199 antibody. Incubation of conditioned media from [35S]methionine-labeled allylamine cells with thrombin decreased the intensity of the 52 kDa protein, while increasing the intensity of a 36 kDa protein. RT-PCR analysis demonstrated expression of a 1.2 kb OPN band in both cell types consistent with the predicted size of OPN mRNA, suggesting that the 36 kDa fragment recognized by OP-199 in allylamine cells was likely not due to altered splicing of the OPN transcript. To determine if OPN and/or the 36 kDa fragment played a central role in the proliferative capacity of allylamine cells, the effect of an antibody to an alpha v integin subunit was examined. An antibody to the alpha v subunit, but not alpha 4, nullified the proliferative advantage of allylamine cells relative to control counterparts, suggesting that integrin-mediated signaling is a key feature of the proliferative phenotype of allylamine cells. We conclude that enhanced proteolytic cleavage of OPN may characterize the modulation of vascular SMCs to a more proliferative phenotype following chemical injury by allylamine.
Allylamine↗
Comparative toxicity of the cardiovascular toxin allylamine to porcine aortic smooth muscle and endothelial cells.
This study supports a recent hypothesis that the cardiovascular toxin, allylamine, is toxic to smooth muscle cells of large elastic arteries (aorta). Cultures of the porcine aortic smooth muscle, endothelial, and fibroblastic cells were exposed to varying concentrations of allylamine ranging from 5 microM to 340 microM. Monitored cytotoxic and cytolytic activities demonstrated that final concentrations of 60 microM allylamine decreased cell population viability of smooth muscle cells as much as 50%. Viability decreased approximately linearly with increasing concentrations of allylamine including spontaneous lysing of smooth muscle cells at 90 microM. Endothelial cells were more resistant to lower concentrations of allylamine requiring 90 microM to decrease cell population viability by 50%. In contrast, fibroblastic cells were very resistant to lower concentrations of allylamine. The specific lytic response of these cells in culture, measured by release of [3H]thymidine, gave findings parallel to the viability studies, i.e. at 100 microM allylamine smooth muscle cells demonstrated 75% specific lysis while endothelial cells showed 29%. Growth studies of cells surviving an 8-h exposure to allylamine indicate that surviving endothelial cells have better growth characteristics than surviving smooth muscle cells; both cell lines are also apparently injured at concentrations of allylamine much lower than the CT50. These studies show that of the cellular components of the vascular wall, smooth muscle cells appear to be the most sensitive to the toxic effects of allylamine.
Allylamine↗
Modulation of phosphoinositide metabolism in aortic smooth muscle cells by allylamine.
Aortic smooth muscle cells (SMC) modulate from a contractile to a proliferative phenotype upon subchronic exposure to allylamine. The present studies were designed to determine if this phenotypic modulation is associated with alterations in the metabolism of membrane phosphoinositides. 32P incorporation into phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bisphosphate (PIP2), and phosphatidic acid (PA) was lower by 31, 35, and 22%, respectively, in SMC from allylamine-treated animals relative to controls. In contrast, incorporation of [3H]myoinositol into inositol phosphates did not differ in allylamine cells relative to control cells. Exposure to dibutyryl (db) cAMP (0.2 mM) and theophylline (0.1 mM) reduced 32P incorporation into PIP and PIP2 in SMC from both experimental groups. Under these conditions, a decrease in [3H]myoinositol incorporation into inositol 1-phosphate was only observed in allylamine cells. The effects of db cAMP and theophylline in allylamine and control SMC correlated with a marked decrease in cellular proliferation. These results suggest that alterations in phosphoinositide synthesis and/or degradation contribute to the enhanced proliferation of SMC induced by allylamine. To further examine this concept, the effects of agents which modulate protein kinase C (PKC) activity were evaluated. Sphingosine (125-500 ng/ml), a PKC inhibitor, decreased SMC proliferation in allylamine, but not control cells. 12-O-Tetradecanoylphorbol-13-acetate (1-100 ng/ml), a PKC agonist, stimulated proliferation in control cells, but inhibited proliferation in cells from allylamine-treated animals. We conclude that allylamine-induced phenotypic modulation of SMC is associated with alterations in phosphoinositide metabolism.
Allylamine↗
Allylamine and acrolein toxicity in perfused rat hearts.
