Lidocaine disposition in obesity

Fourteen obese men (mean weight 124 ± 8 kg (± standard error of the mean), percent ideal body weight (IBW) 169 ± 10%), 11 obese women (96 ± 6 kg; 174 ± 11% IBW), 19 control men (69 ± 1 kg; 93 ± 2% IBW), and 12 control women (59 ± 2 kg; 102 ± 3% IBW), all of similar age and without clinical or laboratory evidence of cardiac or renal dysfunction, received a single 25-mg intravenous dose of lidocaine. Elimination half-life was markedly prolonged in obese compared with control men (2.69 ± 0.2 vs 1.62 ± 0.06 hour, p < 0.001) and in obese compared with control women (2.95 ± 0.1 vs 2.08 ± 0.06 hour, p <0.01). This was not the result of a change in clearance (men, obese vs control: 1,427 ± 117 vs 1,346 ± 86 ml/min, difference not significant, [NS]; women: 1,089 ± 83 vs 1,162 ± 84 ml/min, NS), but rather of an increased absolute volume of distribution (Vd) in obese men (325 ± 29 vs 186 ± 12 liters, p <0.001) and obese women (264 ± 20 vs 209 ± 15 liters, p <0.025). Vd corrected for total body weight was unchanged in obesity for both men (2.67 ± 0.22 vs 2.71 ± 0.18 1/kg, NS) and women (2.88 ± 0.31 vs 3.57 ± 0.25, NS), suggesting that lidocaine Vd increases in parallel with body weight in both sexes. Because lidocaine clearance is determined mainly by hepatic blood flow, these findings suggest that extremes of body weight do not change hepatic blood flow. However, lidocaine distribution is markedly increased in obese subjects of either sex, and is distributed to the same extent into excess body weight as into IBW. Lidocaine loading doses in obese persons should be calculated based on total body weight, but infusion rate should not be changed.     

Cimetidine Disposition in Obesity

Cimetidine pharmacokinetics were studied in 13 otherwise healthy but obese volunteers, having a mean body weight of 113 kg and a mean percentage ideal body weight (IBW) of 179%. Sixteen healthy volunteers of normal body habitus (64 kg, 99% IBW) served as controls. All subjects had normal renal function and no laboratory or clinical evidence of hepatic or cardiac dysfunction. After administration of 200-300 mg of cimetidine by rapid intravenous injection, multiple plasma samples obtained over the next 24 h were analyzed for cimetidine concentration by high pressure liquid chromatography. Elimination half-life was not different between obese and control subjects (2.23 versus 2.08 h). Apparent volume of distribution was also similar between subject groups (120 versus 106), as was total metabolic clearance (616 versus 579 ml/min). Using percentage IBW as a measure of obesity, no relationship was found between percentage IBW and apparent volume of distribution (r = 0.29). Cimetidine similarly distributes into IBW in both obese and normal weight subjects, and there is minimal distribution of cimetidine into excess body weight over IBW. Furthermore, there is no difference in total metabolic clearance or half-life of cimetidine between obese and control subjects. Cimetidine dosage in clinical practice should therefore be calculated on the basis of IBW, which better reflects lean body mass, instead of total body weight, which reflects adipose tissue weight in addition to lean body mass.     

Relationship of plasma sex hormones to different parameters of obesity in male subjects

