The effect of nivazol and cortivazol, novel synthetic steroids containing a phenylpyrazolo A-ring substitution, on blood pressure in sheep

This study investigated the effect of 5 day infusions of two structurally novel synthetic steroids, nivazol and cortivazol on blood pressure and in vivo indices of "glucocorticoid" and "mineralocorticoid" activity. Cortivazol at 24 mg/day raised mean arterial pressure (MAP) by 16 mmHg (P less than 0.001). This was associated with increased cardiac rate, and increased fasting plasma [glucose], polyuria and polydipsia a trilogy characteristic of glucocorticoid effect. Cortivazol had no consistent action on plasma [Na] or [K], but caused an initial transient urinary Na retention and raised urinary excretion of Na and K on days 3 and 4 of treatment. Nivazol at 24 mg/day raised MAP 10 mmHg (P less than 0.001), but cardiac rate was unchanged. This infusion was also associated with the glucocorticoid effects of increased fasting plasma [glucose] and increased urine volume. Plasma [K] fell from a control of 4.4 +/- 0.1 to 4.0 +/- 0.1 mmol/l (P less than 0.01) after 5 days of infusion. There was no significant effect of nivazol on urinary Na or K excretion. This study demonstrates that replacement of the 3-keto group, by a bulky phenylpyrazolo group fused to the A ring at position 2 and 3, does not diminish either pressor or glucocorticoid activity of steroids containing the typical 4-pregnene-3,20-dione nucleus and confirms that the 3 keto group is not essential for optimal glucocorticoid activity. It is the first demonstration of the pressor effect of these novel steroids.     

Oxoproline kinetics and oxoproline urinary excretion during glycine- or sulfur amino acid-free diets in humans

L-5-oxoproline (L-5-OP) is an intermediate in glutathione synthesis, possibly limited by cysteine availability. Urinary 5-OP excretion has been proposed as a measure of glycine availability. We investigated whether 5 days of dietary sulfur amino acid (SAA-free) or glycine (Gly-free) restriction affects plasma kinetics of 5-OP and urinary excretion of L- and D-5-OP in 6 healthy men. On day 6, L-5-[1-(13)C]oxoproline and [3,3-(2)H(2)]cysteine were infused intravenously for 8 h (3 h fast/5 h fed). In a control study (adequate amino acid mixture), plasma oxoproline fluxes were 37.8 +/- 13.8 (SD) and 38.4 +/- 14.8 micromol x kg(-1) x h(-1); oxidation accounted for 85% of flux. Cysteine flux was 47.9 +/- 8.5 and 43.2 +/- 8.5 micromol x kg(-1) x h(-1) for fast and fed phases, respectively. Urinary excretion of L- and D-5-OP was 70 +/- 34 and 31.1 +/- 13.3 micromol/mmol creatinine, respectively, during days 3-5, and 46.4 +/- 13.9 and 22.4 +/- 8.3 micromol/mmol over the 8-h tracer study. The 5-OP flux for the Gly-free diet was higher (P = 0. 018) and tended to be higher for the SAA-free diet (P = 0.057) when compared with the control diet. Oxidation rates were higher on the Gly-free (P = 0.005) and SAA-free (P = 0.03) diets. Cysteine fluxes were lower on the the Gly-free (P = 0.01) and the SAA-free diets (P = 0.001) compared with the control diet. Rates of L-5-OP excretion were unchanged by withdrawal of SAA or Gly for 5 days but increased on day 6 (P = 0.005 and P = 0.019, respectively). Thus acute changes in the dietary availability of SAA and Gly alter oxoproline kinetics and urinary 5-OP excretion.     

