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H Refsum

Publications and source records attributed to H Refsum.

At least 19 recordsLinked to original sources
PubMed2006

Factor V Leiden, pregnancy complications and adverse outcomes: the Hordaland Homocysteine Study.

BACKGROUND: The factor V Leiden (FVL) mutation is the most common cause of inherited thrombophilia in Caucasian populations, and women with this variant allele are at increased risk for pregnancy complications. AIM: To examine whether the FVL allele is associated with pregnancy complications and adverse outcomes in a population-based study, and to identify potential factors that interact with the FVL genotype. DESIGN: Retrospective cohort study in a geographically-defined area. METHODS: Polymorphisms of factor V 1691G-->A, methylenetetrahydrofolate reductase (MTHFR) 677C --> T and 1298A --> C and plasma levels of total homocysteine, folate and vitamin B(12) were determined in blood samples collected in 1992-1993 from 5874 women aged 40-42 years, and linked with 14 474 pregnancies in the same women, recorded in the Medical Birth Registry of Norway, 1967-1996. RESULTS: The allelic frequency of FVL was 3.7% (6.9% heterozygotes, 0.3% homozygotes). Maternal FVL mutation was associated with significantly higher risks of pre-eclampsia (OR 1.63, 95%CI 1.15-2.30), pre-eclampsia at <37 weeks (OR 2.76, 1.34-5.70), low birth weight (OR 1.34, 95%CI 1.03-1.74) and stillbirth (OR 2.20, 95%CI 1.45-3.36). The presence of a variant allele for the 677C --> T MTHFR polymorphism strengthened the association between FVL and stillbirth (OR 3.34, 95%CI 1.95-5.73) (p(interaction) = 0.034). DISCUSSION: FVL mutation is a significant risk factor for pregnancy complications and adverse outcomes, and MTHFR 677CT/TT genotype can further enhance the risk of stillbirth.

Adult↗
PubMed2006

Apolipoprotein E epsilon4 and impaired episodic memory in community-dwelling elderly people: a marked sex difference. The Hordaland Health Study.

BACKGROUND: Among elderly people without dementia, the apolipoprotein E epsilon4 allele (APOE4) has been associated with cognitive deficit, particularly in episodic memory, but few reports are available on whether this association differs by sex. METHODS: In a community-dwelling Norwegian cohort of 2181 elderly people (55% women), aged 70-74 years, episodic memory was examined in relation to sex and APOE4 zygosity, with the Kendrick Object Learning Test (KOLT). RESULTS: Possession of at least one APOE4 allele had a modest, detrimental effect on episodic memory in women, whereas in men, heterozygotes were unaffected and homozygotes had markedly lower scores across the distribution of KOLT scores. This sex difference was found consistently in all analyses: on comparing means and medians, examining trends across quintiles, and studying the distribution of scores and the risk of cognitive impairment. Results were broadly similar when adjusted for known determinants of cognition and also when severely impaired participants were excluded. The adjusted odds ratio (OR) of cognitive impairment in women was shown to be 1.8 (95% confidence interval (CI): 1.1 to 2.8) for heterozygotes and 1.1 (0.3 to 3.7) for homozygotes; the adjusted OR in men was observed to be 1.1 (0.6 to 2.1) for heterozygotes and 10.7 (4.7 to 24) for homozygotes. CONCLUSIONS: Although the harmful effect of APOE4 on episodic memory was modest in women, the risk was found to occur in about 30%. APOE4 was observed to have a dramatic effect on episodic memory in men, but only in homozygotes, who comprised about 3% of men: the whole male homozygous group showed a marked shift to lower memory scores.

Aged↗
PubMed2006

The complexity of active metabolites in therapeutic drug monitoring of psychotropic drugs.

