Effects of 20 mg rosuvastatin on VLDL1-, VLDL2-, IDL- and LDL-ApoB kinetics in type 2 diabetes.

AIMS/HYPOTHESIS: In addition to its efficacy in reducing LDL-cholesterol, rosuvastatin has been shown to significantly decrease plasma triacylglycerol. The use of rosuvastatin may be beneficial in patients with type 2 diabetes, who usually have increased triacylglycerol levels. However, its effects on the metabolism of triacylglycerol-rich lipoproteins in type 2 diabetic patients remains unknown. METHODS: We performed a randomised double-blind crossover trial of 6-week treatment with placebo or rosuvastatin 20 mg in eight patients with type 2 diabetes who were being treated with oral glucose-lowering agents. In each patient, an in vivo kinetic study of apolipoprotein B (ApoB)-containing lipoproteins with [13C]leucine was performed at the end of each treatment period. A central randomisation centre used computer-generated tables to allocate treatments. Participants, caregivers and those assessing the outcomes were blinded to group assignment. RESULTS: Rosuvastatin 20 mg significantly reduced plasma LDL-cholesterol, triacylglycerol and total ApoB. It also significantly reduced ApoB pool sizes of larger triacylglycerol-rich VLDL particles (VLDL1; p = 0.011), smaller VLDL particles (VLDL2; p = 0.011), intermediate density lipoprotein (IDL; p = 0.011) and LDL (p = 0.011). This reduction was associated with a significant increase in the total fractional catabolic rate of VLDL1-ApoB (6.70 +/- 3.24 vs 4.52 +/- 2.34 pool/day, p = 0.049), VLDL2-ApoB (8.72 +/- 3.37 vs 5.36 +/- 2.64, p = 0.011), IDL-ApoB (7.06 +/- 1.68 vs 4.21 +/- 1.51, p = 0.011) and LDL-ApoB (1.02 +/- 0.27 vs 0.59 +/- 0.13, p = 0.011). Rosuvastatin did not change the production rates of VLDL2-, IDL- or LDL-, but did reduce VLDL1-ApoB production rate (12.4 +/- 4.5 vs 19.5 +/- 8.4 mg kg(-1) day(-1), p = 0.035). No side effects of rosuvastatin were observed during the study. CONCLUSIONS/INTERPRETATION: In type 2 diabetic patients rosuvastatin 20 mg not only induces a significant increase of LDL-ApoB catabolism (73%), but also has favourable effects on the catabolism of triacylglycerol-rich lipoproteins, e.g. a significant increase in the catabolism of VLDL1-ApoB (48%), VLDL2-ApoB (63%) and IDL-ApoB (68%), and a reduction in the production rate of VLDL1-ApoB (-36%). The effects of rosuvastatin on the metabolism of triacylglycerol-rich lipoproteins may be beneficial for prevention of atherosclerosis in type 2 diabetic patients.

Normal metabolism of apolipoprotein B100-containing lipoproteins despite qualitative abnormalities in type 1 diabetic men.

AIMS/HYPOTHESIS: Type 1 diabetic subjects are at increased risk of cardiovascular disease and exhibit multiple qualitative abnormalities of apolipoprotein (apo) B100-containing lipoproteins. This stable isotope kinetic experiment was designed to study whether these abnormalities are associated with changes in the synthesis and fractional catabolic rates of VLDL-, IDL- and LDL-apoB100. METHODS: Using a bolus followed by a 16-h constant infusion of 13C-leucine, we performed a kinetic study in eight men with type 1 diabetes treated with a continuous subcutaneous insulin infusion administered by an external pump and in seven healthy men, in the fed state. RESULTS: The mean HbA1c level in the type 1 diabetic patients was 8.00+/-1.48%. Plasma triglyceride, and total, LDL and HDL cholesterol levels were similar in patients and control subjects. VLDL were less triglyceride rich in type 1 diabetic patients than in control subjects (VLDL triglyceride : apoB 6.91+/-0.81 vs 8.29+/-1.24 mmol/g, p=0.05). Conversely, the IDL and LDL of the type 1 diabetic patients contained relatively higher levels of triglycerides (IDL triglycerides : apoB 2.16+/-0.36 vs 1.57+/-0.30 mmol/g, p<0.01; LDL triglycerides : apoB 0.27+/-0.06 vs 0.16+/-0.04 mmol/g, p<0.05). The apoB100 pool size, production and fractional catabolic rates in the two groups of subjects were similar for all lipoprotein fractions. CONCLUSIONS/INTERPRETATION: Despite qualitative abnormalities, especially abnormalities of triglyceride content, the metabolism of apoB100-containing lipoproteins is not altered in type 1 diabetic men with fair glycaemic control with continuous subcutaneous insulin infusion. The high risk of atherosclerosis in these patients cannot be explained by kinetic abnormalities of apoB100-containing lipoproteins.