Role of 20-hydroxyeicosatetraenoic acid in the renal and vasoconstrictor actions of angiotensin II

The present study examined the effects of ANG II on the renal synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) and its contribution to the renal vasoconstrictor and the acute and chronic pressor effects of ANG II in rats. ANG II (10(-11) to 10(-7) mol/l) reduced the diameter of renal interlobular arteries treated with inhibitors of nitric oxide synthase and cyclooxygenase, lipoxygenase, and epoxygenase by 81 +/- 8%. Subsequent blockade of the synthesis of 20-HETE with 17-octadecynoic acid (1 micromol/l) increased the ED(50) for ANG II-induced constriction by a factor of 15 and diminished the maximal response by 61%. Graded intravenous infusion of ANG II (5-200 ng/min) dose dependently increased mean arterial pressure (MAP) in thiobutylbarbitol-anesthetized rats by 35 mmHg. Acute blockade of the formation of 20-HETE with dibromododecenyl methylsulfimide (DDMS; 10 mg/kg) attenuated the pressor response to ANG II by 40%. An intravenous infusion of ANG II (50 ng. kg(-1). min(-1)) in rats for 5 days increased the formation of 20-HETE and epoxyeicosatrienoic acids (EETs) in renal cortical microsomes by 60 and 400%, respectively, and increased MAP by 78 mmHg. Chronic blockade of the synthesis of 20-HETE with intravenous infusion of DDMS (1 mg. kg(-1). h(-1)) or EETs and 20-HETE with 1-aminobenzotriazole (ABT; 2.2 mg. kg(-1). h(-1)) attenuated the ANG II-induced rise in MAP by 40%. Control urinary excretion of 20-HETE averaged 350 +/- 23 ng/day and increased to 1,020 +/- 105 ng/day in rats infused with ANG II (50 ng. kg(-1). min(-1)) for 5 days. In contrast, urinary excretion of 20-HETE only rose to 400 +/- 40 and 600 +/- 25 ng/day in rats chronically treated with ANG II and ABT or DDMS respectively. These results suggest that acute and chronic elevations in circulating ANG II levels increase the formation of 20-HETE in the kidney and peripheral vasculature and that 20-HETE contributes to the acute and chronic pressor effects of ANG II.     

Serum fructosamine in assessment of diabetic control and relation to thyroid function

Measurement of serum fructosamine using a Roche kit is a simple and reliable method for the estimation of glycated serum proteins. The value of serum fructosamine can be affected by hyperglycemia in diabetics and an abnormal turnover rate of serum protein in patients with thyroid dysfunction. We measured the serum fructosamine level in 18 normal control subjects, 71 diabetics (8 IDDM, 63 NIDDM) and 46 non-diabetic untreated patients with thyroid dysfunction (28 hyperthyroidism, 18 hypothyroidism). The serum fructosamine level was significantly increased in the diabetics compared with the normal control subjects (3.84 +/- 0.15 mmol/l vs 2.58 +/- 0.08; mean +/- SE, P less than 0.01). The serum fructosamine level in the diabetics was positively correlated with the fasting plasma glucose and HbAlc level, showing the highest correlation with fasting plasma glucose at 2 weeks before and with the HbAlc level at 2 weeks after serum fructosamine measurement. In the patients with thyroid dysfunction, the serum fructosamine level in hyperthyroidism (2.08 +/- 0.03 mmol/l) and hypothyroidism (3.11 +/- 0.07 mmol/l) were significantly lower (P less than 0.001) and higher (P less than 0.001) than the normal control subjects (2.58 +/- 0.08 mmol/l), respectively. Furthermore, the serum fructosamine level in these patients was negatively correlated with the level of serum thyroid hormones such as T3 (P less than 0.001) and T4 (P less than 0.001). It is concluded that measurement of serum fructosamine is clinically useful for the evaluation of shorter-term glycemic control in diabetics, but its level for diabetic patients with thyroid dysfunction must be cautiously interpreted.     

The influence of endogenous mineralocorticoids on the composition of fetal urine

Experiments were carried out in 10 chronically catheterised fetal sheep aged 121-128 days. In 3 animals infusion of aldosterone (5 micrograms/h) caused a fall in fetal urinary Na/K ratio; an effect that was reversed by spironolactone 2.5 mg/kg followed by an infusion of 100 micrograms/h per kg. In 9 fetal sheep which had no previous treatment the same doses of spironolactone had no effect on fractional sodium excretion although the fractional excretion of potassium decreased (P less than 0.05) and the urinary sodium potassium (Na/K) ratio rose (P less than 0.05). Amiloride had a variable effect on sodium excretion but the fractional excretion of potassium decreased markedly (P less than 0.05). Thus in chronically catheterised fetal sheep, endogenous mineralocorticoid activity altered urinary potassium excretion and the urinary Na/K ratio. However this activity was low, as distal blockade with amiloride further decreased the fractional excretion of potassium and increased the urinary Na/K ratio.     

