Role of glutathione S-transferase 8-8 in allylamine resistance of vascular smooth muscle cells in vitro.

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.     

Inhibition of mitochondrial monoamine oxidase of the rat uterus and liver by clorglyine, pargyline and harmine.

The inhibition of mitochondrial monoamine oxidase (MAO) activity in rat uterus and liver by clorgyline, harmine and pargyline is reported. MAO activity is shown to be present in mitochondria of the rat uterus by rate-zonal centrifugation on a sucrose gradient. Each inhibitor was tested for its ability to inhibit the oxidation of tyramine (TYN). 5-hydroxytryptamine (5HT) and β-phenylethylamine (PEA). TYN deamination by uterine organelles was inhibited in two distinct steps by clorgyline and harmine, whereas in liver mitochondria only clorgyline manifested the two-step inhibition pattern. Elimination of TYN oxidation by pargyline occurred as a single sigmoid curve. Single sigmoid inhibition curves with all three inhibitors were also observed for 5HT and PEA in both tissues. For uterine and liver mitochondria the relative effectiveness of each inhibitor toward the oxidation of the three substrates was as follows: (a) clorgyline and harmine. 5HT > TYN > PEA; (b) pargyline. PEA > TYN > 5HT. It was concluded that, as has been previously demonstrated in liver, two forms of MAO exist in mitochondria isolated from the rat uterus. This conclusion is based upon (1) the biphasic inhibition of TYN deamination by clorgyline and harmine and (2) the reversal of the relative inhibitory effectiveness of the two classes of MAO inhibitors, (a) clorgyline and harmine and (b) pargyline, toward the three substrates. Semicarbazide did not inhibit the oxidation of any of the substrates. This indicates that the mitochondrial enzyme activity from the uterus, as in the liver, is a true monoamine oxidase.     

Properties of a semicarbazide-sensitive amine oxidase in human umbilical artery

The metabolism of some aromatic amines by amine oxidase activities in human umbilical artery homogenates has been studied. The inhibitory effects of clorgyline showed that 5-hydroxytryptamine (5-HT) and tryptamine, 1 mM, were predominantly substrates for monoamine oxidase (MAO) type A, whereas MAO-A and B were both involved in the metabolism of beta-phenylethylamine (PEA), 100 microM, and tyramine, 1 mM. About 20-30% of tyramine and PEA metabolism was resistant to 1 mM clorgyline, but sensitive to inhibition by semicarbazide, 1 mM, indicating the presence of a semicarbazide-sensitive amine oxidase (SSAO). Benzylamine, 1 mM, appeared to be metabolized exclusively by SSAO with a Km (161 microM) at pH 7.8 similar to that found for SSAO in other human tissues. Tyramine and PEA were relatively poor substrates for SSAO, with very high apparent Km values of 17.6 and 13.3 mM, respectively, when determined in the presence of clorgyline, 10(-3) M, added to inhibit any metabolism of those amines by MAO activities. However, kinetic studies with benzylamine indicated that clorgyline, 10(-3) M, also appears to inhibit SSAO competitively such that the true Km values for tyramine and PEA may be about 60% of those apparent values given above. No evidence for the metabolism of 5-HT or tryptamine by SSAO was obtained. The aliphatic amine methylamine was recently shown to be a specific substrate for SSAO in umbilical artery homogenates. We have used benzylamine and methylamine as SSAO substrates in histochemical studies to localize SSAO in tissue sections.(ABSTRACT TRUNCATED AT 250 WORDS)     

山楂叶总黄酮对血管内皮细胞氧化损伤的保护作用

目的：研究溶血磷脂酰胆碱（LPC）和氧自由基（OFR）对血管内皮细胞（VEC）的损伤，及山楂叶总黄酮对损伤后VEC的保护作用。方法：以体外培养的小牛主动脉内皮细胞为材料，测定LPC或黄嘌呤和黄嘌呤氧化酶（X XO）与VEC的作用，以及加入不同浓度的山楂叶总黄酮后，对细胞乳酸脱氢酶（LDH）的泄漏量，细胞丙二醛（MDA）和一氧化氮（NO）的含量及对细胞增殖的影响。结果：当VEC与LPC（5ug/ml)或黄嘌呤和黄嘌呤氧化酶（X XO）（10umol/L 200umol/L)共孵育24h时，表现为细胞LDH泄漏量增多，细胞内MDA含量升高，NO含量减少，细胞生长减缓，存活率下降；当加入不同浓度的山楂叶总黄酮后则可明显抑制细胞LDH的泄漏量，降低MDA含量，提高NO的含量，细胞生长正常，存活率提高，结论：山楂叶总黄酮能通过抗氧化途径对LPC与X XO所致VEC的氧化损伤起保护作用。     

The metabolism of aminoacetone to methylglyoxal by semicarbazide-sensitive amine oxidase in human umbilical artery.