High-density lipoprotein apolipoprotein A-I kinetics in obese insulin resistant patients. An in vivo stable isotope study.

AIMS/HYPOTHESIS: Mechanisms responsible for the decreased high-density lipoprotein (HDL) cholesterol level associated with insulin resistance in obese patients are not clearly understood. To determine the influence of insulin resistance at an early stage on HDL metabolism, we performed a stable isotope kinetic study of apolipoprotein (apo) A-I, in five obese insulin resistant women with normal fasting triglycerides and without impaired glucose tolerance, and in five age-matched control women. METHODS: Each subject received a 16 h constant infusion of L-[1-(13)C]leucine at 0.7 mg/kg/h following a primed bolus of 0.7 mg/kg. RESULTS: ApoA-I fractional catabolic rate (FCR) was significantly increased in insulin-resistant women compared to controls (0.316+/-0.056 vs 0.210+/-0.040 per day, P<0.01), indicating a significant 50% increase of apoA-I catabolism, leading to an important reduction of plasma apoA-I residence time (3.25+/-0.59 vs 4.92+/-1.11, P<0.01). ApoA-I production rate tended to be higher in insulin resistant women than in controls (364+/-77 vs 258+/-60 mg/l/day, P=0.13), but the difference was not statistically significant. ApoA-I FCR was correlated with triglycerides during the fed state (r=0.69; P=0.026) and HDL triglycerides-esterified cholesterol ratio (r=0.73; P=0.016), suggesting that alteration of apoA-I metabolism in insulin resistance may be partly related to HDL enrichment in triglycerides. CONCLUSIONS: Our kinetic study shows that patients, at an early stage of insulin resistance (without impaired glucose tolerance nor fasting hypertriglyceridaemia), already have a significant alteration of apoA-I metabolism (increased apoA-I catabolism), which is consistent with the increased risk of atherosclerosis in this population.

LDL-receptors expression in HIV-infected patients: relations to antiretroviral therapy, hormonal status, and presence of lipodystrophy.

BACKGROUND: Abnormalities in lipid levels and lipodystrophy (LD) have been commonly reported after commencement of highly active antiretroviral therapy (HAART). A major mechanism by which plasma low-density lipoprotein (LDL) cholesterol levels may be influenced is via the regulation of hepatic LDL receptor expression. The activity of LDL receptors is under hormonal control. Moreover, HIV infection and HAART are associated with important modifications of hormonal status. As the cause of these adverse reactions is unknown, the effects of HAART and lipodystrophy on LDL receptors were evaluated. MATERIALS AND METHODS: Thirty-nine HIV treated patients (21 with a protease inhibitor (PI) containing regimen, 18 without PI use) and 22 control subjects were tested for insulin resistance (HOMA model assessment), lipid profile, serum concentration of dehydroepiandrosterone (DHEA) and LDL-R expression. LDL-R on mononuclear cells were quantified by flow cytrometry. RESULTS: Among the 39 HIV infected patients, 14 patients had a lipodystrophy (LD). Patients with LD had significantly higher levels of triglyceride (TG) and insulin resistance compared to patients without LD. There was no significant difference in LDL-R count between patients with or without PI use. In contrast, LDL-R count was significantly lower in patients with LD compared with those without (8504 +/- 3901 vs. 13 200 +/- 4532, P = 0.001). There was no difference in LDL-R count between patients without LD and control subjects. Patients with LD had lower levels of DHEA compared to patients without LD. In HIV-infected patients, we found a significant correlation between LDL-R expression and TG (r = -0.32; P = 0.04) and LDL cholesterol (r = -0.33; P = 0.04). In contrast, we did not observe a correlation between DHEA level and LDL-R count or LDL cholesterol level. CONCLUSIONS: HIV-lipodystrophy is associated with a lower expression of LDL-R. This decreased expression of LDL-R seems independent of DHEA or insulin secretion.