Investigation of the mechanisms by which chronic infusion of an acutely subpressor dose of angiotensin II induces hypertension

The mechanisms by which chronic infusion of an initially subpressor low dose of angiotensin II (ANG II) causes a progressive and sustained hypertension remain unclear. In conscious sheep (n = 6), intravenous infusion of ANG II (2 microg/h) gradually increased mean arterial pressure (MAP) from 82 +/- 3 to 96 +/- 5 mmHg over 7 days (P < 0.001). This was accompanied by peripheral vasoconstriction; total peripheral conductance decreased from 44.6 +/- 6.4 to 38.2 +/- 6.7 ml.min(-1).mmHg(-1) (P < 0.001). Cardiac output and heart rate were unchanged. In the regional circulation, mesenteric, renal, and iliac conductances decreased but blood flows were unchanged. There was no coronary vasoconstriction, and coronary blood flow increased. Ganglion blockade (125 mg/h hexamethonium for 4 h) reduced MAP by 13 +/- 1 mmHg in the control period and by 7 +/- 2 mmHg on day 8 of ANG II treatment. Inhibition of central AT(1) receptors by intracerebroventricular infusion of losartan (1 mg/h for 3 h) had no effect on MAP in the control period or after 7 days of ANG II infusion. Pressor responsiveness to incremental doses of intravenous ANG II (5, 10, 20 microg/h, each for 15 min) was unchanged after 7 days of ANG II infusion. ANG II caused no sodium or water retention. In summary, hypertension due to infusion of a low dose of ANG II was accompanied by generalized peripheral vasoconstriction. Indirect evidence suggested that the hypertension was not neurogenic, but measurement of sympathetic nerve activity is required to confirm this conclusion. There was no evidence for a role for central angiotensinergic mechanisms, increased pressor responsiveness to ANG II, or sodium and fluid retention.     

Pulmonary fibrin microembolism with Echis carinatus venom in dogs: effects of a synthetic thrombin inhibitor

We produced pulmonary fibrin microembolism using an infusion of a prothrombin activator (Echis carinatus venom, 30 min, 0.5 NIH thrombin equivalent units/kg) in open-chest mongrel dogs. To determine the nonclotting effects of this venom on edemagenesis we infused an irreversible thrombin inhibitor, D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK, 57 nmol X kg-1 X min-1 for 120 min), alone (n = 5) or with venom (Echis + PPACK, n = 5). The control group (n = 5) was given 1 ml of 0.9% NaCl. A decline in left atrial pressure (means +/- SE, 5.3 +/- 0.4 to 4.0 +/- 0.5 mmHg, P less than 0.05) and cardiac index (149 +/- 10 to 82 +/- 13 ml X min-1 X kg-1, P less than 0.01) in association with a marked increase in pulmonary arterial pressure (14.5 +/- 0.6 to 26.6 +/- 2.5 mmHg, P less than 0.001) and pulmonary vascular resistance (64 +/- 5 to 304 +/- 42 mmHg X ml-1 X min-1 X kg-1, P less than 0.001) was observed after 20 min of venom infusion. During this interval, pulmonary artery wedge pressure increased (4 +/- 1 to 12 +/- 4 mmHg, P less than 0.01) in four of eight animals. Fibrinogen declined below measurable levels and fibrin microemboli were seen in many pulmonary arterioles. These changes were not observed in the Echis + PPACK, PPACK, or control groups. Leukopenia and thrombocytopenia were observed in the Echis and Echis + PPACK groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary N tau-methylimidazole acetic acid excretion in respiratory disease