Relationships between plasma sex hormones and different parameters of obesity (weight, ideal body weight [IBW], overweight, fat mass, and body surface) were investigated in 70 healthy nonobese and obese males, 20–40 yr of age and with a body weight of 85%–245% of IBW. Plasma sex hormones remained unaffected by weight up to approximately 160% of the IBW. Only in the massively obese subjects was plasma testosterone decreased to 40% of controls (from 6.2 to 2.5 ng/ml), whereas free testosterone remained almost constant. On the other hand, plasma estrone and estradiol exhibited significant increases in obese subjects, ranging from 31.5 ± 5.3 to 52.3 ± 5.8 pg/ml for estrone, and 25.4 ± 5.4 increasing to 44.7 ± 5.0 pg/ml for estradiol. Similarly, free estradiol was shown to significantly increase with obesity in men from 505 ± 118 to 991 ± 123 fg/ml (p < 0.001). The ratios of testosterone/androstenedione, as well as of estradiol/estrone, were not affected by obesity, suggesting that reduction of the 17-oxo-group of the steroids is not influenced by the amount of fat tissue. A significant (p < 0.001) correlation was found between IBW and estrone (r = 0.80) and estradiol (r = 0.75), as well as the ratios of estrone/androstenedione (r = 0.62) and estradiol/testosterone (r = 0.86). This is consistent in its evidence indicating that fat tissue may be able to aromatize androgens. In the obese subjects, there were significant correlations between plasma sex hormones (testosterone, estrone, estradiol, and free estradiol) and the parameters of obesity used. Among these, correlations were best with IBW, overweight, and fat mass (r = 0.74–0.89; p < 0.001); body weight and body surface were less favorable.     

Whole body protein turnover,studied with 15N-glycine,and muscle protein breakdown in mildly obese subjects during a protein-sparing diet and a brief total fast

A modification of the Picou and Taylor-Roberts Model was used to estimate rates of total body protein synthesis (S), breakdown (C), and amino nitrogen (N) flux (Q) in the metabolic N pool of five obese females. The subjects were fed egg white albumin at 1.5/kg ideal body weight (IBW) and total calories at 1.2 times the basal energy expenditure (fat:carbohydrate = 30%:50%) as a formula diet (period 1, 1 wk). This was followed by 3 wk during which the nonprotein calories were omitted (period 2, protein-sparing modified fast [PSMF]) and a 1-wk total fast (period 3). Estimates of body protein turnover and skeletal protein breakdown were made during the last 60 and 48 hr, respectively, of each period. Q, S, and C were 223 ± 22, 154 ± 22, and $\text{150 ± 22 g protein}\text{24 hr}$, respectively, for period 1. These values were unchanged at the end of period 2. Total fasting decreased Q and S by 36% and 27%, respectively (p < 0.001), but C remained unchanged. Skeletal protein breakdown, as estimated by urinary Nτ-methylhistidine excretion, was 108 ± 47 μmole in period 1, 79 ± 51 μmole in period 2 (p < 0.01), and 100 ± 49 μmole in period 3, representing 16 ± 5%, 12 ± 5% (p < 0.01), and 16 ± 4% of whole body breakdown. N balance was unchanged in period 1 (?0.4 ± 1.2 g N) and the final week of period 2 (?0.4 ± 1.5 g N), but was ?5.8 ± 0.6 g N in period 3. These data indicate that weight reduction with a PSMF is associated with a maintenance of total body protein turnover parameters and N balance but a reduction in skeletal protein breakdown, whereas a total fast causes a marked reduction in whole body protein synthesis and amino N flux with little change in the rate of total body and skeletal protein breakdown, resulting in a negative N balance. The minimization of N losses that develops after prolonged starvation is achieved at rates of whole body and skeletal protein breakdown similar to those found when the diet is adequate, suggesting that endogenous fat-derived fuels are as effective as exogenous energy in limiting protein catabolism. However, protein intake is necessary to maintain whole body protein synthesis under these conditions.     

Effect of body weight on the volume of distribution of theophylline

The volume of distribution (Vd) of theophylline and the relevant aminophylline loading dose (LD) are usually calculated on the basis of total body weight (TBW). In obese subjects it has been suggested that lean or ideal body weight (IBW) is the best predictor. In a sample of 40 acutely ill asthmatic patients (aged 22 to 78 yr, weighing 45 to 176 kg) we measured Vd and found that (1) it increases with TBW, (2) it cannot be accurately predicted from either TBW or IBW alone by a simple regression analysis. Power functions have been usefully applied in comparing the pharmacokinetics of animal species, including humans, with different body mass. In our sample, data were best fitted by the equation Vd = 1.29 TBW^0.74, which seems to take care of lean as well as obese patients. Results were confirmed (r = 0.89 between predicted and measured values) in a second independent sample of patients (aged 26 to 77 yr, weighing 38 to 167 kg). This helps to minimize the error in obtaining the target serum concentration of theophylline when giving a LD calculated from a predicted Vd value.     