In therapeutic drug monitoring (TDM) practice of psychotropic agents, it is common to summarize plasma concentrations of parent drugs and metabolites when these are considered equipotent. However, there is no clear definition of the term equipotent and one should be aware that metabolites referred to as equipotent in the literature could display several-fold differences in affinities toward target proteins. The fact that the parent drug and metabolite may have different abilities to penetrate the blood-brain-barrier further complicates the picture. Potential differences in brain distribution imply that various metabolite/drug ratios representing the same total concentration in plasma reflect different active concentrations in the brain. Plasma metabolite/drug ratios could differ extensively according to metabolic phenotype and administration route. An example is risperidone where the plasma metabolite/drug ratio is 30-fold lower in cytochrome P450 2D6 poor metabolizers compared to ultrarapid metabolizers, and four-fold lower after intramuscular compared to oral administration. As risperidone is more lipophilic and less effluxed by P-glycoprotein in the blood-brain-barrier than the active metabolite 9-hydroxyrisperidone, one might speculate that patients with high plasma metabolite/drug ratios obtain lower active concentrations in the brain. However, the relative drug-metabolite brain distribution needs to be quantified in humans to clarify to what degree drug and metabolite plasma levels reflect active brain concentrations. The present review illustrates the complexity of active metabolites in TDM with focus on amitriptyline, clomipramine, doxepin, imipramine, fluoxetine, venlafaxine and risperidone, all psychotropic drugs where target plasma concentration ranges are based on the sum of parent drug and metabolite. In addition, perspectives on the possibility of using distribution- and activity-weighted plasma concentrations are provided.

Brain↗
PubMed2006

The iodinated radiographic contrast medium iohexol mimics the vasodilator effect seen with small increases in extracellular K+ in the isolated rabbit central ear artery.

PURPOSE: To investigate whether iodinated radiographic contrast media (IRCM) mimic the hyperpolarizing and vasodilator effects of K+ by comparing the vasodilator effect of a transient rise in extracellular K+ with that of the IRCM iohexol. MATERIAL AND METHODS: Immersed rabbit central ear arterial rings with and without endothelium and pre-contracted with phenylephrine (PE) were used to investigate the dependency of the endothelium in K+-induced vasodilatation. Perfused rabbit central ear arteries, pre-contracted with PE, were used to study the effects of bolus administrations of the IRCM iohexol or KCl on arterial tone under conditions that mimic those employed during clinical arteriography. RESULTS: A small rise in K+ caused an endothelium-independent and ouabain-sensitive relaxation of PE-constricted rabbit central ear artery rings. The relaxation was not changed in the presence of barium. The IRCM iohexol and KCl, injected as boluses into perfused PE-constricted rabbit ear arteries, caused transient decreases in perfusion pressure. Iohexol- and K+-induced pressure decreases were significantly reduced in the presence of 10 microM ouabain alone or in combination with 30 microM barium. Neither iohexol- nor K+-induced pressure decrease was significantly changed in the presence of barium alone compared to controls. CONCLUSION: The vasodilator effect of IRCM mimics the vasodilator effect seen upon small increase in extracellular K+. Under the experimental conditions employed in the present study, a considerable part of the IRCM-induced vasodilatation appears to be due to activation of Na+/K+-ATPase in the smooth muscle cells.

Analysis of Variance↗
PubMed2006

Serum concentrations of risperidone and 9-OH risperidone following intramuscular injection of long-acting risperidone compared with oral risperidone medication.

OBJECTIVE: To compare serum concentrations of risperidone, 9-hydroxy (OH) risperidone and risperidone plus 9-OH risperidone, as well as the 9-OH risperidone/risperidone ratio in patients receiving depot and oral risperidone. METHOD: Serum concentrations from 78 patients receiving three different doses of risperidone depot were measured and compared with serum concentrations from 82 patients taking three different doses of oral risperidone. RESULTS: Patients receiving risperidone depot had significantly lower serum concentrations of risperidone plus 9-OH risperidone than patients taking oral risperidone. More interestingly, the 9-OH risperidone/risperidone ratio was also significantly lower in patients receiving risperidone depot than in patients taking oral risperidone. CONCLUSION: Serum concentrations of risperidone plus 9-OH risperidone may be a rather poor indication of the antipsychotic efficacy of risperidone unless their ratio is also considered.

Administration, Oral↗
PubMed2005

Prevalences of hyperhomocysteinemia, unfavorable cholesterol profile and hypertension in European populations.