N tau-methylimidazole acetic acid (N tau-MIAA) is the principal urinary metabolite of histamine. The basal urinary excretion rate of N tau-MIAA was determined as 0.117 +/- 0.008 (SE) mg/h, with a renal clearance for N tau-MIAA of 273 +/- 27 ml/min implying active secretion. After subpharmacological infusion of histamine (50 ng.kg-1.min-1 over 2 h) in five volunteers that increased plasma histamine from 0.28 +/- 0.04 to 0.71 +/- 0.15 ng/ml, urinary excretion of N tau-MIAA over 8 h was increased by less than 17% compared with a control saline infusion. Urinary N tau-MIAA excretion in normal controls (273 +/- 14 micrograms/mmol creatinine) was similar to that observed in patients with severe acute asthma (253 +/- 22 micrograms/mmol), antigen-induced bronchoconstriction (269 +/- 21 micrograms/mmol), seasonal allergic rhinitis (304 +/- 31 micrograms/mmol), and clinically stable bronchiectasis (270 +/- 22 micrograms/mmol). In contrast, large increases in metabolite excretion (greater than 7,000 micrograms/mmol creatinine) were observed in a patient with systemic mastocytosis where very high plasma histamine levels were recorded (greater than 500 ng/ml) and marked systemic hemodynamic effects occurred. We conclude that urinary N tau-MIAA will only be increased in pathologies where sustained hyperhistaminemia occurs and that increased local histamine production in the lung or the upper airway does not cause a measurable change in the basal urinary excretion of this metabolite.     

Extracorporeal bicarbonate space after bicarbonate or a bicarbonate-carbonate mixture in acidotic dogs

The effects of sodium bicarbonate and a bicarbonate-carbonate mixture on expired CO2 and the volume of distribution of bicarbonate were studied in eight anesthetized, paralyzed, and ventilated dogs made acidotic with HCl (5 mmol/kg) infused over 90 min. Both sodium bicarbonate and Carbicarb resulted in systemic alkalinization and comparable increases in the serum bicarbonate at 50 min (7.07 +/- 0.91 vs. 7.99 +/- 0.77, respectively; P = NS). Sodium bicarbonate infusion resulted in an increase in CO2 excretion that accounted for a fractional CO2 excretion of 0.20 +/- 0.09, whereas infusion of a bicarbonate-carbonate mixture resulted in a fractional CO2 excretion of -0.06 +/- 0.09 (P less than 0.01). The uncorrected volume of distribution of bicarbonate after sodium bicarbonate infusion was higher than that seen with the bicarbonate-carbonate mixture (0.60 +/- 0.07 vs. 0.34 +/- 0.03 l/kg; P less than 0.01). However, when the volume of bicarbonate distribution was corrected for expired CO2, there was no difference between treatment with sodium bicarbonate and the bicarbonate-carbonate mixture (0.44 +/- 0.07 vs. 0.38 +/- 0.04 l/kg; P = NS). These data demonstrate that, in this animal model of acidosis, sodium bicarbonate treatment of systemic acidosis is accompanied by a generation of a considerable amount of CO2, whereas treatment with a bicarbonate-carbonate mixture is not. This suggests that in states of impaired ventilation, a bicarbonate-carbonate mixture may offer more efficient systemic alkalinization and may be associated with less CO2 generation than sodium bicarbonate.     

Correlation of acute with chronic hypoxic pulmonary hypertension in cattle.

We investigated acute and chronic hypoxic pulmonary pressor responses in two groups of calves, one bred to be susceptible, the other resistant to high-altitude pulmonary hypertension. Twelve 5-mo-old susceptible calves residing at 1,524 m increased their mean pulmonary arterial pressure from 26 +/- 2 (SE) to 55 +/- 4 mmHg during 2 h at a simulated altitude of 4,572 m. In 10 resistant calves pressure increased from 22 +/- 1 to 37 +/- 2 mmHg. Five calves were selected from each group for further study. When 9 mo old, the 5 susceptible calves again showed a greater pressor response to acute hypoxia (27 +/- 1 to 55 +/- 4 mmHg) than did 5 resistant calves (23 +/- 1 to 41 +/- 3 mmHg). When 12 mo old, the 5 susceptible calves also developed a greater increase in pulmonary arterial pressure (21 +/- 2 to 9 +/- 4 mmHg) during 18 days at 4,572 m than did the 5 resistant calves (21 +/- 1 to 64 +/- 4 mmHg). Acute and chronic hypoxic pulmonary pressor responses were highly correlated (r = 0.91; P less than 0.001) indicating that they were probably produced through a common mechanism.     