The aliphatic amine aminoacetone has been described previously as a product of mitochondrial metabolism of threonine and glycine. Here, aminoacetone is shown to be deaminated to methylglyoxal by supernatants obtained by low speed centrifugation (600 g/10 min) of human umbilical artery homogenates, and also by membrane fractions isolated by high speed centrifugation (105,000 g/60 min) of these supernatants. Metabolism of 100 microM aminoacetone was completely inhibited by 1 mM propargylamine and MDL 72145, drugs which are capable of inhibiting the membrane-bound semicarbazide-sensitive amine oxidase (SSAO) activity found in vascular smooth muscle cells, whereas 1 mM pargyline and deprenyl which are inhibitors of monoamine oxidase, were without inhibitory effect. Estimated kinetic constants (at pH 7.8) for aminoacetone metabolism were Km = 92 microM; Vmax = 270 nmol/hr/mg protein. In addition, aminoacetone was a competitive inhibitor (Ki = 83 microM and 128 microM in low speed supernatants and high speed membrane fractions, respectively) of [14C]benzylamine metabolism by SSAO in this tissue. Aminoacetone would appear to be an endogenously occurring amine with a Km for metabolism by SSAO far lower than other aliphatic and aromatic biogenic amines examined previously as potential physiological substrates for the human vascular enzyme and possible implications of this are discussed.     

Semicarbazide-sensitive amine oxidase from the smooth muscles of dog aorta and trachea: activation by the MAO-A inhibitor clorgyline.

Semicarbazide-sensitive amine oxidase (SSAO) has been identified in the dog trachea and aorta smooth muscles. The dog SSAO is blocked by hydrazine inhibitors. SSAOs from several different vascular smooth muscle sources, such as the rat and bovine aorta, and human umbilical artery, as well as the bovine plasma, are insensitive to the MAO-A inhibitor clorgyline; the dog SSAO on the other hand is significantly activated by clorgyline. Two methods, i.e. radioenzymatic and fluorometric methods, have been applied to substantiate this clorgyline-induced activation. The activation was detected with respect to the deamination of different substrates, such as benzylamine, beta-phenylethylamine and longer carbon chain aliphatic amines, but not with respect to methylamine. The clorgyline effect is reversible, non-competitive and time-independent; it depends on electrostatic and hydrophobic interactions between clorgyline and hydrophobic regions of the dog SSAO enzyme.     

Metabolism of amines in the isolated perfused mesenteric arterial bed of the rat.

1. Semicarbazide-sensitive amine oxidase (SSAO) activity has been demonstrated in the isolated mesenteric arterial bed of the rat in vitro by studying the metabolism of benzylamine (Bz) and tyramine (Tyr) added to the perfusing fluid. 2. Pretreatment of rats with (E)-2-(3',4'-dimethoxyphenyl)-3-fluoroallylamine (MDL72145), a potent inhibitor of SSAO in rat mesenteric blood vessels, reduced the amount of metabolites, following the addition of Bz (25 microM) or Tyr (100 microM) to the perfusing fluid, by 83% and 52% respectively. Inactivation of monoamine oxidase type A (MAO-A) by the addition of clorgyline (10 microM) to the perfusing fluid, had little effect on the appearance of metabolites from Tyr. 3. The presence of 3 microM cocaine in the perfusing fluid increased the amount of metabolites produced from Tyr. 4. The metabolites of Tyr appearing in the perfusion fluid from control preparations were 85% p-hydroxyphenylacetic and the remainder consisted of a mixture of p-hydroxyphenylacetaldehyde and, possible, p-hydroxyphenylethanol. 5. The metabolism of Tyr by homogenates of the rat mesenteric vascular bed was carried out by SSAO (60%) and MAO-A (40%) with very little contribution from MAO-B. Homogenates from rats pretreated with MDL 72145 showed metabolism of Tyr by MAO-A only. 6. These data indicate that SSAO is capable of metabolizing amines present in the fluid perfusing blood vessels to metabolites that are readily released. Histochemical evidence has shown that whereas MAO-A is present in the mitochondria of smooth muscle cells and nerve endings, SSAO is located in the plasma membrane of the smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular smooth muscle cells: a major source of the semicarbazide-sensitive amine oxidase of the rat aorta