Impaired 3,5,3'-triiodothyronine (T3) production in diabetic patients.

Serum concentrations of thyroxine (T₄), 3,5,3′-triiodothyronine (T₃), and 3,3′,5′-triiodothyronine (RT₃) were measured in 50 patients with diabetes mellitus. The mean concentrations of serum T₄, T₃, and RT₃ were 8.5 ± 3.7 (SD) μg/dl, 134 ± 41 ng/dl, and 30 ± 13 ng/dl, respectively, which were not significantly different from values of 33 normal control subjects. The serum $\text{T}{}_3\text{T}{}_4$ ratio showed a significant inverse correlation with the level of fasting blood sugar (FBS) (p < 0.01). Turnover studies were carried out in seven normal control subjects and in 5 insulin-independent diabetic patients on T₄ replacement. T₄ turnover was similar in both groups. The T₃ metabolic clearance rate of the diabetic patients was also normal (20.7 ± 4.0 liter/day/70 kg), but the T₃ disposal rate was reduced when compared to that of normal control subjects (17.0 ± 5.6 vs. 40.6 ± 4.8 μg/day). The RT₃ metabolic clearance rate (80.6 ± 20.2 vs. 105.0 ± 14.0 liter/day/70 kg) and the RT₃ disposal rate (29.4 ± 10.8 vs. 49.4 ± 11.6 μg/day) were both reduced in the diabetic patients. In five other diabetic patients on 3 wk of oral T₄ replacement, the serum $\text{T}{}_3\text{T}{}_4$ ratio was below the normal range (0.0059 ± 0.0041 vs. 0.0152 ± 0.0011) and remained unchanged during insulin infusion during 10 hr. The $\text{T}{}_3\text{T}{}_4$ ratio increased but remained below the normal range after 10 days of dietary and insulin treatment (0.0083 ± 0.0032; p < 0.05). Our results suggest that T₃ production from peripheral T₄ monodeiodination is impaired in uncontrolled diabetic patients. This impairment in T₃ production is correlated with the impairment of glucose utilization.     

Effect of body weight on the volume of distribution of theophylline

The volume of distribution (Vd) of theophylline and the relevant aminophylline loading dose (LD) are usually calculated on the basis of total body weight (TBW). In obese subjects it has been suggested that lean or ideal body weight (IBW) is the best predictor. In a sample of 40 acutely ill asthmatic patients (aged 22 to 78 yr, weighing 45 to 176 kg) we measured Vd and found that (1) it increases with TBW, (2) it cannot be accurately predicted from either TBW or IBW alone by a simple regression analysis. Power functions have been usefully applied in comparing the pharmacokinetics of animal species, including humans, with different body mass. In our sample, data were best fitted by the equation Vd = 1.29 TBW 0.74, which seems to take care of lean as well as obese patients. Results were confirmed (r = 0.89 between predicted and measured values) in a second independent sample of patients (aged 26 to 77 yr, weighing 38 to 167 kg). This helps to minimize the error in obtaining the target serum concentration of theophylline when giving a LD calculated from a predicted Vd value.     

Diminished energy requirements in reduced-obese patients

In assessing the reasons for the frequent regaining of weight by reduced-obese patients, we examined retrospectively the seven-day energy intake requirements for weight maintenance of 26 obese patients (12 males, 14 females) at maximum weight (152.5 ± 8.4 kg) and after weight loss (100.2 ± 5.7 kg). These results were compared with those obtained in 26 age- and sex-matched control patients who had never been obese (62.6 ± 2.3 kg). The obese and control subjects required comparable caloric intakes: 1432 ± 32 kcal/m²/d vs 1341 ± 33 kcal/m²/d, respectively. Following weight loss, the reduced-obese subjects required only 1021 ± 32 kcal/m²/d, a 28% decrease (P < 0.001) in requirements relative to their obese state and a 24% decrease relative to the control patients (P < 0.001). The mean individual energy requirement of the reduced-obese subjects (2171 kcal/d) was less than that for the control subjects (2280 kcal/d) despite the fact that they still weighed 60% more than the controls. In order to maintain a reduced weight, some reduced-obese or even partially reduced patients must restrict their food intake to approximately 25% less than that anticipated on the basis of metabolic body size. The reasons why this finding is unlikely to be an artifactual consequence of changes in lean body mass or body water content are discussed. This finding has implications with regard to the pathophysiology and treatment of obesity in humans.     