BACKGROUND: Hyperhomocysteinemia (HHCY) is a risk factor for cardiovascular diseases (CVD). HHCY may interact with hypertension (HTEN) and an unfavorable cholesterol profile (UNFAVCHOL) to alter the risk of CVD. OBJECTIVES: To estimate the prevalences of HHCY (1) isolated and (2) in combination with UNFAVCHOL and/or HTEN in different age categories. To provide information that may improve the screening and treatment of subjects at risk of CVD. DESIGN: Cross-sectional data on 12,541 men and 12,948 women aged 20 + y were used from nine European studies. RESULTS: The prevalence of isolated HHCY was 8.5% in subjects aged 20-40 y, 4.7% in subjects aged 40-60 y and 5.9% in subjects aged over 60 y. When combining all age groups, 5.3% had isolated HHCY and an additional 5.6% had HHCY in combination with HTEN and/or UNFAVCHOL. The combinations of risk factors increased with age and, except for HHCY&UNFAVCHOL, were more prevalent than predicted by chance. Of the young subjects (20-40 y), 24% suffered from one or more of the investigated CVD risk factors. This figure was 75.1% in the old subjects (60+ years). CONCLUSIONS: A substantial number of subjects in selected European populations have HHCY (10.9%). In half of these cases, subjects suffer also from other CVD risk factors like UNFAVCHOL and HTEN. Older people in particular tend to have more than one risk factor. Healthcare professionals should be aware of this when screening and treating older people not only for the conventional CVD risk factors like UNFAVCHOL and HTEN but also HHCY, as this can easily be reduced through increased intake of folic acid via supplement or foods fortified with folic acid.

Adult↗
PubMed2004

Distribution and determinants of serum creatinine in the general population: the Hordaland Health Study.

BACKGROUND: Serum creatinine is a well-recognized risk factor for cardiovascular disease (CVD) and is also a rough measure of glomerular filtration rate. The purpose of the present study was to investigate determinants of serum creatinine in the general population. METHODS: The participants were recruited as a part of the Hordaland Health Study, and included 6952 men aged 41-49 years, 8218 women aged 41-49 years, 1470 men aged 71-74 years and 1865 women aged 71-74 years. Data on lifestyle factors, medical history and medication were obtained through questionnaires. Body size and blood pressure measurements as well as non-fasting blood samples were obtained during a health examination. Determinants of serum creatinine were identified using multiple linear and logistic regression analyses. RESULTS: Male and older participants had higher levels of serum creatinine than female and middle-aged participants. For older participants, creatinine was associated with serum triglycerides, CVD, upper-arm circumference and use of antihypertensive drugs as well as inversely associated with cigarette smoking. For middle-aged participants, creatinine was associated with upper-arm circumference, serum lipids and physical exercise, as well as inversely associated with smoking and alcohol intake. The associations with CVD risk factors were much stronger for older participants than for middle-aged participants and most associations were significant after adjustments as well as present within the reference range of serum creatinine. CONCLUSIONS: In this general population sample, high serum creatinine levels were associated with risk factors for CVD. These associations were stronger in older subjects, whereas in middle-aged subjects lifestyle variables were relatively more important.

Adult↗
PubMed2004

Vitamin B12 and folate deficiency in later life.

OBJECTIVES: to examine the prevalence of vitamin B12 deficiency and folate deficiency in later life in representative samples of the elderly population in the United Kingdom. DESIGN: a population-based cross-sectional analysis of 3,511 people aged 65 years or older from three studies was used to estimate the age-specific prevalence of vitamin B12 deficiency and of folate deficiency. Vitamin B12 deficiency is conventionally diagnosed if serum vitamin B12 < 150 pmol/l ('low vitamin B12'). We defined 'metabolically significant vitamin B12 deficiency' as vitamin B12 < 200 pmol/l and blood total homocysteine >20 micro mol/l. Folate deficiency, which usually refers to serum folate <5 nmol/l, was defined as 'metabolically significant' if serum folate was <7 nmol/l and homocysteine >20 micro mol/l. RESULTS: the prevalence of vitamin B12 deficiency, whether defined as low vitamin B12 or metabolically significant vitamin B12 deficiency increased with age in all three studies, from about 1 in 20 among people aged 65-74 years to 1 in 10 or even greater among people aged 75 years or greater. The prevalence of folate deficiency also increased with age, and was similar to that for vitamin B12 deficiencies, but only about 10% of people with low vitamin B12 levels also had low folate levels. CONCLUSION: the high prevalence of vitamin B12 and folate deficiency observed in older people indicates a particular need for vigilance for deficiency of these vitamins. Reliable detection and treatment of vitamin deficiency could reduce the risk of deficiency-related disability in old age.

Age Factors↗
PubMed2003

Low vitamin B-12 status in confirmed Alzheimer's disease as revealed by serum holotranscobalamin.