Several methods have been used to study the distribution of the semicarbazide-sensitive amine oxidase (SSAO) within the wall of the rat aorta. After separation of the smooth muscle-containing layers of the tunica media from the connective tissue of the tunica adventitia, much higher specific enzyme activity (measured with 1 microM benzylamine) was found in homogenates of the media than of adventitia. Similar results were obtained for MAO-A (with 1 mM 5-HT as substrate). SSAO activity was also considerably higher in homogenates of cells (predominantly smooth muscle) isolated from medial tissue by enzymatic dissociation with collagenase and elastase compared with homogenates of cells (mostly of connective tissue origin) from the adventitia. Histochemical staining resulting from SSAO activity (with benzylamine as substrate) occurred predominantly and intensely over the tunica media in rat aortic sections, although some occasional staining of adventitial sites was also observed. Staining was prevented by the SSAO inhibitors hydroxylamine (1 microM) and semicarbazide (1 mM), but not by the MAO inhibitor, clorgyline (1 mM). These results indicate that SSAO is associated predominantly, although not exclusively, with the smooth muscle cells in the rat aorta. Our findings that beta-aminopropionitrile (BAPN) is a reversible, competitive inhibitor (Ki around 2 X 10(-4)M) of SSAO, in contrast to the irreversible inhibition of the connective tissue lysyl oxidase by BAPN reported by others, provides further evidence that these enzymes are not identical.     

The influence of amine metabolizing enzymes on the pharmacology of tyramine in the isolated perfused mesenteric arterial bed of the rat.

1. The pressor response to the infusion of tyramine (Tyr) into the isolated perfused mesenteric arterial bed of the rat has been studied at both a low and a high dose (0.2 and 2.0 mumol) and the effect of monoamine oxidase-A (MAO-A) and semicarbazide-sensitive amine oxidase (SSAO) inhibition was examined. Very little MAO-B activity is found in homogenates of this tissue when Tyr is used as substrate. 2. Inhibition of SSAO by treating rats with 1 mg kg-1 (E)-2-(3',4'-dimethoxyphenyl)-3-fluoroally lamine (MDL 72145) 1 h before dissection, had no significant effect on the maximum pressure attained or the area under the curve (AUC) of the response to both low and high doses of Tyr. Inhibition of MAO-A, by inclusion of 10 microM clorgyline in the perfusing fluid, resulted in no significant potentiation at both low or high doses of Tyr. The inhibition of both these enzymes together substantially increased the AUC of the pressor response. 3. Cocaine (3 microM) significantly potentiated the responses to adrenaline (Ad). At this dose, cocaine significantly reduced the peak height and the AUC of the responses to both doses of Tyr. 4. Inhibition of extraneuronal uptake mechanisms with corticosterone (29 microM) did not potentiate the response to Ad and did not significantly alter the response to Tyr (low dose). 5. The effects of MDL 72145 and clorgyline on the directly acting amine, Ad, were studied. MDL 72145 caused a small but significant increase in the EC50 and in the maximum response to Ad, whilst clorgyline (10 microM) increased the EC50 value slightly and decreased the maximum response.     

Methylamine metabolism to formaldehyde by vascular semicarbazide-sensitive amine oxidase.

The capacity of the vascular enzyme, semicarbazide-sensitive amine oxidase (SSAO), to metabolize methylamine to the potentially toxic product, formaldehyde, was tested using rat aortic homogenates and purified porcine aortic SSAO. Formaldehyde production in incubations of enzyme source with methylamine (1 mM) was detected by high performance liquid chromatography and product was confirmed by desorption chemical ionization mass spectrometry (DCI-MS). Inhibitor studies using the specific SSAO inhibitor semicarbazide and the monoamine oxidase inhibitor pargyline indicate that SSAO is responsible for metabolism of methylamine to formaldehyde. These results suggest the possibility that elevated methylamine found in several pathologic states (such as uremia and diabetes mellitus), or generated from exogenous sources, could result in overproduction of formaldehyde in tissues with high SSAO activity, especially blood vessels.     