We assessed the in vitro toxicity of the cardiovascular toxicant allylamine, and its presumed in vivo metabolite, acrolein. In dose-response experiments, rat hearts perfused with allylamine (10-30 mM) or acrolein (0.01-3.0 mM) for 2 hr were assessed by standard histopathology and assay of creatine kinase (CK) in effluent. Allylamine-perfused hearts showed no grossly apparent functional abnormality except at 30 mM, but acrolein-perfused hearts beat irregularly and stopped rapidly (within 15 min at 0.01-0.3 mM, and by 5 min at 3.0 mM). Extensive contraction band necrosis and an apparently dose-dependent loss of CK were evident in allylamine-perfused hearts, whereas acrolein perfusion resulted in no morphologic lesions or CK loss. Additional experiments, however, suggest that acrolein perfusion results in denaturation of CK, making it undetectable in effluent. In hemodynamic preparations of rat hearts perfused with 10 mM allylamine, contraction band necrosis and extensive mitochondrial changes were seen by electron microscopy. Allylamine caused a marked rise in left ventricular pressure at 5 and 10 min, followed by a slow decline to a markedly depressed level at the end of 2 hr. End diastolic pressure rose steadily throughout the 2-hr perfusion. Coronary flow was similar in control and allylamine-perfused hearts for 1 hr, but then declined slowly. These experiments suggest that vascular spasm or alterations in coronary flow are not the cause of allylamine-induced myocardial damage. Allylamine's toxic effect on myocardium in this model may be mediated through its metabolism and subsequent injurious intracellular events.
Acrolein↗
Semicarbazide protection from in vivo oxidant injury of vascular tissue by allylamine.
Allylamine is a specific cardiovascular toxin that causes vascular and myocardial lesions. Previous studies showed that allylamine-induced chronic lesions are markedly reduced by semicarbazide, an inhibitor of semicarbazide-sensitive amine oxidase (SSAO), and that allylamine is metabolized to the aldehyde, acrolein, by SSAO. We hypothesized that inhibitors of SSAO might reduce the acute cardiovascular toxicity of allylamine. To test our hypothesis, we fed 150 mg/kg allylamine to semicarbazide-pretreated (3 h; 98 mg/kg) rats. Animals were sacrificed 1 h after allylamine treatment. Aorta, epicardium, and endocardium were assayed for SSAO, glutathione peroxidase, catalase, thiol status and lipid peroxidation. SSAO activity was decreased significantly in aorta, epicardium and endocardium. Activity was 30-times higher in aorta than in epicardium and endocardium. A striking decrease in malonaldehyde level (lipid peroxidation) was found in aorta of pretreated rats as compared to allylamine-only treated rats. The reduction of free-SH content in aortic mitochondria was also attenuated in pretreated rats. Changes were not so marked in epicardium and endocardium. These results suggest that in vivo pretreatment with semicarbazide at least partially protects aortic mitochondria from allylamine toxicity. The mechanism can be explained on the basis of the fact that semicarbazide inhibits acrolein formation in allylamine-treated rats.
Allylamine↗
Lipid peroxidation and oxidative stress during acute allylamine-induced cardiovascular toxicity.
Allylamine is an aliphatic amine that causes vascular lesions in aorta and medium-sized arteries. This primary amine has been shown to be metabolized to acrolein both in vivo and in vitro. Acrolein may cause allylamine's toxic effects, since it acts as a strong peroxidizing agent itself; in addition, deamination of allylamine is accompanied by production of hydrogen peroxide. To investigate the relative roles of oxidative stress and lipid peroxidation in allylamine intoxication, we conducted an acute in vivo time-course study following administration of allylamine (150 mg/kg) to rats by gavage. Animals were sacrificed at 1, 3 and 5 h after allylamine treatment, and subcellular fractions of aorta, epicardium and endocardium were assayed for enzymes of the oxidant defense system and thiol (-SH) status, capacity for lipid peroxidation, and .OH radical generation. Results suggest that in vivo treatment with allylamine causes preferential damage to aortic mitochondria. A marked depletion of total and free -SH content was found in aorta, epicardium and endocardium, with a striking increase in the formation of thiobarbiturate-reactive substance by aortic mitochondria at all time points. A significant increase in the capacity to generate .OH was found in aorta (with lesser increases in epicardium and endocardium) after allylamine treatment. Levels of defense system enzymes were not consistently altered, however. In a totally in vitro experiment, liposomes incubated with acrolein (0.2-2 mM) showed a proportional increase in lipid peroxidation of liposomal membrane. A likely basis of allylamine's cardiovascular toxicity is acrolein-induced lipid peroxidation, especially in mitochondria.