OBJECTIVE: To examine the possible association of holotranscobalamin, the active fraction of serum cobalamin, with Alzheimer's disease. METHODS: 51 patients with pathologically confirmed Alzheimer's disease and 65 cognitively screened elderly controls were studied. Serum holotranscobalamin was measured by a new solid phase radioimmunoassay. RESULTS: Geometric mean levels showed no significant case-control differences for serum total cobalamin, but lower levels of holotranscobalamin in Alzheimer's disease (41.1 pmol/l) than in controls (57.1 pmol/l) (p < 0.001). The odds ratio of Alzheimer's disease was significant for low holotranscobalamin but not for low total cobalamin. CONCLUSIONS: Disturbed cobalamin status is common in Alzheimer's disease and accordingly measurement of holotranscobalamin should be considered in the assessment of cognitively impaired patients.

Aged↗
PubMed2001

Investigation of relationship between reduced, oxidized, and protein-bound homocysteine and vascular endothelial function in healthy human subjects.

Previous studies investigating homocysteine and vascular disease have relied on total plasma homocysteine as the sole index of homocysteine status. We examined the dynamic relationship between vascular endothelial function and concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine to identify the homocysteine form associated with endothelial dysfunction in humans. We investigated 14 healthy volunteers (10 men, 4 women). Brachial artery flow-mediated dilatation was measured at baseline and at 30, 60, 120, 240, and 360 minutes after oral (1) L-methionine (50 mg/kg), (2) L-homocysteine (5 mg/kg), and (3) placebo. Plasma concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine were measured at each time point, and nitroglycerin-induced dilatation at was assessed at 0, 120, and 360 minutes. Flow-mediated dilatation fell, and concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine increased after oral homocysteine and oral methionine (all P<0.05 for difference in time course compared with placebo). Flow-mediated dilatation showed a reciprocal relationship with reduced homocysteine during both homocysteine and methionine loading. In both loading studies, peak reduction in flow-mediated dilatation coincided with maximal reduced homocysteine concentrations. In contrast, there was no consistent relationship between flow-mediated dilatation and free oxidized homocysteine, protein-bound oxidized homocysteine, or related species. Nitroglycerin-induced dilatation was unchanged by oral homocysteine and oral methionine (P>0.10 compared with placebo). Reduced homocysteine is closely associated with endothelial dysfunction during oral methionine and oral homocysteine loading. Our observations support the hypothesis that reduced homocysteine is the deleterious form of homocysteine for vascular function in vivo and suggest a less important role for other homocysteine species.

Administration, Oral↗
PubMed2001

Plasma total cysteine as a risk factor for vascular disease: The European Concerted Action Project.

BACKGROUND: Elevated plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. Although cysteine is structurally similar and metabolically linked to tHcy, its relation to the risk of cardiovascular disease has received little attention. We studied the relation between plasma total cysteine (tCys) levels and the risk of vascular disease in the coronary, cerebral, and peripheral vessels. METHODS AND RESULTS: This case-control study included 750 patients with vascular disease and 800 age- and sex-matched control subjects recruited from 19 centers in 9 European countries. Conventional risk factors for cardiovascular disease were recorded. In addition, plasma levels of tCys, tHcy, folate, B(6), B(12), and creatinine were measured. Overall, a U-shaped relationship was observed between tCys and risk of vascular disease. With the middle range of 250 to 275 micromol/L tCys used as the reference category, the adjusted risk of vascular disease at low (</=225 micromol/L) tCys levels was 2.1 (95% CI 1.2 to 3.6), and the risk at high (>300 micromol/L) tCys levels was 1.6 (95% CI 1.1 to 2.3). Different shapes of the dose-response relationship were seen for the 3 vascular disease categories. The relation with peripheral vascular and cerebrovascular disease was U-shaped, whereas a weak positive relation was observed with coronary heart disease. CONCLUSIONS: Our data show a significant U-shaped relationship between tCys and cardiovascular disease after adjustment for tHcy, creatinine, and other cardiovascular disease risk factors.

Adult↗
PubMed2001

Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathionine beta-synthase deficiency: relationship between genotype and phenotype.