Inhibition of MAO‐A Activity Enhances Behavioural Activity of Rats Assessed Using Water Maze and Open Arena Tasks

Abstract: To determine if the inhibition of MAO‐A and/or MAO‐B activities can influence cognitive processes in adult rats, we analysed whether chronic treatment with clorgyline, l‐deprenyl and pargyline could modify the performance of adult rats in a modified version of the water maze task. The effects of these treatments on locomotor activity and enzyme activities were also assessed. Rats were treated for 24 days with clorgyline (0.2 mg/kg), l‐deprenyl (0.25 mg/kg) and pargyline (1 or 10 mg/kg). The treatments were started two weeks before the water maze experiment and continued until the end of testing. The rats were trained to find a submerged platform (6 days:1 trial/day; 7 th day: probe trial). Over the next three days, locomotor activity was assessed in an open arena. Treatments with clorgyline (MAO‐A inhibitor), l‐deprenyl (MAO‐B inhibitor) and pargyline (non‐selective MAO inhibitor) did not improve the finding of the hidden platform, when compared to treatment with saline, but significantly increased the swimming speed of the rats. The different treatments, when compared to saline, failed to modify the distance covered and the number of groomings performed in the open arena. However, clorgyline and pargyline, 10 mg/kg, increased the number of faecal boli and clorgyline enhanced the number of rearings made when compared to saline, l‐deprenyl and pargyline, 10 mg/kg. These results indicate that near total inhibition of MAO‐A by clorgyline and pargyline as assessed by MAO activity measurement induces an increase in locomotor activity but that inhibition of MAO‐A or MAO‐B, either alone or combined, does not facilitate spatial learning in adult rats.     

Inhibition of MAO-A activity enhances behavioural activity of rats assessed using water maze and open arena tasks.

To determine if the inhibition of MAO-A and/or MAO-B activities can influence cognitive processes in adult rats, we analysed whether chronic treatment with clorgyline, 1-deprenyl and pargyline could modify the performance of adult rats in a modified version of the water maze task. The effects of these treatments on locomotor activity and enzyme activities were also assessed. Rats were treated for 24 days with clorgyline (0.2 mg/kg), 1-deprenyl (0.25 mg/kg) and pargyline (I or 10 mg/kg). The treatments were started two weeks before the water maze experiment and continued until the end of testing. The rats were trained to find a submerged platform (6 days: I trial/day; 7 th day: probe trial). Over the next three days, locomotor activity was assessed in an open arena. Treatments with clorgyline (MAO-A inhibitor), 1-deprenyl (MAO-B inhibitor) and pargyline (non-selective MAO inhibitor) did not improve the finding of the hidden platform, when compared to treatment with saline, but significantly increased the swimming speed of the rats. The different treatments, when compared to saline, failed to modify the distance covered and the number of groomings performed in the open arena. However, clorgyline and pargyline, 10 mg/kg, increased the number of faecal boli and clorgyline enhanced the number of rearings made when compared to saline, 1-deprenyl and pargyline, 10 mg/kg. These results indicate that near total inhibition of MAO-A by clorgyline and pargyline as assessed by MAO activity measurement induces an increase in locomotor activity but that inhibition of MAO-A or MAO-B, either alone or combined, does not facilitate spatial learning in adult rats.     

前胡丙素对牛主动脉平滑肌细胞增殖的抑制作用

目的:探讨前胡丙素(pra-C)对牛主动脉平滑肌细胞(SMC)增殖的影响 方法:细胞DNA的合成量由~3H-胸腺嘧啶核苷[~3H]TdR)掺入试验测定,应用流式细胞术测定细胞周期,用乳酸脱氢酶活性测定观察药物的毒性.结果:无论有无血管紧张素Ⅱ(AngⅡ),在0.01μmol/L到10μmol/L浓度范围内,pra-C均可呈浓度依赖性地抑制SMC的增殖,抑制作用主要与阻止细胞进入有丝分裂期有关,而与细胞毒性无关.结论:pra-C能够完全阻断Aug Ⅱ诱导SMC的增殖效应,部分阻止小牛血清诱导的细胞分裂,这对于血管增生性疾病的防治有重要意义.     