Mitral valve E point to ventricular septal separation in infants and children

This investigation establishes heretofore unavailable norms that permit clinical application of mitral valve E point to ventricular septal separation (EPSS) as an ejection phase index in infants and children. The study consisted of 105 normal subjects (1 day through 15 years of age, mean 7.4 years) and 67 patients of comparable age. Fifty-seven patients had increased left ventricular (LV) volume with normal function (ventricular septal defect or patent ductus arteriosus) and 10 patients had increased LV volume with depressed function (dilated cardiomyopathy). In normal subjects, EPSS was 2.5 ± 1.7 mm and “normalized” EPSS, that is, the ratio of EPSS to end-diastolic dimension ($\text{EPSS}\text{EDD}$), was 0.08 ± 0.06 (mean ± standard deviation); there was no correlation between either of these indexes and age, body surface area, height or weight. In patients with ventricular septal defect or patent ductus arteriosus, or both, the EPSS and $\text{EPSS}\text{EDD}$ were similar to those of normal subjects (3.2 ± 2.3 mm and 0.09 ± 0.06 mm, respectively). In patients with dilated cardiomyopathy, these indexes were significantly increased (p > 0.05) ($\text{EPSS}\text{16.5 ± 5.1}\text{mm;}\text{EPSS}\text{EDD}\text{0.39 ± 0.09}$). The data provide normal values for EPSS and $\text{EPSS}\text{EDD}$ in infants and children and show that these indexes are independent of age, body surface area, height or weight. Mitral valve EPSS and $\text{EPSS}\text{EDD}$ can now be used in pediatric echocardiography as a simple, practical and accurate means of separating normal from abnormal LV function.     

The effects of hypothyroidism,age, and nutrition on LDL catabolism in the rat

To determine the effects of thyroid deficiency on LDL metabolism and degradation, the plasma clearance of ¹²⁵I-LDL was determined in normal rats and rats fed chow containing propylthiouracil (PTU) 0.1% w/w and KI $\text{0.16 gm}\text{1}$ in the drinking water. After two weeks, T₄ levels were significantly lower in the PTU groups compared to controls and plasma LDL cholesterol increased from $\text{17.5 ± 1.2}{}^1\text{1}\text{Results given as mean ± SEM.}\text{mg}\text{100 ml}$ in controls to $\text{32.5 ± 3.0 mg}\text{100 ml}$ in the hypothyroid animals. Human ¹²⁵I-LDL (d 1.019–1.045) was injected intravenously under light anesthesia and tail tip blood was sampled repeatedly over 33–100 hr periods. In a semi-log plot the curve of ¹²⁵I-LDL clearance described a log-linear profile suggesting a two-pool model. Compartmental analysis according to Matthews revealed two exponential curves, an initial rapid phase representing equilibration with an extravascular compartment (exponential 2), and a later slow phase of irreversible degradation (exponential 1). There was a marked delay in clearance of ¹²⁵I-LDL in the hypothyroid rats as the slope of exponential 1 was 0.043 ± 0.001 ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 16.2 hr}$) versus 0.065 ± 0.002 ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 10.7 hr}$) in controls (P < 0.01). Additionally, the fractional catabolic rate of LDL was reduced (P < 0.01) from 0.079 ± 0.003 in normals to 0.054 ± 0.002 (pools/hr) in hypothyroid rats. The delay in LDL clearance which occurred in hypothyroidism occurred in both growing and mature rats. Pair-feeding excluded any artifact due to the weight loss commonly seen in hypothyroid rats. LDL clearance was age-dependent as the slope of exponential 1 was significantly lower in mature (521 ± 3 gms) as compared to growing (256 ± 12 gm) rats. Experiments performed after a 24 hr fast showed that acute starvation did not affect LDL clearance. The data suggest that the hypercholesterolemia of hypothyroidism is at least partly secondary to an acquired catabolic defect of LDL, and implies that the LDL catabolic pathway(s) is influenced by thyroid hormones.     