We have investigated 31 subjects from five unrelated families with one or more members with cystathionine beta-synthase (CBS) deficiency. On the basis of their CBS genotype, the subjects were grouped as normal (n = 11) or heterozygotes (n = 20). Based on pyridoxine effect in the probands, the heterozygotes were further classified as pyridoxine-responsive (n = 9) or non-responsive (n = 11). Heterozygous subjects had normal fasting total plasma homocysteine (tHcy), but median urinary tHcy excretion rate was significantly elevated compared to healthy controls (0.39 micromol/h vs 0.24 micromol/h, P < 0.05). An abnormal tHcy response after methionine loading identified 73% of the pyridoxine non-responsive heterozygotes, but only 33% of the pyridoxine responsive participants. The increase in cystathionine or the change in tHcy relative to cystathionine did not improve diagnostic accuracy of the methionine loading test. After Hcy loading, the maximal increase in tHcy was significantly elevated, whereas t(1/2) was normal in heterozygotes. In conclusion, a single biochemical test cannot discriminate CBS heterozygotes from controls. Abnormal tHcy response after methionine loading was the most sensitive test. Our data suggest that the urinary tHcy excretion rate is a simple, non-invasive approach for studying mild disturbances in Hcy metabolism.

Adolescent↗
PubMed2001

The effect of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women from the British regional heart study.

Total blood levels of homocysteine (tHcy) have been shown to depend on both environmental and genetic factors, and to be associated with the risk of developing atherosclerosis with its complications of coronary heart disease (CHD) and stroke. In this study, 408 men and 346 women from two towns, Dewsbury and Maidstone were examined for tHcy levels and genotyped for the C677T and the A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene. Blood tHcy was significantly higher in men from the CHD high risk town of Dewsbury (12.7 micromol/l) than in the low CHD risk town of Maidstone (11.5 micromol/l) P<0.001, but not in women (10.7 vs. 10.5 micromol/l), with women in both towns, thus, showing significantly lower tHcy than men. There was no difference between towns in folate or vitamin B12 levels but the conventional inverse relationship with tHcy was seen. Smoking men and women from both towns had significantly higher tHcy and lower folate levels than non-smoking individuals (P<0.001). The frequency of the 677T allele in Dewsbury was 0.35 (95% CI; 0.32-0.39) compared with 0.29 (95% CI; 0.26-0.32) in Maidstone (P<0.01). Similar frequency difference of borderline statistical significance was seen both for men (P=0.054) and women (P=0.048) in both the towns, suggesting a true regional frequency difference. The effect of the 677T on tHcy was highly significant in the group as a whole with the most profound effect seen in men (12.0 micromol/l for CC vs. 14.1 micromol/l for TT, P<0.001). By contrast, there was no significant effect of the A1298C polymorphism on tHcy, folate or vitamin B12 levels, with no evidence for an interaction with the C677T genotype. The regional differences in tHcy levels were still present after the adjustment for folate and vitamin B12 levels, smoking and the effect of the C677T polymorphism. This suggests that there may be other unidentified factors, either environmental or genetic, affecting tHcy levels, and thus potentially having an impact on the risk of developing hyperhomocysteinaemia and CHD. These observations may have a bearing on regional differences in tHcy levels and the variation in CHD risk between regions in the UK.

Aged↗
PubMed2001

The Hordaland Homocysteine Studies.

The Hordaland Homocysteine Study is a population-based screening of total plasma homocysteine (tHcy) in approximately 18,000 men and women aged 40-67 yr that took place in 1992-1993 in the county of Hordaland in Western Norway. In this cohort, tHcy was associated with several physiologic and life-style factors, including age and gender, blood pressure, serum cholesterol, smoking, alcohol and coffee consumption, physical activity, diet, and vitamin status. All associations with established cardiovascular risk factors were in the direction expected to confer increased risk. In a subset of 5,883 women aged 40-42 yr, tHcy was associated with previous pregnancy outcomes, including preeclampsia, placental abruption, and neural tube defects. This article reviews the published results from the Hordaland Homocysteine Study in the light of relevant literature. The Hordaland Homocysteine cohort will be used for future investigations of the stability of tHcy and vitamin status over time, and to investigate associations with mortality and morbidity including cancer incidence.

Adult↗
PubMed2001

Biological and clinical implications of the MTHFR C677T polymorphism.

The enzyme methylenetetrahydrofolate reductase (MTHFR) directs folate species either to DNA synthesis or to homocysteine (Hcy) remethylation. The common MTHFR C677T polymorphism affects the activity of the enzyme and hence folate distribution. Under conditions of impaired folate status, the homozygous TT genotype has been regarded as harmful because it is associated with a high concentration of plasma total Hcy, increased risk of neural tube defects and colorectal neoplasias, and can also predispose individuals to adverse effects from drugs with antifolate effects. The MTHFR C677T polymorphism shows no consistent correlation with cardiovascular risk and longevity but, in combination with positive folate balance, the TT genotype is associated with decreased risk of colorectal neoplasias. Because of the high prevalence of this polymorphism in most populations, the TT variant might represent an ancestral genetic adaptation to living constraints (tissue injury or unbalanced vitamin intake) that has become a determinant of disease profiles in modern times.

