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A double-blind cross-over trial of the non-selective beta-blocker propranolol and the beta1-selective blocker metoprolol was carried out in 8 hypertensive patients. At the end of each 4-week period of treatment haemodynamic and respiratory indices and perceived exertion were studied during moderate exercise. Both beta-blockers resulted in reduced heart rate, cardiac output, and blood pressure, whereas the stroke volume increased. Total peripheral resistance did not change. During exercise the expiratory peak flow rate equally increased in every period. However, the peak flow rate at rest, as well as during exercise, was reduced by propranolol, while metoprolol had no such influence. Neither of the beta-blockers changed O2 consumption, CO2 production, tidal volume, or respiratory rate. Moreover, they did not influence perceived exertion. These results suggest that the arteriolar and bronchiolar beta2-receptors do not play a major role in the alteration of circulation and ventilation during exercise. As far as their practical use as antihypertensive agents is concerned, this study shows no advantage in the use of either of these beta-blockers. [ABSTRACT FROM PUBLISHER]

Haemodynamic effects of a cold pressor test (foot immersion for 6 min in water at 5 degrees C) without medication and after the non-selective beta-adrenoceptor blocker propranolol and the selective beta- adrenoceptor blocker metoprolol were studied in 17 volunteers. In the control study as well as in the study with the beta-adrenoceptor blockers cold exposure caused comparable changes, namely a blood pressure rise and a reduction of forearm blood flow. The increase in heart rate during cold exposure was clearly and equally reduced by both beta-adrenoceptor blockers. Plasma noradrenaline rose significantly by 47%, plasma adrenaline did not change. It is concluded, that as to this kind of stress, beta 1-selective-adrenoceptor blockade confers no important advantage over non-selective beta-adrenoceptor blockade. [ABSTRACT FROM AUTHOR]

Every doctor should be able to make a probable diagnosis of congestive heart failure by clinical examination. The most revealing clinical sign is an elevated jugular venous pressure. The measurement of this pressure was introduced by Lewis in 1930 and refined and standardised by Borst and Molhuysen in 1952. Still, this method has fallen into disuse and is thought to be not very sensitive for diagnosing congestive heart failure. A study of the methods described in the literature reveals that variations in technique are responsible for great differences in normal values. It is argued that smaller elevations of jugular venous pressure can only be measured reliably by adhering strictly to the conditions put forward by Borst and Molhuysen. In this way the sensitivity will improve considerably. A plea is made for an intensive training in this method for doctors and medical students.

A comparison has been made of insulin absorption rate and its variability in healthy subjects (n = 12), matched Type 1 diabetic patients (n = 12), and brittle Type 1 diabetic patients (n = 13) after subcutaneous injection with a standardized injection technique. In each individual 8 U of iodinated neutral human soluble insulin were injected twice, at the fat-muscle boundary. Disappearance of radioactivity was measured for 8 h. Differences in absorption rate could not be demonstrated (T50 207 +/- 30 (+/- SD), 224 +/- 73 and 217 +/- 80 min in the three groups, respectively). Intra-individual variance was similar in the three groups (intra-individual SD of T50 14 +/- 9, 10 +/- 6 and 12 +/- 10%, respectively). Injection with the skinfold technique each patient usually employed, did not alter mean absorption rate or its variability significantly (T50 179 +/- 52 min; intra-individual SD 12 +/- 8%). In a group of Type 1 diabetic patients (n = 26) the absorption rate after deep injection was compared with that after superficial injection. No differences were found (T50 207 +/- 66 vs 236 +/- 66 min). In some of these patients (n = 10) plasma free insulin and glucose concentrations were measured. The increase in free insulin concentrations was significantly different only at some time-points, but insulin curves and plasma glucose concentrations did not differ significantly. Thus neither insulin absorption nor its variability differ between healthy subjects and diabetic patients, between deep and superficial subcutaneous injection, or between stable and brittle diabetic patients.