Allylamine↗
Ethanol ingestion on allylamine-induced experimental subendocardial fibrosis.
Effects of ethanol ingestion on allylamine-induced subendocardial fibrosis of the myocardium and intimal hyperplasia of the intramyocardial coronary artery were investigated in male Wistar rats. The toxic effect of allylamine is ascribed to acrolein produced from allylamine by benzylamine oxidase. Animals were forced to drink allylamine solution for 12 weeks. Incidence and size of subendocardial fibrosis were examined, and the lesions of the intramyocardial artery were scrutinized. Effects of ethanol on the systemic blood pressure and benzylamine oxidase activity were investigated in another experiment. Treatment with allylamine resulted in subendocardial fibrosis (size = 4.2%) in 4 of 12 rats. The incidence of fibrosis was increased (up to 6/12) and the area of fibrosis was augmented (to 6.8%) in animals additionally treated with epinephrine. The lesions in the intramyocardial vasculature were also augmented. Ethanol ingestion reduced allylamine-induced subendocardial fibrosis and intramyocardial coronary lesions. The effects were significant in animals additionally treated with epinephrine. Systemic blood pressure and benzylamine oxidase activity were not significantly affected by allylamine or by ethanol. The vasodilatory effect of ethanol may have prevented the development of microvascular spasm induced by allylamine.
Alcohol Drinking↗
Allylamine cardiotoxicity--IV. Metabolism to acrolein by cardiovascular tissues.
Acrolein was detected in homogenates of rat aorta, lung, skeletal muscle, and heart incubated with allylamine. Semicarbazide and hydralazine, which protect against allylamine-induced myocardial injury in vivo in the rat, inhibited acrolein formation. Hydrogen peroxide, a product of oxidative deamination, was generated during allylamine oxidation. Acrolein was also produced from allylamine by bovine plasma amine oxidase and porcine kidney diamine oxidase but not by rat liver or brain homogenates. Allylamine competitively inhibited benzylamine oxidation in rat aorta, but pargyline-sensitive monoamine oxidase was not involved in acrolein production. The high activity in aorta, the competition with benzylamine, and the sensitivity to benzylamine oxidase inhibitors indicate that benzylamine oxidase is the active enzyme in oxidizing allylamine. The formation of acrolein may be the basis of the cardiotoxic action of allylamine.
Acrolein↗
Binding of [14C] allylamine to isolated mitochondria from rat heart and aorta.
This study demonstrates specific and saturable binding of [14C] allylamine to mitochondria derived from rat aorta and heart. Specific binding is linear with respect to mitochondrial concentration and has a pH optimum of 7.0. Saturation isotherms reveal anomalous kinetics of specific binding on heart mitochondria with a high affinity site (KD 16 nM) and a lower affinity site (KD 80 nM); Scatchard plots have a common intercept. Exhaustive flow dialysis in the presence of SDS demonstrates that as much as 23.5% of bound radioactive moieties in aorta mitochondria are covalently bound, and as much as 42.6% are covalently bound in heart mitochondria. Hydrolysis of heart mitochondria with phospholipase C markedly enhances saturation of [14C] allylamine, and greatly increases the quantity of covalently bound radioactive ligand. Phospholipase C hydrolysis of heart mitochondria increased monoamine oxidase B activities and unmasked a small amount of benzylamine oxidase activity, whereas hydrolysis of mitochondria with phospholipases A2 and D diminish MAO-B activity. The monoamine oxidase B inhibitor, deprenyl, significantly reduced both specific and covalent binding of the 14C-activity from [14C] allylamine to phospholipase hydrolyzed mitochondria. The benzylamine oxidase inhibitor, phenelzine, significantly decreased specific binding but had no effect on the degree of covalent binding of [14C] allylamine to phospholipase C hydrolyzed mitochondria. The benzylamine oxidase inhibitor, semicarbazide, had no effect in inhibiting [14C] allylamine binding. Covalent binding of 14C-moiety from [14C] allylamine to mitochondria--which express specific binding sites for the [14C] allylamine--and inhibition of binding by monoamine oxidase inhibitors, suggest the formation of highly reactive intermediates.
Allylamine↗
Inhibition of rat heart mitochondrial electron transport in vitro: implications for the cardiotoxic action of allylamine or its primary metabolite, acrolein.