Characterization of elevated plasma alkaline phosphatase activity in genetically obese mice

Alkaline phosphatase activity in obese mice ($\text{C57BL}\text{6J}\text{ob}\text{ob}$) was significantly increased from 18 to 63 weeks of age when compared to that of their lean controls ($\text{C57BL}\text{6J}\text{+/?}$). In 5 week old animals, the earliest age examined, the circulating activity of alkaline phosphatase was similar in both obese mice and their lean counterparts. To characterize the circulating alkaline phosphatase activity in the obese mouse and its lean counterpart, the response of the enzyme to fasting, various inhibitors, heat inactivation, and urea denaturation was examined and compared. L-homoarginine and L-p-bromotetramisole inhibited to a large extent the circulating activity of alkaline phosphatase in both obese mice and their lean controls in the fed state, while L-phenylalanine had essentially no effect. Even though the response of alkaline phosphatase in plasma to several inhibitors was similar, the rate of denaturation by urea of enzyme activity in plasma was significantly slower in obese mice than in their lean controls in the fed state. While the rate of inactivation of alkaline phosphatase activity in plasma for the initial two minutes at 56°C was similar in obese mice and their lean counterparts, the subsequent rate of heat inactivation was significantly slower in the plasma from obese mice. Thus, both obese and lean mice in the fed state have a circulating activity of alkaline phosphatase in plasma with a greater contribution from a skeletal isoenzyme and a lesser one of intestinal origin. Even though the contribution of the bone isoenzyme could not be completely differentiated from that of liver, the circulating alkaline phosphatase activity in the obese mouse has a component of greater stability to both urea denaturation and heat inactivation, presumably hepatic in origin.     

Non-paroxysmal A-V junctional tachycardia associated with acute myocardial infarction

The hospital records of 48 subjects with acute myocardial infarction complicated by non-paroxysmal A-V junctional tachycardia (NPJT) were reviewed. Fifteen of 48 subjects (31 per cent) so affected died. NPJT was most commonly associated with inferior wall infarction ($\text{24}\text{48}$, 50 per cent). Although ten of 16 (63 per cent) patients with acute anterior wall infarction and NPJT died, 23 of 24 patients with acute inferior wall myocardial infarction survived. Mean heart rates during NPJT were significantly greater in subjects with anterior wall infarction (113.4 ± 35.3 vs. inferior wall 85.4 ± 28.1, P < 0.01). Peak SGOT levels were significantly higher in those patients who died (488 ± 579 vs. survivors 152 ± 114, P < 0.01). NPJT altered the clinical status of only six subjects. It is concluded that NPJT indicates a poor prognosis in subjects with acute anterior wall infarction but is generally associated with a benign clinical course in patients with inferior infarction. These differences may be based on a greater extent of myocardial damage in the former group.     

Triglyceride removal efficiency and lipoprotein lipases: effects of Oxandrolone

Very low density lipoprotein triglyceride turnover rate, fractional turnover rate, and half-life were studied using Glycerol ^?3H to label VLD-TG in 16 patients with familial Type IV hyperlipoproteinemia. The patients were maintained on an isocaloric diet with determination of triglyceride turnover after 2 wk of placebo, and a second determination after 2 wk of Oxandrolone (an anabolic-androgenic synthetic steroid). On placebo, mean very low density lipoprotein triglyceride (VLD-TG) was 539, falling on Oxandrolone to $\text{254 mg}\text{100 ml}$ (p < 0.05). Mean half-life ($\text{T}\text{1}\text{2}$) was 10.3 hr on placebo and was shortened to 5.2 hr on drug (p < 0.05). The fractional turnover rate (FTR) on placebo was 0.104 ± 0.016 hour^?1, and rose to 0.166 ± 0.016 on drug (p < 0.05). Mean turnover rate (TR) rose slightly from 17.6 mg/kg/hr on placebo to 19.04 mg/kg/hr on Oxandrolone. Both postheparin lipolytic activity (PHLA) and postheparin triglyceride lipase (TGL) were appreciably increased on drug, rising respectively from 0.297 μeq FFA/ml/min and 11.7 mμeq FFA/ml/hr (on placebo) to 0.396 and 23.7 (on drug). The changes (Δ) in VLD-TG on Oxandrolone correlated with $\text{Δ T}\text{1}\text{2}$ (R = 0.761) and with Δ FTR (R = ?0.532). Oxandrolone may lower very low density lipoprotein triglyc eride by substantially increasing fractional turnover rate and shortening half-life while slightly augmenting turnover rate and improving efficiency of VLD-TG removal.     