The effect of partial ileal bypass surgery (PIB) on lipoprotein concentrations and compositions and on the catabolism of low-density lipoproteins (LDL) was studied in Watanabe heritable hyperlipidemic (WHHL) rabbits. After PIB, total serum cholesterol was 65% lower (6.22 +/- 1.58 vs. 17.24 +/- 3.22 mmol/l) and LDL cholesterol 81% lower (2.02 +/- 0.95 vs. 10.90 +/- 3.60 mmol/l) than in control WHHL rabbits; cholesteryl esters, expressed as percentage of mass, were 55% lower in the very-low and intermediate-density lipoprotein (VLDL + IDL) fractions, and 45% lower in LDL, whereas triacylglycerols were 89% higher in VLDL + IDL and 121% higher in LDL. The fractional catabolic rate (FCR) of LDL protein (apoLDL) from operated animals was 10% higher than that from controls in all animals (0.55 +/- 0.10 vs. 0.50 +/- 0.10 pools/day; P less than 0.01). The FCR of autologous apoLDL in PIB rabbits was 50% higher than that of autologous apoLDL in control rabbits (0.63 +/- 0.05 vs. 0.42 +/- 0.06 pools/day); this was not caused by induction of receptor-mediated clearance of LDL. The production rate of apoLDL after PIB in PIB rabbits was 50% lower compared to control apoLDL in controls (26.0 +/- 6.7 vs. 51.7 +/- 16.4 mg/kg per day). We conclude that PIB lowers LDL cholesterol in WHHL rabbits by a decreased production of LDL, by an increased non-specific clearance of LDL and by compositional changes, which lead to LDL particles containing less cholesterol.

Twenty patients with primary and 11 with secondary Raynaud's syndrome were treated with the alpha-adrenoceptor blocker phenoxybenzamine (10-20 mg daily). In the secondary group mean age and mean duration of symptoms as well as presence of positive ANA and positive Clq binding test were significantly higher than in the primary group. In both groups a beneficial effect of the medication on finger temperature 12 min after finger cooling and on clinical symptoms was established. Secondary Raynaud's syndrome reacted at least as well as primary syndrome.

In this retrospective study we report the results of treatment with clofibrate during at least 7 years in 9 patients with severe type III hyperlipoproteinemia. Initial treatment consisted of a diet, restricted in fat and calories, because of insufficient response additional therapy with 2 g clofibrate daily was given. Serum cholesterol decreased significantly from 14.3 +/- 4.4 mmol/l (mean +/- SD), on diet therapy, to average annual values ranging from 9.0 +/- 4.9 to 7.9 +/- 2.0 and serum triglycerides decreased significantly from 5.6 +/- 1.9 to average annual values from 3.8 +/- 1.8 to 2.0 +/- 0.7, despite a slight gain in bodyweight. Serious side-effects did not occur. After several years of treatment with clofibrate the drug was withdrawn temporarily. Serum lipids increased significantly in all patients to a level, not different from that before the start of drug therapy. It is concluded that clofibrate is a strong hypolipidemic drug for the treatment of type III hyperlipoproteinemia, which does not lose efficacy even after 7 years of use.

We studied polyethylene glycol 6000 precipitation of lipoproteins other than high-density lipoproteins, before cholesterol is estimated in the supernate. Other lipoproteins in the supernatant fractions were detected by using rocket immunoelectrophoresis. A polyethylene glycol concentration of 75 g/L in the final mixture appeared to be optimal, and results agreed with those obtained by ultracentrifugation. Differences in serum pH, use of polyethylene glycol from different suppliers, or the presence of ethylenediaminetetraacetate resulted in values that differed significantly (by 40 to 60 mumol/L) from the reference values. Polyethylene glycol did not interfere in four different methods for determination of cholesterol. In combination with an enzymic cholesterol method, the polyethylene glycol method appeared to be very precise, even when lipemic sera (triglycerides up to 5.5 mmol/L) were analyzed that had diminished high-density lipoprotein cholesterol values. We consider this method a method of choice, especially when lipemic sera are tested and enzymic cholesterol analysis is used.