Urocortin 1 administration from onset of rapid left ventricular pacing represses progression to overt heart failure

Urocortin 1 (Ucn1) may be involved in the pathophysiology of heart failure (HF), but the impact of Ucn1 administration on progression of the disease is unknown. The aim of this study was to investigate the effects of Ucn1 in sheep from the onset of cardiac overload and during the subsequent development of HF. Eight sheep underwent two 4-day periods of HF induction by rapid left ventricular pacing (225 beats/min) in conjunction with continuous infusions of Ucn1 (0.1 microg.kg(-1).h(-1) iv) and a vehicle control (0.9% saline). Compared with control, Ucn1 attenuated the pacing-induced decline in cardiac output (2.43 +/- 0.46 vs. 3.70 +/- 0.89 l/min on day 4, P < 0.01) and increases in left atrial pressure (24.9 +/- 1.0 vs. 11.9 +/- 1.1 mmHg, P < 0.001) and peripheral resistance (38.7 +/- 9.4 vs. 25.2 +/- 6.1 mmHg.l(-1).min, P < 0.001). Ucn1 wholly prevented increases in plasma renin activity (4.02 +/- 1.17 vs. 0.87 +/- 0.1 nmol.l(-1).h(-1), P < 0.001), aldosterone (1,313 +/- 324 vs. 413 +/- 174 pmol/l, P < 0.001), endothelin-1 (3.8 +/- 0.5 vs. 2.0 +/- 0.1 pmol/l, P < 0.001), and vasopressin (10.8 +/- 4.1 vs. 1.8 +/- 0.2 pmol/l, P < 0.05) during pacing alone and blunted the progressive increases in plasma epinephrine (2,132 +/- 697 vs. 1,250 +/- 264 pmol/l, P < 0.05), norepinephrine (3.61 +/- 0.73 vs. 2.07 +/- 0.52 nmol/l, P < 0.05), and atrial (P < 0.05) and brain (P < 0.01) natriuretic peptide levels. Ucn1 administration also maintained urine sodium excretion (0.75 +/- 0.34 vs. 1.59 +/- 0.50 mmol/h on day 4, P < 0.05) and suppressed pacing-induced declines in creatinine clearance (P < 0.05). These findings indicate that Ucn1 treatment from the onset of cardiac overload has the ability to repress the ensuing hemodynamic and renal deterioration and concomitant adverse neurohumoral activation, thereby delaying the development of overt HF. These data strongly support a use for Ucn1 as a therapeutic option early in the course of the disease.     

Effect on maternal and fetal renal function and plasma renin activity of a high salt intake by the ewe

The effect on renal function of replacing maternal drinking water with a solution containing 0.17 M NaCl was studied in 9 ewes and their chronically catheterised fetuses over a period of 9 days. Maternal sodium intake increased from control values of 2.19 +/- 0.09 mmol/h to 44.3 +/- 7.4 (P less than 0.001) and 46.3 +/- 6.5 mmol/h (P less than 0.001) on the 3rd and 6th days of salt ingestion. Maternal plasma sodium levels were not affected, but the urinary sodium/potassium ratio increased from 0.15 +/- 0.07 to 2.26 +/- 0.34 (P less than 0.001) after 6 days and plasma renin activity fell from 2.87 +/- 0.76 to 1.00 +/- 0.25 ng/ml per h (P less than 0.05). The changes in maternal sodium intake had no effect on fetal plasma sodium levels nor on fetal plasma renin activity. Sodium excretion and fetal urinary sodium/potassium ratio did not change. However, 3 days after the ewes returned to drinking water fetal plasma renin activity was significantly higher than it was prior to maternal ingestion of 0.17 M NaCl. Fetal plasma renin activity was inversely related to fetal plasma sodium levels (P less than 0.01). The results show that changes in maternal sodium intake had no long term effect on fetal plasma sodium levels nor on fetal renal sodium excretion. The fall in maternal plasma renin activity in the absence of any change in the fetal renin activity, indicates that the fetal renin angiotensin system is controlled by factors other than those influencing the maternal renin angiotensin system. Since fetal urinary sodium/potassium ratios remained unchanged it would suggest that fetal sodium excretion is not influenced by maternal levels of aldosterone.     