Inefficiency of insulin therapy to correct apolipoprotein A-I metabolic abnormalities in non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with low high density lipoprotein (HDL) cholesterol and apoA-I, related to an increased apoA-I fractional catabolic rate. This stable isotope kinetic experiment, using L-[1-(13)C] leucine, was designed to study the effect of insulin therapy on HDL apoA-I and A-II metabolism in poorly controlled NIDDM patients. A kinetic study was performed in five control subjects and in six NIDDM patients before and two months after the introduction of insulin therapy. ApoA-I and A-II were modelled using a monoexponential function. Insulin treatment was able to correct neither the low HDL apoA-I concentration observed in NIDDM patients (1.14+/-0.19 vs. 1.16+/-0. 12 g l(-1) (controls: 1.33+/-0.14)), nor the HDL apoA-I hypercatabolism (0.39+/-0.11 vs. 0.34+/-0.05 pool d(-1), (controls: 0.23+/-0.01, P< 0.01)). HDL apoA-I production rate was increased in NIDDM patients compared to control subjects and was not modified by insulin (0.45+/-0.12 vs. 0.39+/-0.08 g d(-1) l(-1), (controls: 0. 31+/-0.04, P< 0.05)). HDL apoA-II kinetic parameters were initially not significantly different between NIDDM patients and control subjects, and were not modified by insulin. The decreased insulin sensitivity, assessed by the insulin suppressive test, was not modified by insulin therapy in NIDDM patients. HDL apoA-I fractional catabolic rate was significantly correlated to HDL triglyceride/cholesteryl ester and triglyceride/protein ratios, which were significantly higher in NIDDM patients than in controls and were not modified by insulin therapy. The persistence of insulin resistance and of high neutral lipid exchanges between triglyceride rich lipoproteins and HDL in insulin-treated NIDDM patients probably explain the inefficiency of insulin therapy to correct HDL apoA-I metabolic abnormalities.

Metabolic abnormalities of apolipoprotein B-containing lipoproteins in non-insulin-dependent diabetes: a stable isotope kinetic study.

BACKGROUND: Kinetic abnormalities of apolipoprotein B (apoB)-containing lipoproteins in noninsulin-dependent diabetes mellitus (NIDDM) remain poorly understood. To get further insight into these abnormalities we performed a stable isotope kinetic experiment comparing the metabolism of apoB-containing lipoproteins in moderately severe NIDDM patients and healthy control subjects. METHODS: The study was performed in the fed state. Subjects underwent a primed infusion of 0.7 mg kg(-1) of L-[1-(13)C]leucine followed by a 16-h constant infusion of 0.7 mg kg(-1) h(-1). [13C]Leucine enrichment in apoB was measured by gas chromatography/combustion/isotope ratio mass spectrometry. RESULTS: In NIDDM patients, we observed a 3.49- and 4.52-fold increase of very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) apoB plasma concentrations, respectively (P<0.01). VLDL apoB production was increased by 41% (P<0.05) and fractional catabolic rate towards IDL and low-density lipoprotein (LDL) was decreased by 61% (P<0.05). The increased IDL apoB plasma concentration was also related to a major catabolic defect (-78%; P<0.01). For most patients, plasma LDL apoB concentration was comparable to that of controls. Nevertheless, LDL apoB metabolism was impaired in NIDDM subjects, with both a decreased LDL catabolic rate (-28%; P<0.05) and a trend towards a diminished synthesis. CONCLUSION: NIDDM is associated with multiple apoB metabolism abnormalities that are potentially atherogenic. In addition to the increased number of circulating VLDL and IDL particles, the increased residence time observed on all apoB-containing lipoproteins may promote the development of atherosclerotic lesions, by potentiating their oxidizability.

Significant improvement of apolipoprotein B-containing lipoprotein metabolism by insulin treatment in patients with non-insulin-dependent diabetes mellitus.