Various claims, partially conflicting, have been made in recent years for abnormalities in cation pumps and fluxes in erythrocytes of patients with essential hypertension. In view of the obvious significance of such abnormalities for diagnostic purposes, and possibly for our understanding of the pathophysiology of essential hypertension, we have investigated these claims. We have determined the following parameters of erythrocytes from essential hypertensives and normotensives: 1. (Na+ + K+)-ATPase activity and the Km values for Na+, K+ and ATP; 2. ouabain-sensitive fluxes of Na+ and K+ in Na+-enriched cells after cold treatment and after treatment with p-chloromercuribenzenesulphonate; 3. furosemide-sensitive, ouabain-insensitive cotransport efflux of Na+ + K+. No significant differences were observed, except for a slight decrease in the ouabain-sensitive K+ influx after cold treatment in hypertensives. Hence, we conclude that determination of these parameters in erythrocytes does not seem to be useful for the diagnosis of essential hypertension.

The effects of chlorthalidone, spironolactone and propranolol in reducing blood pressure were compared in the same 11 normoreninemic hypertensive patients. All three drugs decreased the blood pressure significantly and no agent had a superior blood pressure-lowering effect. The blood pressure did not normalize. The data suggest that no one variable--volume factors, relative hyperactivity of the renin-aldosterone system or beta-adrenergic hyperactivity--is the prime mover in normoreninemic hypertension. Long-term treatment with chlorthalidone resulted in slight hyperreninism (26.3 +/- 4.9 ng-ml-1-3 hours-1) (mean +/- standard error) with concomitant changes in plasma aldosterone (23.0 +/- 3.2 ng-100 ml-1). The body weight decreased significantly (--1.8 kg, P less than 0.005). Plasma potassium concentrations were low (3.2 +/- 0.1 mEq-liter -1). Creatinine clearance was unimpaired (117 +/- 6 ml-min-1). Treatment with spironolactone resulted in more marked hyperreninism (47.0 +/- 14.3 ng-ml-1-3 hours-1) and hyperaldosteronism (61.9 +/-11.8 ng-100 ml-1). The body weight decreased significantly (--1.9 kg, P less than 0.004). Significant hyperkalemia occurred (4.4 +/- 0.1 mEq-liter-1). The glomerular filtration rate decreased significantly to 93 +/- 3 ml-min-1 (P less than 0.004). Treatment with propranolol resulted in marked suppression of the plasma renin activity (1.8 +/- 0.2 ng-ml-1-3 hours-1) and plasma aldosterone levels (8.9 +/- 1.3 ng-100 ml-1). A significant increase in body weight occurred (+2.3 kg, P less than 0.013). The plasma potassium concentration increased to a level not significantly different from the value found after treatment with spironolactone (4.2 +/- 0.1 mEq-liter-1). The creatinine clearance decreased significantly to 99 +/- 5 ml-min-1 (P less than 0.008). Hyperreninemia (by spironolactone and chlorthalidone), effective hyperaldosteronism (by chlorthalidone) and volume retention (by propranolol) are considered to represent expressions of mechanisms counteracting the depressor effects of these different pharmacologic maneuvers, leading to the maintenance of supranormal blood pressure.

Hypertensive patients have an unfavorable pressor response to exogenous epinephrine during nonselective beta-blockade. We studied hemodynamics during epinephrine release induced by handgrip exercise and mental arithmetic to examine the clinical relevance of this phenomenon. Twenty-two hypertensive patients were examined in a double-blind crossover experiment with placebo, propranolol (240 mg daily), placebo-washout, and metoprolol (300 mg daily). Changes induced by stress tests for systolic and diastolic blood pressure, heart rate (HR), and forearm blood flow (FBF) were of the same order on both beta-blockers. Rises in HR and FBF were equally reduced by both drugs. Neither handgrip exercise nor mental arithmetic induced significant differences in reaction during selective and nonselective beta-blockade.

A double-blind randomized study was designed to investigate differences in the recovery of finger skin temperature after finger cooling during dosing with placebo or one of four beta-blockers: propranolol, atenolol, pindolol, and acebutolol. In 11 normotensive nonsmoking subjects, finger skin temperature was measured with a thermocouple before and 20 minutes after immersion of one hand in a water bath at 16 degrees C. This finger cooling test caused no significant changes in systemic hemodynamics such as arterial blood pressure, heart rate, and forearm blood flow. The recovery of finger skin temperature during propranolol dosing was better than that during pindolol and atenolol dosing. There were no differences between the recoveries of skin temperature during pindolol, atenolol, and acebutolol dosing. Thus we could demonstrate no favorable effect of intrinsic sympathomimetic activity or beta 1-selectivity on the recovery of finger skin temperature after finger cooling.