Antihypertensive effect of α- and β-adrenergic blockade in obese and lean hypertensive subjects

The purpose of this study was to determine the contribution of the adrenergic system in mediating hypertension in obese and lean patients. Thirteen obese, hypertensive patients with a body mass index (BMI) ≥28 kg/m² (obese) and nine lean patients with a BMI ≤25 kg/m² (lean) were recruited. After a 1-week washout period, participants underwent daytime ambulatory blood pressure monitoring (ABPM). Participants were then treated with the α-adrenergic antagonist doxazosin, titrating to 4 mg QHS in 1 week. In the next week, the β-adrenergic antagonist atenolol was added at an initial dose of 25 mg/day and titrated to 50 mg/day within 1 week. One month after the addition of atenolol, all patients underwent a second ABPM session.There were no differences between the obese and lean subjects in baseline systolic (SBP), diastolic (DBP), or mean arterial pressures (MAP) measured by office recording or ABPM. However, obese subjects had higher heart rates than lean subjects (87.5 ± 2.4 v 76.8 ± 4.9 beats/min). After 1 month of treatment with the adrenergic blockers, obese patients had a significantly lower SBP (130.0 ± 2.5 v 138.9 ± 2.1 mm Hg, P = .02) and MAP (99.6 ± 2.3 v 107.0 ± 1.5 mm Hg, P = .02) than lean patients. Obese patients also tended to have a lower DBP than lean patients (84.3 ± 2.5 v 90.9 ± 1.6 mm Hg, P = .057), but there was no significant difference in heart rate after 1 month of adrenergic blockade.These results indicate that blood pressure is more sensitive to adrenergic blockade in obese than in lean hypertensive patients and suggest that increased sympathetic activity may be an important factor in the maintenance of hypertension in obesity.     

The effects of chronic uremia and dexamethasone on triglyceride kinetics in the rat.

The effects of chronic uremia and dexamethasone administration on triglyceride (TG) kinetics were studied in the rat. Uremia was produced by a two-stage, $\text{5}\text{6}$ nephrectomy, and resulted in a fourfold rise in BUN levels. The elevation in BUN level led to a rise in mean ( ± SE) TG levels from $\text{46 ± 4 to 62 ± 6 mg}\text{100 ml}$. The increase in TG levels was associated with a marked prolongation in very low density lipoprotein (VLDL) removal rate from plasma, without any change in triglyceride secretion rate (TG-SR). The combined effects of uremia and glucocorticoid treatment were evaluated by treating chronically uremic rats with either low (0.05 mg/kg body weight) or high (0.25 mg/kg body weight) doses of dexamethasone. The low dose of dexamethasone led to a further rise in mean TG levels of chronically uremic rats ($\text{107 ± 14 mg}\text{100 ml}$), and the hypertriglyceridemia was further accentuated when chronically uremic rats were treated with high-dose dexamethasone ($\text{179 ± 15 mg}\text{100 ml}$). The elevation of TG levels in uremic rats receiving the low dose of dexamethasone was associated with a prolongation of VLDL removal which was not statistically significant. Treatment with the higher dose of dexamethasone resulted in an increase in TG-SR and a further prolongation of VLDL removal, both of which were statistically significant. Thus, hypertriglyceridemia in the chronically uremic rat is due to a defect in VLDL removal. Dexamethasone treatment is capable of accentuating this removal defect, as well as increasing TG-SR. The combined effect of both is to lead to a marked degree of hypertriglyceridemia.     