AIMS/HYPOTHESIS: Patients with Type II (non-insulin-dependent) diabetes mellitus have multiple abnormalities in apolipoprotein B (apoB)-containing lipoprotein metabolism. These abnormalities are likely to play an important part in the development of premature atherogenesis in these patients. This stable isotope kinetic experiment was designed to study the effect of insulin therapy on apoB metabolism in poorly controlled Type II diabetic patients. METHODS: Using L-[1-13C] leucine, we studied apoB metabolism in five control subjects without insulin resistance and in six poorly controlled Type II diabetic patients before and 2 months after the introduction of insulin therapy. RESULTS: Insulin treatment induced a decrease of very low density lipoprotein apoB plasma concentration [121 +/- 42 vs 158 +/- 91 mg.l-1, p < 0.05 (control subjects: 48 +/- 20)], related to an increased catabolism of very low density lipoprotein towards intermediate density lipoprotein or low density lipoprotein [0.20 +/- 0.08 vs 0.14 +/- 0.07 pool.h-1, p < 0.05 (control subjects: 0.36 +/- 0.10)]. On the other hand, insulin treatment induced an acceleration of intermediate density lipoprotein apoB turn-over without changing its plasma concentration [77 +/- 37 vs 61 +/- 18 mg.l-1, (control subjects: 17 +/- 3)], by increasing both its production rate [22.6 +/- 9.2 vs 18.2 +/- 9.6 mg.l-1.h-1, p < 0.05 (control subjects: 18.4 +/- 3.2)] and its catabolic rate towards low density lipoprotein [0.34 +/- 0.22 vs 0.22 +/- 0.16 pool.h-1, p < 0.05 (control subjects: 1.02 +/- 0.13)]. Likewise, insulin treatment increased low density lipoprotein apoB production rate [20.2 +/- 7.4 vs 16.9 +/- 7.7 mg.l-1.h-1, p < 0.05 (control subjects: 16.9 +/- 2.3)] and restored a normal low density lipoprotein apoB fractional catabolic rate [0.022 +/- 0.004 vs 0.018 +/- 0.004 pool.h-1, p < 0.05 (control subjects: 0.025 +/- 0.004)], resulting in a constant low density lipoprotein apoB plasma concentration [965 +/- 485 vs 984 +/- 558 mg.l-1 (control subjects: 699 +/- 106)]. CONCLUSION/INTERPRETATION: Insulin treatment in Type II diabetes induces profound metabolic modifications of lipoprotein, resulting in significant decrease of the intravascular residence time of very low density lipoprotein, intermediate density lipoprotein and low density lipoprotein particles. This is likely to make these particles less harmful.

Role of lipoprotein-bound NEFAs in enhancing the specific activity of plasma CETP in the nephrotic syndrome.

Plasma cholesteryl ester transfer protein (CETP) activity, evaluated by the transfer of radiolabeled cholesteryl esters from a tracer dose of tritiated HDL to the plasma apolipoprotein B-containing lipoproteins, was significantly higher in patients with untreated idiopathic nephrotic syndrome (n = 15) than in normolipidemic control subjects (n = 22) (81.5 +/- 8.4 versus 43.1 +/- 3.1 micrograms CE.mL-1.h-1, respectively; P < .001). The increased CETP activity in nephrotic plasma was explained by a significant rise in both the CETP mass concentration (3.2 +/- 0.2 versus 2.1 +/- 0.1 mg/L; P < .001), and the specific CETP activity, calculated as the ratio of CETP activity to CETP mass (25.3 +/- 1.7 versus 20.4 +/- 1.6 micrograms CE.mg-1.h-1; P < .05). Elevated CETP activity in nephrotic patients was shown to be associated with a significant decrease in the mean size of LDL (24.4 +/- 0.5 versus 26.3 +/- 0.5 nm; P < .0001) as well as in the relative abundance of HDL2a (29.6 +/- 1.6% versus 34.8 +/- 1.1%; P < .05). The nephrotic syndrome was characterized by a significant increase in the relative proportion of lipoprotein-bound nonesterified fatty acids (NEFAs) (35.4 +/- 7.7% versus 7.6 +/- 3.0% of total; P < .01), leading to a significant increase in the electronegative charge of LDL (-4.3 +/- 0.1 versus -3.9 +/- 0.1 mV; P < .05) and HDL (-11.5 +/- 0.1 versus -11.1 +/- 0.2 mV; P < .05). Compared with native, non-supplemented plasma, removal of lipoprotein-bound NEFAs by addition of fatty acid-poor albumin to total plasma from nephrotic patients or control subjects significantly decreased CETP activity and specific CETP activity. Specific CETP activity no longer differed between nephrotic and control groups after albumin supplementation (19.7 +/- 1.5 versus 17.7 +/- 1.5 micrograms CE.mg-1.h-1; NS). It is concluded that, in addition to elevated CETP mass concentration, lipoprotein-bound NEFAs, by increasing the negative electrostatic charge of nephrotic lipoproteins, can facilitate the CETP-mediated neutral-lipid transfer reaction in total plasma from nephrotic patients.

