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Biomedical subjects

V Manninen

Publications and source records attributed to V Manninen.

At least 55 records · Page 3Linked to original sources
PubMed1992

Effects of gemfibrozil treatment on serum levels of androstanediol glucuronide and adrenal androgens.

We have prospectively investigated the role of adrenal cortical androgens as a risk factor for coronary heart disease in the Helsinki Heart Study population. Simultaneously we studied the effects of gemfibrozil treatment on the serum levels of dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and their metabolite androstanediol glucuronide (3 alpha AdiolG) with those of placebo. Gemfibrozil (n = 133) vs placebo (n = 159) treatment was associated with significant elevation of mean (SD) DHEAS (mumol/l) 8.35 (5.31) vs 6.98 (3.85); P less than 0.02, and of 3 alpha AdiolG (nmol/l) 17.45 (7.57) vs 8.62 (3.56); P less than 0.001), and of almost significant elevation of DHEA (nmol/l) 10.12 (6.64) vs 8.78 (5.86); P less than 0.07). These new observations suggest that gemfibrozil treatment increases the production and turnover of DHEA and DHEAS and may in addition stimulate the 5 alpha-reduction of androgens.

Androgens↗
PubMed1992

Endothelium-dependent and -independent effects of exogenous ATP, adenosine, GTP and guanosine on vascular tone and cyclic nucleotide accumulation of rat mesenteric artery.

1. The effects of exogenous guanosine 5'-triphosphate (GTP) and guanosine on vascular tone and cyclic nucleotide accumulation of noradrenaline-precontracted endothelium-intact and endothelium-denuded rat mesenteric artery rings were compared with the effects of the known purinoceptor agonists adenosine 5'-triphosphate (ATP) and adenosine. 2. GTP (10 microM-1 mM) dose-dependently relaxed endothelium-intact mesenteric artery rings by producing a rapid initial response followed by sustained relaxation resembling the relaxant response to acetylcholine. GTP also slightly relaxed endothelium-denuded artery rings. The acetylcholine- and GTP-induced relaxations of endothelium-intact rings were attenuated by NG-nitro L-arginine methyl ester (L-NAME, 330 microM) which attenuation was reversed with L-arginine (1 mM). 3. Guanosine (10 microM-1 mM) relaxed both endothelium-intact and -denuded artery rings in a dose-dependent manner. The relaxations were more pronounced in endothelium-intact preparations and were only slightly attenuated by L-NAME (330 microM). 4. ATP (1 microM-1 mM) and adenosine (10 microM-1 mM) dose-dependently relaxed endothelium-intact and -denuded artery rings. The responses were more pronounced in endothelium-intact vascular preparations. 5. GTP (100 microM) and guanosine (100 microM) increased guanosine 3':5'-cyclic monophosphate (cyclic GMP) accumulation in both endothelium-intact and -denuded artery rings corresponding to the relaxations observed. The concentrations of adenosine 3':5'-cyclic monophosphate (cyclic AMP) were not affected. 6. ATP (100 microM) increased cyclic GMP concentration of endothelium-intact artery rings. The concentrations of cyclic AMP were not affected by ATP (100 microM) and adenosine (100 microM) in endothelium-intact and -denuded vascular preparations.7. These results provide evidence that exogenous GTP and guanosine relax precontracted endothelium-intact and -denuded rat mesenteric artery rings by increasing cyclic GMP accumulation. The response to GTP of endothelium-intact rings can mainly be explained by the release of endothelium-derived relaxing factor (EDRF), but that of guanosine is only partly due to EDRF, and is a combination of endothelium-dependent and -independent effects. The endothelium-independent response of GTP and guanosine is a direct, unknown effect on smooth muscle and guanylate cyclase.

Acetylcholine↗
PubMed1992

Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment.