Cardioadrenergic factor in essential hypertension

Determination of STI in 54 untreated essential hypertensive subjects and 17 normal subjects revealed marked differences among three groups of patients. Those with borderline hypertension (29) had a short PEP and IVC periods (93 ± 2.1 and 28 ± 0.7 msec., respectively, p < 0.001) (mean ± S.E.) reduced $\text{PEP}\text{LVET}$ (0.323 ± 0.009, p < 0.05) and increased $\text{DP}\text{IVC}$ (3,484 ± 257 mm. Hg per second, p < 0.001). Among those with established hypertension, two groups of equal age and diastolic pressure were identified: nine with marked variations in blood pressure and a hyperkinetic heart clinically and 16 with fixed hypertension; none had cardiac or renal decompensation. Those with a hyperkinetic circulation had normal PEP, IVC, and $\text{PEP}\text{LVET}$ despite a high diastolic pressure (122 ± 7.1 mm. Hg); $\text{DP}\text{IVC}$ was elevated (3,651 ± 497 mm. Hg per second, p < 0.001) as in those with borderline hypertension. In contrast, the patients with fixed hypertension had longer PEP and IVC (p < 0.001), higher $\text{PEP}\text{LVET}$ (p < 0.001), and normal $\text{DP}\text{IVC}$. Propranolol (10 mg. intravenously) slowed heart rate and prolonged PEP and IVC more in patients with a hyperkinetic circulation and in those with borderline hypertension than in those with fixed hypertension.These results suggest the presence of an increased cardioadrenergic drive not only in borderline hypertension, but also in a subgroup of patients with established hypertension. Left ventricular hypertrophy (ECG) was found in 1 out of 9 patients with hyperkinetic heart but in 6 out of 16 with fixed hypertension; cardiac index was high normal in the first group but reduced in the latter (3.32 vs 2.38 L./min./M.², p < 0.001). This factor as determined by the systolic time interval might, therefore, be important in determining cardiac prognosis or planning therapy.     

The disposal of an intravenously administered amino acid load across the human forearm

This study was designed to examine the role of the skeletal muscle in man in the disposal of an intravenously administered L-amino acid solution. Arterio-deep venous differences of amino acids, glucose and lactate, and blood flow across the human forearm were measured in 9 healthy normal male volunteers (age = 27 ± 2 yr, weight = 79 ± 4 kg and height = 180 ± 2 cms) after an overnight fast (12 hr). Glucose and alanine turnover rates were estimated using a continuous infusion of 3-³H-glucose and U-¹⁴C-alanine isotopes. All measurements were obtained during steady state conditions, basally and two hours after the start of an L-amino acid infusion (8.5% solution). During the control period there was a significant release of total alpha amino nitrogen (AAN) equal to $\text{300 ± 97 nmole}\text{100 g}$ forearm muscle/min with alanine and glutamine accounting for over 80% of that amount ($\text{260 ± 24 nmole}\text{100 g}\text{forearm muscle/min}$). The release of the branched chain amino acids (BCAA) was only significant for valine, while the release of each of the keto acids of leucine and valine, α-ketoisocaproate and α-ketoisovalerate ($\text{37 ± 12 and 36 ± 7 nmole}\text{100 ml}\text{forearm muscle/min respectively}$) was significant from zero and exceeded the release of the corresponding amino acids ($\text{13 ± 17 and 24 ± 7 nmole}\text{100 g}\text{forearm muscle/min for leucine and valine respectively}$). The infusion of the L-amino acid solution resulted in a reversal of amino acid balance across the forearm. There was a net uptake of AAN of $\text{1195 ± 209 nmole}\text{100 g}$ forearm muscle/min with the BCAA accounting for $\text{513 ± 75 nmole}\text{100 g}$ forearm muscle/min or 49 ± 6% of the uptake. The net uptake of BCAA by skeletal muscle did not exceed 35% of the amount infused. The release of α-ketoisocaproate and α-ketoisovalerate showed no significant change from basal levels. The output of alanine and glutamine persisted in response to the infusion; while alanine output dropped by 40%, glutamine output increased by 50% ($\text{68 ± 23 and 218 ± 42 nmole}\text{100 g}\text{forearm muscle/min respectively}$), yet the combined release of alanine and glutamine did not change significantly from basal levels. Amino acid infusion resulted in a twofold increase in insulin and glucagon. Plasma glucose fell from 5.3 ± 0.05 mM basally to 5.04 ± 0.06 mM (p < 0.05), while blood lactate increased from 0.587 ± 0.03 mM to 0.639 ± 0.025 mM (p < 0.05); similarly there was a time dependent increase in glucose uptake by muscle ($\text{from}\text{0.857 ± 0.08}\text{to}\text{1.27 ± 0.07 μ}\text{mole}\text{100 g}\text{forearm muscle/min}$, p < 0.05) and lactate release ($\text{0.226 ± 0.03}\text{to}\text{0.297 ± 0.045 μ}\text{mole}\text{100 g}\text{forearm muscle/min}\text{, p < 0.05}$). These results indicate that a significant amount of the amino acids infused, and specifically the BCAA are extracted by human skeletal muscle, and mostly retained as such for later use. The data obtained under the conditions of the present study also indicate that tissues other than skeletal muscle are as important in the overall handling of these amino acids. However, it remains to be seen whether these findings can be extrapolated to other physiological conditions.     

Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: Studies with somatostatin

To study the role of glucagon in human glucose homeostasis, experimental glucagon deficiency was produced by infusing somatostatin (i.v. 250 μg bolus, followed by infusion of 500 μg/hr) in six normal subjects and in two hypophysectomized patients—an insulin-dependent diabetic and a nondiabetic. In normal subjects, somatostatin lowered plasma glucagon from a mean (± SE) basal level of 85 ± 15 to 33 ± 10 pg/ml, p < 0.001. Concurrently, plasma glucose fell from $\text{90 ± 2 to 73 ± 3 mg}\text{100 ml}$, p < 0.001. Serum insulin and growth hormone fell slightly during somatostatin infusion, while plasma free fatty acids rose. In both hypophysectomized patients, somatostatin lowered plasma glucagon and glucose levels. In all subjects, after stopping somatostatin infusions, plasma glucagon and glucose returned promptly to control values, while serum growth hormone did not change. In additional in vitro studies, somatostatin (1 μg/ml) had no effect on muscle glucose uptake. Since it is known that somatostatin has no direct effect on hepatic glucose production, these results suggest that the fall in plasma glucose during somatostatin infusion resulted from inhibition of glucagon secretion, thus providing evidence that this hormone plays a physiologic role in the maintenance of fasting euglycemia in man.     

Effect of clofibrate on arginine-stimulated glucagon and insulin secretion in man

Insulin and glucagon have been reported to have opposing effects upon the mechanisms regulating serum triglyceride concentration. Glucagon in excess of insulin will lower serum lipids in man. In the present studies, we have examined the possibility that a change in glucagon and insulin regulation might contribute to the hypolipemic action of the drug clofibrate. Control insulin and glucagon secretion were evaluated in 24 normal subjects by intravenous arginine infusion, which resulted in a prompt rise in both serum immunoreactive insulin and glucagon concentration. During the maximum rise in concentration of these hormones, plasma triglyceride concentration was acutely reduced from basal levels of $\text{104 ± 6}\text{mg}\text{100}\text{ml}$ to $\text{75 ± 5}\text{mg}\text{100}\text{ml}$ (p ≤ 0.001). Following 7 days of clofibrate therapy, basal plasma triglyceride concentration attained a new mean level of $\text{78 ± 5}\text{mg}\text{100}\text{ml}$, while basal insulin and glucagon concentrations remained unchanged. However, arginine infusion now resulted in a reduction of the insulin secretory response to 56% of the preclofibrate studies with an associated normal glucagon secretory response. Serum triglyceride concentration was further reduced during arginine infusion to $\text{46 ± 3}\text{mg}\text{100}\text{ml}$, demonstrating this minimum level as maximum plasma glucagon levels were attained, representing an excess of this hormone relative to the reduced insulin concentration. These observations are consistent with an effect of clofibrate on the hormonal regulation of triglyceride physiology in man. Glucose tolerance was unimpaired by clofibrate therapy in these normal subjects, in spite of an apparent reduction in glucose-stimulated insulin secretion.