Cardiovascular Diseases↗
PubMed2001

Homocysteine and methylmalonic acid levels in pregnant Nepali women. Should cobalamin supplementation be considered?

OBJECTIVE: The aim of this study was to investigate homocysteine and methylmalonic acid levels as markers of functional cobalamin and folate status in pregnant Nepali women. DESIGN: Cross-sectional study. SETTING: Patan Hospital, Kathmandu, Nepal. SUBJECTS: A sub-sample (n=382) of all pregnant women (n=2856) coming for their first antenatal visit in a 12 month period, 1994-1995. The selection of the sub-sample was based on maternal haematocrit values, categorised into three groups: severely, moderately and non-anaemic women. As serum levels of total homocysteine (s-tHcy) and methylmalonic acid (s-MMA) were similar in the three groups, pooled data are presented. Women who had already received micronutrient supplementation (n=54) were excluded. The remaining women (n=328) were included in the statistical analysis. RESULTS: Overall mean values (+/-s.d.) of s-tHcy and s-MMA were 9.5 (+/-4.2) micromol/l and 0.39 (+/-0.32) micromol/l, respectively. Elevated s-tHcy (>7.5 micromol/l) was found in 68% of the women, while 61% had elevated s-MMA (>0.26 micromol/l). Low s-cobalamin values (<150 pmol/l) were observed in 49% of the women, while only 7% had low s-folate values (< or =4.5 nmol/l). s-tHcy was significantly correlated with s-MMA (r=0.28, P<0.001), s-cobalamin (r=-0.30, P<0.001) and s-folate (r=-0.24, P<0.001). s-MMA was significantly associated with s-cobalamin (r=-0.40, P<0.001), but not with s-folate. CONCLUSIONS: Functional cobalamin deficiency was very common in the study population, while functional folate deficiency was rather uncommon. We suggest considering cobalamin supplementation to pregnant Nepali women. SPONSORSHIP: The Norwegian Research Council and the Norwegian Universities Committee for Development, Research and Education.

Adolescent↗
PubMed2001

Cardioprotective effects of the MR contrast agent MnDPDP and its metabolite MnPLED upon reperfusion of the ischemic porcine myocardium.

PURPOSE: To evaluate whether manganese dipyridoxyl diphosphate (MnDPDP) or its metabolite manganese dipyridoxyl ethyldiamine (MnPLED) reduces post-ischemic myocardial injury. MATERIAL AND METHODS: Left anterior descending artery (LAD) in anesthetized pigs was occluded (30 min) followed by reperfusion (120 min) during hemodynamic monitoring and infarct assessment. Three micromol/kg MnDPDP, 1 micromol/kg MnPLED (or a mixture of both) or saline was injected i.v. 10 min before reperfusion followed by infusion of either 3 micromol/kg/h MnDPDP, 1 micromol/kg/h MnPLED (or a mixture of both) or saline. The plasma concentrations of MnDPDP, MnPLED and other metabolites (e.g., ZnDPDP and ZnPLED) were analyzed. RESULTS: Femoral blood flow was reduced by 60% during early reperfusion in controls, whereas only 23 and 31% reductions were seen in animals treated with MnDPDP and MnPLED. During that time, +LV/dP and -LV/dP (maximum rate of left ventricular isovolumic contraction and relaxation, respectively), systolic pressure and diastolic pressure fell significantly less in animals treated with MnDPDP or MnPLED. Three out of 5 control animals experienced ventricular fibrillation (VF) during reperfusion, whereas VF was not seen in any of the pigs treated with MnPLED or/and MnDPDP. The infarct sizes in saline- and MnPLED-treated animals were 39+/-6 and 16+/-5%, respectively, of the occluded areas. MnDPDP did not reduce the infarct size. A mixture of MnDPDP and MnPLED significantly reduced infarct size (10+/-4%). When reperfusion started and throughout reperfusion, almost all injected MnDPDP was present as Zn-metabolites. CONCLUSION: MnPLED seems to reduce reperfusion-induced cardiac dysfunction and infarct size in pigs. MnDPDP does not reduce infarct size in the pig, probably because of the rapid exchange of Mn2+ for Zn2+ taking place in the pig.

Animals↗