BACKGROUND: We studied the joint effect of baseline triglyceride and lipoprotein cholesterol levels on the incidence of cardiac end points in the trial group (n = 4,081) of the Helsinki Heart Study, a 5-year randomized coronary primary prevention trial among dyslipidemic middle-aged men. The relative risks (RR) were calculated using Cox proportional hazards models with a dummy variable technique that allows simultaneous study of subgroup combinations from the placebo and treatment groups. METHODS AND RESULTS: In the placebo group (n = 2,045), the low density lipoprotein cholesterol (LDL-C)/high density lipoprotein cholesterol (HDL-C) ratio was the best single predictor of cardiac events. This ratio in combination with the serum triglyceride level revealed a high-risk subgroup: subjects with LDL-C/HDL-C ratio greater than 5 and triglycerides greater than 2.3 mmol/l had a RR of 3.8 (95% CI, 2.2-6.6) compared with those with LDL-C/HDL-C ratio less than or equal to 5 and triglyceride concentration less than or equal to 2.3 mmol/l. In subjects with triglyceride concentration greater than 2.3 mmol/l and LDL-C/HDL-C ratio less than or equal to 5, RR was close to unity (1.1), whereas in those with triglyceride level less than or equal to 2.3 mmol/l and LDL-C/HDL-C ratio greater than 5, RR was 1.2. The high-risk group with LDL-C/HDL-C ratio greater than 5 and triglyceride level greater than 2.3 mmol/l profited most from treatment with gemfibrozil, with a 71% lower incidence of coronary heart disease events than the corresponding placebo subgroup. In all other subgroups, the reduction in CHD incidence was substantially smaller. CONCLUSIONS: Serum triglyceride concentration has prognostic value, both for assessing coronary heart disease risk and in predicting the effect of gemfibrozil treatment, especially when used in combination with HDL-C and LDL-C.

Adult↗
PubMed1992

Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study.

OBJECTIVE: To determine coronary heart disease (CHD) incidence among dyslipidemic subjects with non-insulin-dependent diabetes mellitus (NIDDM) and to assess the effect of lipid-modifying treatment on serum and lipoprotein lipids and the CHD incidence in these patients. RESEARCH DESIGN AND METHODS: Of the 4081 men participating in the Helsinki Heart Study, a coronary primary prevention trial with gemfibrozil in middle-aged men with high non-high-density lipoprotein (HDL) cholesterol (greater than 5.2 mM; 200 mg/dL), 135 had NIDDM at entry. The incidence of definite myocardial infarction and cardiac death and changes in serum and lipoprotein lipids were determined during the 5-yr trial in the NIDDM patients and compared with those observed in nondiabetic trial participants. RESULTS: Compared with nondiabetic subjects, NIDDM patients had lower HDL cholesterol (P less than 0.001), higher triglyceride concentration (P less than 0.0001), and greater body mass index (P less than 0.001), there were more hypertensive patients (P less than 0.001) among them. The incidence of myocardial infarction and cardiac death was significantly higher among diabetic than nondiabetic participants (7.4 vs. 3.3%, respectively, P less than 0.02). CHD incidence in the gemfibrozil-treated diabetic men (n = 59) was 3.4% compared with 10.5% in the placebo group (NS). In multivariate analysis, diabetes (P less than 0.05), age (P less than 0.0001), smoking (P less than 0.0001), low HDL cholesterol (P less than 0.05), and high low-density lipoprotein cholesterol (P less than 0.005) were independently related to CHD incidence. Gemfibrozil-induced serum and lipoprotein lipid changes in diabetic patients were similar to those observed in nondiabetic subjects. CONCLUSIONS: Compared with similarly dyslipidemic nondiabetic subjects, patients with NIDDM are at markedly increased risk of CHD. This elevated risk can be somewhat reduced by gemfibrozil.

Blood Glucose↗
PubMed1992

Gemfibrozil also corrects dyslipidemia in postmenopausal women and smokers.