Modulation of the activity of the human cholesteryl ester transfer protein by carboxylated derivatives. Evidence for 13-cis-retinoic acid as a potent activator of the protein's activity in plasma.

The influence of palmitic acid, 13-cis-retinoic acid, all-trans-retinoic acid, and all-trans-retinol on the activity of the human cholesteryl ester transfer protein (CETP) was evaluated either in total human plasma supplemented with a tracer dose of 3H-labeled cholesteryl-ester-containing high-density lipoprotein sub-fraction 3 ([3H]CE-HDL3), or in reconstituted mixtures containing [3H]CE-HDL3, isolated low-density lipoproteins (LDL), and purified CETP. In reconstituted mixtures, all the carboxylated derivatives increased progressively and significantly the transfer of 3H-labeled cholesteryl esters from [3H]CE-HDL3 towards LDL in the 20-100 microM concentration range. Under identical experimental conditions, CETP activity was only minimally modified in the presence of all-trans-retinol. When present at a concentration of 60, 80, or 100 microM, 13-cis-retinoic acid was a significantly more potent activator of CETP activity than all the other derivatives studied (P < 0.01 in all cases). In contrast to observations made with reconstituted mixtures, only 13-cis-retinoic acid, but not palmitic acid, was able to induce a significant, concentration-dependent stimulation of CETP activity in total human plasma. In fact, differences in the ability of 13-cis-retinoic acid and palmitic acid to modulate the plasma cholesteryl ester transfer reaction were linked to their relative affinity for albumin and lipoprotein substrates: fatty-acid-poor albumin reduced CETP activity to a significantly greater extent in reconstituted mixtures containing palmitic acid than in reconstituted mixtures containing 13-cis-retinoic acid (P < 0.01 for all the incubation mixtures in the 1-10 g/l albumin concentration range); palmitic acid presented a markedly lower ability to increase the electrophoretic mobility of LDL and HDL fractions in total plasma than 13-cis-retinoic acid. In support of a key role of the negatively charged carboxylic group of 13-cis-retinoic acid in upregulating CETP activity, cholesteryl ester transfer rates correlated positively with the electrophoretic mobility of LDL (r = 0.98; P < 0.0002) and HDL (r = 0.96; P < 0.0008) in total plasma supplemented with the carboxylated compound. It is concluded that 13-cis-retinoic acid can upregulate the CETP-mediated cholesteryl ester transfer reaction both in reconstituted mixtures containing isolated lipoproteins and purified CETP, and in total normolipidemic human plasma.

Increased cholesteryl ester transfer activity in plasma from analbuminemic patients.

Hypercholesterolemia associated with analbuminemia, an inherited disease manifesting low plasma albumin concentration, is characterized by enhanced LDL cholesterol levels and reduced HDL cholesterol levels. In addition, compared with normal counterparts, the esterified cholesterol:triglyceride ratio tends to be higher in analbuminemic apoB-containing lipoproteins and lower in analbuminemic HDL. The aim of the present study was to investigate the mechanism that may account for the association of a hypoalbuminemic state with alterations in the concentration and composition of plasma lipoprotein fractions. To this end, endogenous cholesterol esterification activity, phospholipid transfer activity, and cholesteryl ester transfer activity were measured in total plasma from three analbuminemic patients and five control subjects. Whereas endogenous cholesterol esterification and phospholipid transfer rates were not significantly affected in analbuminemia, the transfer of radiolabeled cholesteryl esters from HDL toward apoB-containing lipoproteins was constantly higher in analbuminemic plasmas than in normal control plasma (473.6+/-107.3% x h(-1) x mL(-1) versus 227.5+/-84.0% x h(-1) x mL(-1), respectively; P=.036). The rise in cholesteryl ester transfer protein (CETP) activity in analbuminemic plasma was due to a significant increase in the transfer of radiolabeled cholesteryl esters toward LDL but not toward the triglyceride-rich lipoproteins. The CETP mass was higher in analbuminemic patients than in control subjects, but the difference did not reach the significance level (5.18+/-0.82 mg/L versus 3.13+/-1.19 mg/L respectively; P=.07). Since abnormally elevated nonesterified fatty acid (NEFA) levels were shown to be associated with analbuminemic lipoproteins, mostly LDL, the direct role of lipoprotein-bound NEFA in enhancing CETP activity was suspected. In support of this view, supplementation of total plasmas with fatty acid-poor albumin was shown to reduce CETP activity to a significantly greater extent in analbuminemic plasmas than in normal control plasma. It is concluded that hyperlipidemia associated with the hypoalbuminemic state can relate, at least in part, to the combined effect of CETP and NEFA in promoting the transfer of cholesteryl esters from the antiatherogenic HDL toward the proatherogenic apoB-containing lipoproteins.