Allylamine (3-aminopropene) is a specific cardiac toxicant that causes aortic, valvular and myocardial lesions in many species. Myocardial necrosis can be observed 24 h after a single dose. Acute toxicity is believed to involve metabolism of allylamine to highly reactive acrolein (2-propenal). Allylamine has been shown to bind to mitochondria from aorta and heart, suggesting that the subcellular site of injury is at or near the mitochondrion. The present investigation compared the effect of allylamine and its primary metabolite, acrolein, on electron transport and oxidative phosphorylation in mitochondria isolated from rat heart (RHM). Both compounds weakly inhibited mitochondrial electron transport with either the combination of glutamate, malate, and malonate (GMM, NADH-linked) or succinate as substrate. Comparisons of the slopes of concentration-effect regression (range of concentrations tested, 0.20-2.0 mM) lines showed acrolein to have significantly greater inhibitory effects than allylamine (range of concentrations tested, 0.22-6.4 mM) on GMM oxidation, while no significant difference in the abilities of the compounds to inhibit succinate oxidation were observed, indicating site preferences for inhibitory action. The addition of an uncoupling agent could not reverse inhibition with either substrate system. These results indicate that both the parent compound and its proposed metabolite primarily inhibit electron transport with little direct effect on the coupling mechanism. The State III EC50 (effective concentrations for 50% inhibition of control mitochondrial enzyme activities) for allylamine (2.29 mM with succinate as substrate and 1.22 mM with GMM) and acrolein (0.80 mM with succinate as substrate and 0.39 mM with GMM) are probably too great to invoke the direct action of either the parent compound or its oxidized metabolite on mitochondrial electron transport as a primary mechanism in the cardiotoxic action of allylamine.
Acrolein↗
Role of benzylamine oxidase in the cytotoxicity of allylamine toward aortic smooth muscle cells.
In this study we demonstrate that by inhibiting benzylamine oxidase (BzAO) with either semicarbazide or phenelzine, aortic smooth muscle cells (ASMCs) are protected from cytolethal injury by the cardiovascular toxin allylamine. We find that although both semicarbazide and phenelzine inhibit BzAO or ASMCs grown in vitro, phenelzine is the more effective inhibitor. We further demonstrate that although semicarbazide--at concentrations inhibiting BzAO--protects ASMCs from cytolethal concentrations of allylamine, it does not fully protect ASMCs from sublethal injury as assessed by [3H]uridine uptake. In contrast, phenelzine appears to afford complete protection of ASMCs from allylamine injury. Although semicarbazide and phenelzine pretreatment does not interfere with [14C]allylamine uptake by ASMCs, retention time of the 14C-moiety from radiolabeled allylamine is less in pretreated ASMCs. Subcellular distribution studies of ASMCs exposed to [14C]allylamine demonstrate that inhibiting BzAO activity in ASMCs results in marked derangement of the distribution pattern of 14C-moiety in subcellular fractions of ASMCs, with 14C-moiety not localized to mitochondrial/endoplasmic reticulum enriched fractions.
Allylamine↗
Mechanism of reaction of allylamine with the quinoprotein methylamine dehydrogenase.
Allylamine did not serve as an efficient substrate for methylamine dehydrogenase (EC 1.4.99.3) in a steady-state assay of activity and appeared to act as a competitive inhibitor of methylamine oxidation by methylamine dehydrogenase. Transient kinetic studies, however, revealed that allylamine rapidly reduced the tryptophan tryptophylquinone (TTQ) cofactor of methylamine dehydrogenase. The rate of TTQ reduction by allylamine was 322 s-1, slightly faster than the rate of reduction by methylamine. These data were explained by a kinetic mechanism in which allylamine and methylamine are alternative substrates for methylamine dehydrogenase. The apparent competitive inhibition by allylamine is due to a very slow rate of release of the aldehyde product, 0.28 s-1, relative to a rate of 18.6 s-1 for the release of the aldehyde product of methylamine oxidation. A reaction mechanism is proposed for the oxidative deamination of allylamine by methylamine dehydrogenase. This mechanism is discussed in relation to the reaction mechanisms of topa-bearing quinoprotein amine oxidases, the flavoprotein monoamine oxidase and the mammalian semicarbazide-sensitive amine oxidase.
Allylamine↗
Allylamine cardiovascular toxicity: VI. Subcellular distribution in rat aortas.