We compared the efficacy of three formulations and two dosage regimens of gemfibrozil in 322 dyslipidemic (non-high-density lipoprotein [HDL] cholesterol level, greater than or equal to 5.2 mmol/L [greater than or equal to 200 mg/dL]) middle-aged male and postmenopausal female patients in a 1-year open-label trial. Of the patients studied, 109 received the standard 1200-mg dose of gemfibrozil, ie, two 300-mg capsules twice daily; 107 received one 600-mg tablet twice daily; and 106 received a single dose of 900 mg of gemfibrozil in two 450-mg tablets in the evening. The three treatment groups showed equal changes in each lipoprotein measure studied, ie, in serum levels of triglycerides, total cholesterol, low-density lipoprotein and HDL cholesterol, HDL subfractions HDL2 and HDL3, and apolipoproteins A-I, A-II, and B. When the therapeutic responses were analyzed separately in men (n = 219) and women (n = 103), significantly greater decreases in serum levels of total triglycerides, low-density lipoprotein cholesterol, and apolipoprotein B, and a significantly greater increase in HDL3 cholesterol level and apolipoprotein A-I/B ratio, were seen in the women. When the study population was divided into smokers (n = 80) and nonsmokers (n = 242), the changes were similar in all lipoprotein measures except HDL3 cholesterol level, in which a significantly greater increase was seen in the non-smokers. This study showed that gemfibrozil is as effective, or more so, in dyslipidemic postmenopausal women as in dyslipidemic middle-aged men, and that smoking does not abolish its lipid-regulating effects. Importantly, a daily dose of 900 mg was found to be as effective as the standard dose of 1200 mg.

Apolipoproteins B↗
PubMed1991

Polymorphisms of the gene encoding cholesterol ester transfer protein and serum lipoprotein levels in subjects with and without coronary heart disease.

We determined TaqI-A, TaqI-B and EcoNI genotypes at the cholesteryl ester transfer protein (CETP) locus in 111 healthy volunteers and in 187 hyperlipidemic men of whom 72 had suffered a myocardial infarction. There were no significant differences in the allele distributions at these polymorphic loci either between the population sample and the hyperlipidemic subjects, or between patients with and without previous myocardial infarction. To detect the associations between the CETP polymorphisms and serum lipid and apoprotein levels, we determined the serum concentrations of total cholesterol, triglycerides, high density lipoprotein (HDL)-cholesterol, apoA-I, apoA-II and apoB in the subjects studied and correlated them to the 3 RFLPs. No significant differences were observed in the serum levels of apoproteins and lipid parameters between subjects with different genotypes in any of these polymorphic CETP loci, either in the population sample or in hyperlipidemic men. Multivariate analyses did not reveal a significant independent role for any of the 3 polymorphisms in determining serum HDL-cholesterol or apoA-I levels after adjusting for triglyceride and low density lipoprotein cholesterol concentrations. This was evident for the group of healthy volunteers and for hyperlipidemic subjects, including those who had survived a myocardial infarction. We conclude that, in Finns, the CETP RFLPs are not useful markers for the risk of coronary heart disease.

Adult↗
PubMed1991

Lipoprotein (a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants.

To prospectively assess the role of lipoprotein(a) (Lp(a)) as a risk factor for coronary heart disease, the serum Lp(a) concentration was determined in 130 subjects without coronary events and in 138 patients in whom coronary events (i.e. fatal and non-fatal myocardial infarction and cardiac death) occurred during the 5-year Helsinki Heart Study. The participants of this study (n = 4081) were 40-55-year-old men who were devoid of coronary heart disease at the beginning of the trial; half were randomized to gemfibrozil and the other half to placebo treatment. In patients with coronary events blood pressure and total cholesterol were not significant predictors of the events but their LDL cholesterol was higher than compared to the control group in this cohort (P less than 0.05). The serum Lp(a) concentration was determined by immunoassay from samples obtained 3 months after the beginning of the trial and then stored at -20 degrees C until analysed. Studies on the effect of long term storage at -20 degrees C on serum Lp(a) levels did not reveal significant changes in Lp(a) concentration in sera stored for up to 8.5 years. The distribution of Lp(a) concentrations were similar in the men with coronary events and the controls. Nor did the mean or median levels of Lp(a) differ significantly between the two groups. Measurements of Lp(a) levels in fresh samples using 2 different immunoassays did not reveal any significant difference between the participants who had survived a myocardial infarction or participants without cardiac events. Thus, we conclude that in the Helsinki Heart Study cohort the serum Lp(a) level was not a predictor of future coronary events.