Evidence for nonesterified fatty acids as modulators of neutral lipid transfers in normolipidemic human plasma.

The relations between the level of plasma nonesterified fatty acid (NEFA) and both the mass concentration and activity of the cholesteryl ester transfer protein (CETP) were studied in fasted normolipidemic subjects. Plasma NEFA correlated positively with both CETP mass concentration (r = .50; P < .01) and the transfer of cholesteryl ester from HDL toward plasma VLDL+LDL (CETHDL-->VLDL+LDL activity) (r = .46; P < .05) but not with the transfer of cholesteryl ester from LDL toward plasma HDL (CETLDL-->HDL activity) (r = .05; NS). The high binding capacity of albumin for NEFA was used to investigate whether lipoprotein-bound NEFAs were implicated in the modulation of the cholesteryl ester transfer reaction. As compared with nonsupplemented controls, the addition of an excess of fatty acid-free albumin (8 g/L) to total normolipidemic plasmas reduced CETHDL-->VLDL+LDL activity (18.3 +/- 5.5% versus 9.8 +/- 3.1%; P < .0001) but not CETLDL-->HDL activity (22.3 +/- 4.5% versus 23.3 +/- 5.1%; NS). Moreover, CETHDL-->VLD+LDL and CETLDL-->HDL activities correlated negatively when measured in native plasma (r = -.45; P < .05) but positively when measured in albumin-supplemented plasma (r = .40; P < .05). In long-term incubation experiments, lipoprotein-bound NEFA increased the net mass transfer of cholesteryl esters from HDL toward VLDL+LDL but reduced the net mass transfer of triglycerides in the opposite direction, from VLDL+LDL toward HDL. Taken together, data of the present study brought strong and concordant arguments in favor of a dual effect of plasma NEFA in modulating both the mass and the activity of CETP in vivo.

Polyacrylamide gradient gel electrophoresis as a method to measure transfers of radiolabeled cholesteryl esters between several plasma lipoprotein fractions.

In human plasma, cholesteryl esters can redistribute between various lipoprotein fractions through an exchange reaction mediated by the cholesteryl ester transfer protein. In the present study, liquid scintillation counting of polyacrylamide gradient gel fragments was applied to the determination of transfers of radio-labeled cholesteryl esters between different lipoprotein fractions. This method consisted in four successive steps: (1) incubation of total human plasmas with a tracer dose of high-density lipoproteins (HDL) containing tritium 3H-labeled cholesteryl esters, (2) separation of plasma lipoprotein fractions by electrophoresis in 20-160 g/liter polyacrylamide gels, (3) cutting off and dissolution with a NaOCl solution of polyacrylamide gel fragments which contained the different lipoprotein fractions, (4) liquid scintillation counting of the dissolved gel fragments. The present method provided a convenient and accurate method of determining the rate of cholesteryl ester transferred between several plasma lipoprotein classes. As an example, it was applied to the measurement of the rates of radiolabeled cholesteryl esters transferred from either HDL3 or HDL2 toward the two other main plasma lipoprotein fractions, very-low-density lipoproteins and low-density lipoproteins.

Kinematics of spontaneous breathing: the ventilatory system as a non-linear oscillator.

The kinematics of spontaneous breathing at rest and during moderate exercise is described exactly by a non-linear differential equation, the parameters of which are determined by observation with a pneumotachograph. Analogue circuits are used for the determination of the coefficients and for the comparison by superimposition of the actual spirogram with its simulation. The ventilatory system, taken as a whole and without any assumption concerning its structure, works as a non-linear oscillator. If the classical distinction between a passive and an active ventilatory system is accepted, the concept of a linear equivalent of a non-linear oscillator is valid for the description of the properties of the passive system. It affords some of the advantages of linear mechanics and indicates the restrictions put upon the use of a linear hypothesis. The role of the different terms in determining the pattern of breathing is displayed and the correlation of scale factors with body size is shown. The physiological meaning of the components of muscle action is discussed.