Inhibition of semicarbazide-sensitive amine oxidase by monoamine oxidase B inhibitors from the oxazolidinone series

The purpose of the present work was to study the semicarbazide-sensitive amine oxidase (SSAO) inhibitory properties of MD 240931 and MD 240928 (the two enantiomers of MD 780236) as well as those of the corresponding primary amines, MD220662 and MD220661, in rat heart and aorta. MD240928 and MD240931 are rather weak SSAO inhibitors, MD 240931 being more potent than MD 240928. Of the four compounds studied, the most potent inhibitor of SSAO is MD 220662, its IC50 value ranging from 2.10(-6) to 6.10(-6)M. The SSAO inhibitory potency of this compound does not change significantly with the time of preincubation in both the absence and presence of clorgyline (10(-4)M). MD 220661 is also an inhibitor of SSAO; however, its SSAO inhibitory potency, which without preincubation is comparable to that of MD 220662, does decrease with the time of preincubation to the same extent in both the absence and presence of clorgyline (10(-4)M). These results suggest that MD 220661 is not only an inhibitor of SSAO, but is also a substrate of the enzyme.     

The role of plasma semicarbazide-sensitive amine oxidase in allylamine and beta-aminopropionitrile cardiovascular toxicity: mechanisms of myocardial protection and aortic medial injury in rats

Allylamine (AA; 3-aminopropene) and beta-aminopropionitrile (betaAPN) combined treatment (AA + betaAPN) results in myocardial protection from AA-induced subendocardial necrosis and a rapid and extensive aortic medial smooth muscle injury in rats. To determine the mechanisms of AA + betaAPN-induced vascular toxicity, cardiovascular parameters were monitored during a 10-day exposure by gavage in male Sprague-Dawley rats (180-200 g). Water intake and urine output were measured in rats treated with water, AA (100 mg kg(-1) body weight), betaAPN (1 g kg(-1) body weight), and AA + betaAPN for 10 days in metabolic cages. Plasma and urine samples were analyzed for blood urea nitrogen, CO2, creatinine, hematocrit, electrolytes (Na+, K+, Cl-), and osmolality. Heart and plasma semicarbazide-sensitive amine oxidase metabolic capacity (SSAO)was also measured following 1, 3 and 10 days of treatment. Following 10 day exposure to control or AA + betaAPN treatment, thoracic aortic rings (approximately 3 mm) were removed, and aortic reactivity to contractile and relaxant agonists was tested in vitro. In addition, cultured rat aorta vascular smooth muscle cells or rat heart beating myocytes were exposed to various concentrations of AA and betaAPN or AA metabolites and betaAPN to test for synergism in vitro. Several of the changes in in vivo cardiovascular parameters were shared, both in direction and magnitude, between the AA + betaAPN and the AA alone or the betaAPN alone treatments. This suggests that these effects (e.g. increased water intake and urine flow, decreased hematocrit, decreased heart and plasma SSAO metabolic capacity) were dependent on an AA alone or a betaAPN alone effect and were not AA + betaAPN specific effects. Significant inhibition of plasma and heart SSAO metabolic capacity occurred in the betaAPN alone and the AA + betaAPN treatments, but not in the AA alone treatment. Aortic rings from AA + betaAPN treated rats were contracted significantly less than anatomically-matched control rat aortic rings by 100 mM potassium chloride or by 10 microM norepinephrine. BetaAPN offered substantial protection against AA cytotoxicity in cultured vascular smooth muscle cells and beating myocytes, but did not alter the cytotoxicity of AA metabolites (i.e. acrolein, H2O2, or ammonia) in vascular smooth muscle cells as determined by the MTT viability assay. Overall, these data suggest that myocardial protection from AA injury that occurs in the combined AA + betaAPN treatment is likely due to inhibition of plasma SSAO. This may result in an increase in the AA dose accumulation and metabolism in the aorta leading to the severe aortic medial injury.     