Adult↗
PubMed1991

Lifestyle determinants of HDL2- and HDL3-cholesterol levels in a hypercholesterolemic male population.

In this cross-sectional study we investigated the role of lifestyle and other factors in determining serum HDL2- and HDL3-cholesterol levels among 82 dyslipidemic (total cholesterol minus HDL-cholesterol greater than or equal to 5.2 mmol/l) middle-aged participants of the Helsinki Heart Study. Alcohol consumption correlated positively with both subfractions of HDL-cholesterol, while leisure time physical activity had a significant correlation with the HDL3-subfraction only. HDL levels were lower in smokers than in non-smokers but the differences were not statistically significant. Using the multiple linear regression model, alcohol consumption emerged as the only significant factor influencing both HDL cholesterol subfraction levels. Leisure time physical activity had an independent contribution to HDL3-level, but lifestyle variables other than alcohol consumption did not contribute significantly to HDL2-cholesterol level. The model incorporating alcohol consumption, physical activity, smoking and relative body weight explained 13.4% of the variation in HDL2 and 17.5% in HDL3-cholesterol.

Alcohol Drinking↗
PubMed1991

Apolipoprotein E polymorphism influences the serum cholesterol response to dietary intervention.

The association between apolipoprotein (apo) E polymorphism and the response of serum cholesterol to dietary counseling and to gemfibrozil treatment was investigated in 230 dyslipidemic middle-aged participants of the Helsinki Heart Study. Baseline lipid levels were not significantly different between subjects with or without the epsilon 4 allele. Following dietary counseling, participants with the epsilon 4 allele exhibited a greater reduction in serum total cholesterol (P less than .01) and low-density lipoprotein (LDL)-cholesterol (P less than .02) than those without the epsilon 4 allele, while the changes in high-density lipoprotein (HDL)-cholesterol and triglycerides were similar in the two groups. The alterations observed in total cholesterol, HDL-cholesterol, and triglycerides during treatment with gemfibrozil were not different between subjects with or without the epsilon 4 allele. The presence of the epsilon 4 allele and baseline serum cholesterol independently predicted the degree of cholesterol reduction following dietary counseling.

Adult↗
PubMed1991

DNA polymorphisms of apolipoprotein B and AI/CIII genes and response to gemfibrozil treatment.

Apolipoprotein B XbaI polymorphism and apolipoprotein AI/CIII SstI polymorphism have been found to be associated with variations in serum lipoprotein levels. We investigated whether these gene polymorphisms are involved in determining the lipid-modulating action of gemfibrozil. Of the 221 male subjects with hyperlipidemia studied, 121 responded well to the treatment with more than a 25% reduction in the non-high-density lipoprotein cholesterol level, whereas 100 were nonresponders. Among responders, but not nonresponders, homozygosity for the apolipoprotein B X2 allele (XbaI site present) and heterozygosity for the apolipoprotein AI/CIII S2 allele (SstI site present) were associated with elevated baseline serum low-density lipoprotein cholesterol and triglyceride levels, respectively. However, the hypolipidemic effect of gemfibrozil among the responders was independent of these gene polymorphisms. These data indicate that common polymorphisms of the apolipoprotein B and apolipoprotein AI/CIII gene loci influence serum lipid levels by mechanisms that are amenable to an intervention with gemfibrozil.

Adult↗
PubMed1991

Cigarette smoking alters sympathoadrenal regulation by decreasing the density of beta 2-adrenoceptors. A study of monitored smoking cessation.