We evaluated the density-gradient ultracentrifugation method in a swinging-bucket rotor (Anal Biochem 111, 149-157, 1981) in a slightly modified version for isolation and determination of high-density lipoprotein (HDL) subfractions. We prestained the serum with Coomassie Brilliant Blue R, which did not change the hydrated densities of the lipoproteins, and after only 2.2 X 10(8) gav . min obtained an equilibrium distribution of the lipoproteins along the gradient. The density distribution of the HDL of 120 sera obtained from apparently healthy persons and from patients with different types of hyperlipoproteinemia was bimodal. The HDL2 could be isolated in the density range 1.072-1.098 kg/L and the HDL3 at 1.100-1.176 kg/L, the latter fraction being more heterogeneous. At a solvent density of 1.100 we obtained similar results for HDL2-and HDL3-cholesterol by ultracentrifugation in two different fixed-angle rotors with tube angles of 15 degrees or 35 degrees. Independent of the rotor and the ultracentrifugation technique, subfractionation at d = 1.100 resulted in more distinct stained entities than ultracentrifugation at d = 1.125. In the swinging-bucket rotor procedure, interference by sinking pre-beta-lipoproteins was minimized because, having hydrated densities between 1.058 and 1.075, they could be removed without aspirating the HDL2. The method is both accurate and precise. For HDL2- and HDL3-cholesterol determined in a thawed frozen serum pool, CVs were 8.8 and 6.3%, respectively (n = 18).

Two low-density lipoprotein subfractions, LDL-1 and LDL-2, with density ranges of respectively 1.023-1.034 and 1.036-1.041 g/ml, were isolated by aspiration after density gradient ultracentrifugation of human pooled serum. In vitro interactions of both LDL subfractions with the LDL receptor of human cultured fibroblasts, human hepatoma cell line Hep G2 and human hepatocytes were compared. No difference in association (binding and internalization) nor in degradation between LDL-1 and LDL-2 by these cells was found. However, kinetic studies in guinea pigs showed that LDL-2 disappeared faster from the circulation and accumulated to a greater extent in the liver, compared to LDL-1. Thus, we were unable to show a difference in the LDL receptor-mediated uptake of both LDL subfractions by various cells in vitro. The results obtained in vivo suggest that LDL-1 is more atherogenic than LDL-2, because its longer half-life renders the particle more susceptible to uptake by the scavenger LDL receptor on macrophages.

Several studies report a substantial rise in plasma catecholamines after caffeine. Epinephrine infusion induces a pressor response after nonselective beta-blockade. We studied the hemodynamic and humoral effects of drinking coffee after placebo and after both nonselective (propranolol) and beta 1-selective (metoprolol) blockade in 12 normotensive subjects. After placebo, coffee induced a rise in systolic and diastolic blood pressure and a fall in heart rate, whereas forearm blood flow did not change. Plasma catecholamines, especially epinephrine (+150%), rose and plasma renin activity, fell after drinking coffee. The effects of coffee on blood pressure, forearm blood flow, and all humoral parameters were not altered by pretreatment with propranolol or metoprolol. The fall in heart rate after coffee, however, seemed to be greater during propranolol. We conclude that the rise in plasma epinephrine after coffee was too small to reveal differences in reaction in propranolol- and metoprolol-pretreated subjects.

The influence of insulin antibodies on absorption rate and plasma free insulin concentrations after subcutaneous injection of insulin, was studied in two groups of insulin-treated diabetic patients, one without insulin antibodies (n = 9) and a second with high plasma concentrations of antibodies (n = 14). Except for antibody concentration there were no differences in clinical variables. During 8 h after the injection of 12 U of iodinated neutral human insulin, residual radioactivity at the injection site, plasma glucose, and free and total insulin were measured. Significant differences in absorption rate of insulin were not found between the groups. Plasma glucose (basal value 16.8 +/- 4.4 SD vs 16.1 +/- 4.2 mmol l-1) and free insulin (basal value 8.3 +/- 1.4 vs 11.4 +/- 2.3 mU l-1, maximum after 90 min 36.9 +/- 19.5 vs 30.5 +/- 18.7 mU l-1) were never significantly different between the groups, nor were areas under the curve for free insulin (191.4 +/- 69.2 vs 170.8 +/- 98.6 mU l-1 h). In the high antibody group a small increase in bound insulin was found.