The cardiovascular toxin allylamine (3-aminopropene) has been shown to concentrate in elastic and muscular tissues. In this study the 14C-moiety of [14C]allylamine was traced in aortas of adult Sprague-Dawley rats after intravenously injecting 30 microCi of [14C]allylamine (spec. act. = 0.4 mCi/mM). At 5, 10, 15 and 20 min after injection 33.3-29.8% of the 14C-moiety was sequestered in aortas; at 30 min 16.8% was still present. Subcellular fractionation of the postnuclear supernatant by isopycinic centrifugation in sucrose demonstrated that 5 min after administration of [14C]allylamine, the 14C-moiety displayed a modal density peak of 1.20 g/ml. Similar activities were observed up to 30 min exposure. This modal density was similar to the distribution pattern of mitochondria based on analysis of malate dehydrogenase activities. As early as 20 min post-exposure, mitochondrial malate dehydrogenase activities of aortic mitochondria decreased, while cytosolic malate dehydrogenase activities increased, suggesting mitochondrial membrane perturbation. We suggest that the subcellular site for allylamine injury to the aorta is the mitochondrion.
5'-Nucleotidase↗
Effects of naftifine and terbinafine, two allylamine antifungal drugs, on selected functions of human polymorphonuclear leukocytes.
Many antimycotic agents negatively affect the natural immune response. Typically, these drugs impair polymorphonuclear leukocyte (PMN) production of superoxide anion, chemotaxis, or the killing of pathogens. Allylamines are a new class of antimycotic compounds with a new mechanism of antifungal action, i.e., inhibition of the fungal squalene epoxidase. The trial that we describe aimed to evaluate the effects of two allylamines, terbinafine and naftifine, on selected functions of PMNs, i.e., superoxide anion production, chemotaxis, and killing of Candida albicans blastospores. Terbinafine and naftifine on their own did not affect superoxide anion production when they were added to PMNs. When PMNs were preincubated with allylamines and were then stimulated by N-formyl-Met-Leu-Phe or phorbol 12-myristate 13-acetate, superoxide anion production was increased (priming effect). Since intracellular free calcium (Ca2+i) is involved in the control of superoxide anion production, we evaluated the effects of the allylamines on the Ca2+i concentration ([Ca2+]i). In the presence of terbinafine or naftifine, the [Ca2+]i increased in a dose-dependent manner; the source of Ca2+i was not extracellular since it was not affected by extracellular calcium chelation with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. In the presence of terbinafine or naftifine, chemotaxis of PMNs was not impaired. Terbinafine and naftifine slightly but significantly increased the killing of C. albicans blastospores (P < 0.05 at 10 and 100 microM). In conclusion, in contrast to imidazole-like drugs, the allylamine antimycotic compounds terbinafine and naftifine enhance selected functions of PMNs.
Allylamine↗
Myocardial mechanics in allylamine-induced myocardial fibrosis.
To examine the effect of fibrosis on myocardial mechanics, we studied isolated left ventricular papillary muscles from 18 rats given 0.1% allylamine, an agent known to cause myocardial fibrosis, in drinking water for 4-8 wk. Six control rats were given tap water. Left ventricular hydroxyproline concentration was higher in the allylamine-treated group [3.47 +/- 2.12 vs. 2.10 +/- 0.66 (SD) micrograms/mg dry wt; P less than 0.01]. Because of variable and heterogeneous involvement of the ventricle by fibrosis, preparations from allylamine-fed rats were divided into two subgroups; data from four papillary muscles with more than 25% fibrosis by point counting (AL-B group) were compared with eight control muscles from nonallylamine-treated rats. A third subgroup of nine muscles from allylamine-treated rats but with normal left ventricular hydroxyproline concentration and fibrosis as determined by point counting served as another control group (AL-A) for the evaluation of effects of allylamine not due to fibrosis. Myocardial fiber diameters of AL-B preparations were significantly larger than other groups (controls, 12.1 +/- 1.7 microns; AL-A group, 12.7 +/- 1.7 microns; AL-B group, 18.0 +/- 1.2 microns; P less than 0.01). Passive and active stiffness constants in AL-B muscles were significantly increased compared with control and AL-A preparations (P less than 0.05). Electromechanical delay plus time to peak tension and the time for tension to fall from its peak to one-half of that value at the peak of the length-tension curve were significantly prolonged in AL-B muscles.(ABSTRACT TRUNCATED AT 250 WORDS)
Allylamine↗