We report the effects of monitored smoking cessation on adrenergic regulation in chronic smokers. The beta 2 adrenoceptor density of mononuclear leukocytes (MNLs) and plasma catecholamines was analyzed before cessation and 2, 3, and 8 weeks after cessation. We found a progressive increase in beta-adrenoceptor density after smoking cessation. During smoking the beta-adrenoceptor density was 1.456 +/- 83 (mean +/- SEM) binding sites per cell (n = 10), whereas 3 weeks after cessation the density was 1,774 +/- 157 sites per cell (n = 10; p less than 0.05), and at 8 weeks, 1,900 +/- 227 sites per cell (n = 8; p less than 0.05), representing an overall increase of 23%. Smoking cessation had no effect on binding affinity nor on lymphocyte subgroup distribution. The density of MNL cell beta-adrenoceptors in age-matched nonsmoking men was higher, at 1,896 +/- 271 sites per cell, than that of the chronic smokers before cessation, 1,419 +/- 117 sites per cell (n = 14; p less than 0.01). Plasma epinephrine decreased as a result of cessation from 0.36 pmol/ml (0.26-0.44, 95% confidence interval; baseline) to 0.26 pmol/ml (0.20-0.32) at 8 weeks (p less than 0.05), and norepinephrine decreased from 2.09 pmol/ml (1.38-2.80) to 1.69 pmol/ml (1.14-2.24; p = 0.06). We conclude that stopping smoking progressively increases beta 2-adrenoceptor density on MNL cells. Eight weeks after cessation the adrenoceptor density reaches the corresponding level of nonsmokers. These reversible changes in adrenergic regulation after smoking cessation may be associated with the relatively rapid reduction in cardiovascular disease risk among ex-smokers.

Adrenergic Fibers↗
PubMed1991

Modification of nitrovasodilator effects on vascular smooth muscle by exogenous GTP and guanosine.

The effects of exogenous guanosine 5'-triphosphate (GTP) and guanosine on nitroglycerin-, sodium nitrite- and SIN-1-induced guanosine 3',5'-cyclic monophosphate (cyclic GMP) accumulation and smooth muscle relaxation were studied using endothelium-denuded rat mesenteric artery rings precontracted with noradrenaline. Preincubation of contracted artery rings with GTP (100 microM) or guanosine (100 microM) before eliciting relaxations with nitrovasodilators significantly shifted the dose-response curves of nitrocompounds to the left and augmented the increases in cyclic GMP. GTP and guanosine alone also induced cyclic GMP accumulation in pre-contracted artery rings. These effects of GTP and guanosine on nitrovasodilator responses were not related to the preincubation period (0-30 min). The present results raise the possibility of a cell membrane site of action for GTP and guanosine, which mediates the activation of soluble guanylate cyclase and leads to increased nitrovasodilator-induced cyclic GMP accumulation and arterial smooth muscle relaxation.

Animals↗
PubMed1991

Medication compliance and serum lipid changes in the Helsinki Heart Study.

1. To control the bias caused by poor medication compliance in the Helsinki Heart Study three methods were used to measure medication compliance during the total 5 years follow up time: continuous capsule counting, semi-annual urine gemfibrozil analysis and a new method, the digoxin marker at the end of the third and fifth study years. 2. The serum lipid responses to gemfibrozil treatment varied linearly with the level of medication compliance, e.g. the mean change in serum total cholesterol was -11.4% among those whose apparent capsule consumption was greater than or equal to 90% of the scheduled dosage, -11.2% among those who had greater than or equal to 90% positive gemfibrozil analyses and -11.4% among those with good compliance according to both digoxin marker measurements. In contrast the mean serum cholesterol change was only -0.02% if the mean daily capsule count was less than 50%, -1.7% with fewer than 50% positive gemfibrozil analyses and -1.1% if the result was poor in both digoxin marker measurements. 3. Combining the different method findings revealed that the cholesterol changes tended to be small in those groups who had poor compliance classification measured by any of the methods, even if the other results showed good compliance.

Capsules↗
PubMed1991

Exogenous GTP enhances the effects of sodium nitrite on cyclic GMP accumulation, vascular smooth muscle relaxation and platelet aggregation.