In the oral glucose tolerance test (OGTT), divergent doses of glucose remain in use by virtue of the prevailing conviction that the size of the loading dose hardly affects the outcome of the test. We compared the results of OGTTs with 100-gm. and 50-gm. loads in 85 patients, who were selected for slightly impaired glucose tolerance (plasma glucose at 120 minutes after 100 gm. of glucose was between 130 and 200 mg./dl.) The mean between-load difference in this group appeared to be nearly three times as great (54 mg./dl. at 120 minutes) as reported in the literature for normal subjects. The small impact of the dose in normal subjects could be confirmed in a group of 22 controls. As subjects with normal and with slightly impaired glucose tolerance react divergently to a change in the glucose dose, tests with different loads are not comparable and select different populations. The results can therefore also not be converted to one another by conversion formulas. The finding might be explained by the delay of the additional rise of the plasma insulin in patients after the higher load.

Early insulin responses were measured after a high dose (50 g/1.73 m2) of rapidly injected glucose in 31 subjects who had repeatedly shown "lag-storage" curves in the OGTT, in 24 controls and in 19 mild maturity-onset diabetics. Division between controls and diabetics was virtually complete, when the insulin responses were expressed as "insulinogenic index" (delta insulin/delta glucose). Twenty out of 31 patients with lag curves showed normal early insulin responses and 11 patients showed diabetic responses. In patients with lag curves, presence of obesity, and absence of family history of diabetes were associated with normal insulin responses. It is concluded that the finding of a lag curve is of little consequence in obese persons but, when in conjunction with a genetic background of diabetes, is suggestive of diabetes.

A comparative study of the effects of cholestyramine and neomycin has been carried out in 35 patients with severe type II hyperlipoproteinaemia. Both agents were administered during a period of 18 weeks, the daily dosages being 12, 16 or 20 g cholestyramine and 1, 1.5 or 2 g neomycin. The mean decrease in cholesterol concentration was 22% with cholestyramine and 23% with neomycin. There was no difference in effect between the two agents and between the doses used. No significant influence on triglyceride concentration and on body weight was observed. No signs of deficiencies in fat-soluble vitamins were found. Anticoagulant requirements increased during cholestyramine medication. No signs of hyperchloraemic acidosis were observed during treatment with colestyramine. Cholestyramine was tolerated less well than neomycin: it had to be discontinued in 8 cases. Neomycin was not tolerated by 3 patients. The majority of the patients preferred neomycin.

Ethinylestradiol (1 microgram/kg/day during 15 days) resulted in a gradual decrease of serum cholesterol, serum triglycerides (TG), very low density lipoprotein (VLDL) cholesterol and VLDL-TG in 2 postmenopausal women and 2 men with type III hyperlipoproteinemia (HLP). The turnover rate of VLDL-TG did not change. These findings contrast with previous observations in normal subjects and patients with type IV HLP. Thus, the catabolism of VLDL and VLDL-remnants increased during treatment with estrogen in type III HLP, probably by direct degradation of VLDL-remnants because in the initial days of treatment no increase of LDL-cholesterol was observed.

Skin temperature of one finger was measured before and after immersion of the gloved fingers of both hands in 16 degrees C water for 5 min [room temperature (Ta) 24 or 20 degrees C]. At Ta 24 degrees C, 23 of 25 normal nonsmokers (92%) had finger rewarming to above 24 degrees C in 12 min after cold immersion, at Ta 20 degrees C, only 1 of 12 (8%) had similar rewarming. Among 12 habitual smokers only 4 (33%) rewarmed above 24 degrees C (Ta 24 degrees C) following a 1-h abstinence from smoking, but 8 (67%) did so after a 24-h abstinence. Only 2 of these 8, however, did so in a retest 10 min after smoking a cigarette. The smokers were not tested at Ta 20 degrees C. We conclude that air temperature and cigarette smoking are important determinants of finger rewarming following a finger-cooling test.