Treatment with clorgyline and pargyline differentially decreases clonidine-induced hypotension and bradycardia

Summary A study was made of the effects of acute and chronic treatment with monoamine-oxidase (MAO) inhibitiors on the peripheral and central cardiovascular response induced by clonidine in anaesthetized normotensive rats. Clonidine (30 nmoles · kg^–1 i.v.) produced a biphasic change in mean blood pressure; an initial transient increase was followed by a prolonged hypotensive effect, coinciding with the maximal bradycardia. Twenty-four hours after acute (single) or chronic (daily for 7 days) administration of MAO inhibitors (pargyline 10 mg · kg^–1 SC or clorgyline 0.3 mg · kg^–1 SC) there was no effect either on the basal cardiovascular parameters or on the initial pressor response induced by clonidine. Chronic but not acute treatment with clorgyline, an inhibitor of type A MAO, greatly decreased the hypotension and bradycardia induced by clonidine for as long as 5 days after its discontinuation. On the other hand, after chronic administration of pargyline (10 mg · kg^–1), a preferential type B MAO inhibitor, the hypotension and bradycardia caused by clonidine were differently affected. There was a reduction in the bradycardia up to the third day following the discontinuation of pargyline, whereas the hypotensive response induced by clonidine was only attenuated for 24 h and unaffected with a lower dose of pargyline (0.3 mg · kg^–1).It is concluded that chronic administration of the type A MAO inhibitor, clorgyline, attenuates the central responses to clonidine through the reduction in sensitivity of brain -adrenoceptors. Pargyline, that preferentially inhibits type B MAO, reduces only the bradycardia induced by clonidine. This result may indicate a different modulation of the receptors involved in this response to clonidine.     

Effect of pyridoxamine on semicarbazide-sensitive amine oxidase activity of rabbit lung and heart

Rabbit lung and heart show clorgyline-resistant benzylamine oxidase activity which is sensitive to semicarbazide (SSAO) and alpha-amino-guanidine. This SSAO activity is inhibited by pyridoxamine with an IC50 of 6.3 x -6 M for lung and of 1.1 x 10(-5) M for heart, the inhibition being non-competitive and only partially reversed by dialysis at 4 degrees C. Semicarbazide, alpha-aminoguanidine and pyridoxamine show a similar time-dependent type of inhibition of rabbit lung and heart SSAO.     

Role of type A and B monoamine oxidase on the formation of 3,4-dihydroxyphenylacetic acid (DOPAC) in tissues from the brain of the rat

The role of monamine oxidase (MAO), type A and B, on the deamination of dopamine in the striatum, nucleus accumbens and frontal cortex of the rat was studied. Levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) tissue were quantified by means of high pressure liquid chromatography with electrochemical detection. Rats were given pargyline (75 mg/kg), selegyline (5 mg/kg) or clorgyline (2 mg/kg) by the intraperitoneal route, 60 min before sacrifice; in another set of experiments, clorgyline (2 mg/kg, i.p.) was given 15 or 30 min before sacrifice. Only clorgyline and pargyline were found to reduce significantly the formation of DOPAC and HVA in all the three areas of brain under study (83-97% reduction). The inhibition of deamination of dopamine by clorgyline and pargyline was accompanied by an increase in levels of dopamine in tissue. The increase of the levels of amine in tissue, as a result of inhibition of MAOA was more marked in the frontal cortex (52% increase) and the accumbens (39% increase), than in the striatum (25% increase). The results suggest that a substantial amount of DOPAC in brain derives from the deamination of dopamine by MAOA.     

Comparative behavioral effects of clorgyline and pargyline in man: A preliminary evaluation

The antidepressant and other behavioral effects of clorgyline, a preferential inhibitor of monoamine oxidase (MAO) type A, were compared with those of pargyline, a preferential inhibitor of MAO type B, in 16 depressed patients. In a subgroup of more severely depressed patients, clorgyline treatment for 4 weeks resulted in significant improvement on both observer-rated and self-rated scales, while minimal changes occurred during pargyline treatment. Similarly, in a crossover study that included 8 patients examined with multiple scales, clorgyline had generally greater antidepressant and antianxiety effects than did pargyline, although pargyline had some activating effects and also tended to produce more side effects. MAO type A inhibition may be more important than MAO type B inhibition for antidepressant efficacy.