Exogenous guanosine triphosphate (GTP) (1-2 x 10(-4)M) resulted in increased concentrations of cyclic GMP both in endothelium denuded rat mesenteric artery (RMA) and in human ADP-stimulated platelets. Sodium nitrite (3.3 x 10(-4)M) relaxed precontracted RMA by 34%. When the arteries were preincubated with GTP (2 x 10(-4)M) sodium nitrite administration resulted in a significantly greater relaxation (58%) of the RMA with concomitant 2-fold increase in cGMP. Sodium nitrite (1 x 10(-4)M) had an inhibitory effect on ADP-induced platelet aggregation. Preincubation with GTP enhanced significantly the sodium nitrite-induced inhibition of ADP-induced platelet aggregation with a simultaneous 5-fold increase in cGMP. These results indicate that exogenous GTP enhances the sodium nitrite-induced stimulation of guanylate cyclase and thus enhances the effects of sodium nitrite on arterial smooth muscle and platelets.

Animals↗
PubMed1991

The Helsinki Heart Study: central findings and clinical implications.

This paper describes the central findings and discusses the clinical implications of the Helsinki Heart Study. This was a controlled primary prevention trial to test the hypothesis that using gemfibrozil to lower the concentrations of serum low density lipoprotein (LDL) and very low density lipoprotein (VLDL) and to raise that of high density lipoprotein (HDL) protects subjects against coronary heart disease.

Adult↗
PubMed1991

Cadmium as a tool for studying calcium-dependent cation permeability of the human red blood cell membrane.

Three Ca(2+)-dependent procedures known to increase cation permeability of red blood cell membranes were tested with Cd2+ ions which equal Ca2+ ions both in their charge and the crystal radius, 1. Increase of non-selective permeability for monovalent cations by incubating the red cells in a Ca(2+)-free sucrose medium. Addition of Cd2+ to the suspension of leaky cells failed to restore the initial impermeability of the red cell membrane while a repairing effect of Ca2+ was evident both in the presence and absence of Cd2+. Thus, in low electrolyte medium, Cd2+ could neither mimic Ca2+, nor prevent the latter from interacting with membrane structures which control cation permeability. 2. Increase of the K(+)-selective permeability by propranolol plus Ca2+. Cd2+ added to a Ca(2+)-free Ringer type medium containing propranolol enhanced K+ permeability similar to that obtained with Ca2+. No changes of membrane permeability could be detected in the presence of 0.5 mmol/l Cd2+ in absence of propranolol. The Cd(2+)-stimulated K+ channels were different from those induced by Ca2+. They proved to be insensitive to quinine, exhibited a low K+/Na+ selectivity, and showed no tendency to self-inactivation. 3. Stimulation of K+ permeability by electron donors plus Ca2+. Substitution of Ca2+ by Cd2+ yielded results similar to those obtained with propranolol. The ability of Cd2+ to overtake the role of Ca2+ appears to depend on the system studied. It supplies information allowing to distinguish between the diverse Ca(2+)-dependent systems in cell membranes.

Ascorbic Acid↗
PubMed1990

Predictive value for coronary heart disease of baseline high-density and low-density lipoprotein cholesterol among Fredrickson type IIa subjects in the Helsinki Heart Study.

In the Helsinki Heart Study 2,590 subjects (63.5% of total) had a type IIa hyperlipoproteinemia at screening. Baseline low-density lipoprotein (LDL) cholesterol (mean 193 mg/dl; 5 mmol/liter) and high-density lipoprotein (HDL) cholesterol (mean 50.2 mg/dl; 1.3 mmol/liter) showed no statistical correlation (r = 0.046). Both the placebo (1,293 patients) and gemfibrozil groups (1,297 patients) were divided into tertiles by baseline HDL and LDL cholesterol to determine the relative predictive risk of developing coronary artery disease. In a population with elevated LDL cholesterol, it is significant that the lipoprotein fraction with the greatest predictive value was HDL cholesterol. The severity of LDL cholesterol elevation did not provide any differential predictive value for coronary artery disease.

Cholesterol, HDL↗