TNF-alpha inhibition reduces renal injury in DOCA-salt hypertensive rats

Studies suggest that the inflammatory cytokine TNF-alpha plays a role in the prognosis of end-stage renal diseases. We previously showed that TNF-alpha inhibition slowed the progression of hypertension and renal damage in angiotensin II salt-sensitive hypertension. Thus, we hypothesize that TNF-alpha contributes to renal inflammation in a model of mineralocorticoid-induced hypertension. Four groups of rats (n = 5 or 6) were studied for 3 wk with the following treatments: 1) placebo, 2) placebo + TNF-alpha inhibitor etanercept (1.25 mg.kg(-1).day(-1) sc), 3) deoxycorticosterone acetate + 0.9% NaCl to drink (DOCA-salt), or 4) DOCA-salt + etanercept. Mean arterial blood pressure (MAP) measured by telemetry increased in DOCA-salt rats compared with baseline (177 +/- 4 vs. 107 +/- 3 mmHg; P < 0.05), and TNF-alpha inhibition had no effect in the elevation of MAP in these rats (177 +/- 8 mmHg). Urinary protein excretion significantly increased in DOCA-salt rats compared with placebo (703 +/- 76 vs. 198 +/- 5 mg/day); etanercept lowered the proteinuria (514 +/- 64 mg/day; P < 0.05 vs. DOCA-salt alone). Urinary albumin excretion followed a similar pattern in each group. Urinary monocyte chemoattractant protein (MCP)-1 and endothelin (ET)-1 excretion were also increased in DOCA-salt rats compared with placebo (MCP-1: 939 +/- 104 vs. 43 +/- 7 ng/day, ET-1: 3.30 +/- 0.29 vs. 1.07 +/- 0.03 fmol/day; both P < 0.05); TNF-alpha inhibition significantly decreased both MCP-1 and ET-1 excretion (409 +/- 138 ng/day and 2.42 +/- 0.22 fmol/day, respectively; both P < 0.05 vs. DOCA-salt alone). Renal cortical NF-kappaB activity also increased in DOCA-salt hypertensive rats, and etanercept treatment significantly reduced this effect. These data support the hypothesis that TNF-alpha contributes to the increase in renal inflammation in DOCA-salt rats.     

Changes to metabolite concentration in fetal sheep subjected to prolonged hypobaric hypoxia

The effect of hypobaric hypoxaemia on the concentration of metabolic substrates in the ovine fetus and pregnant ewe with implanted vascular catheters, was investigated. At 120 to 141 days of gestation sheep were subjected to hypobaria (mean fetal carotid PO2 12.7 +/- 0.7 torr; n = 9) or normobaria (mean fetal carotid PO2 22.7 +/- 0.7 torr; n = 11; P less than 0.001). At 141 days gestation mean fetal weight was 3.46 +/- 0.72 kg in the hypobaric group compared to 4.15 +/- 0.51 in the normobaric group (P less than 0.05). Concentrations of glucose in maternal and fetal plasma and fructose in fetal plasma were similar in hypobaric and normobaric fetuses. The concentration of lactate in fetal plasma rose from 1.68 +/- 1.34 to 8.79 +/- 5.8 mmol/l (P less than 0.001) within 24 h of onset of hypoxia, but fell to 3.36 +/- 1.13 mmol/l by day 3 of treatment, though still significantly above the concentration of lactate in the control fetuses (1.47 +/- 0.47; P less than 0.001). There was no significant effect of hypoxia on the concentration of lactate or alanine in maternal plasma. Alanine concentration in the plasma of fetuses subjected to hypoxia significantly increased within 24 h of exposure (0.28 +/- 0.10 vs 0.58 +/- 0.39 mmol/l; P less than 0.01) and remained elevated for the duration of the study. There was no significant effect of gestational age on the concentration of metabolic substrates in either the control or experimental groups. Hypoxia is associated with a sustained rise in the concentration of plasma lactate and alanine in the fetus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipoproteins status in professional football players after period of vacation and one month after a new intensive training program

Plasmatic lipoproteins were evaluated in a group of 11 professional football-players after a 3-week rest, and one month later, after an intensive training (characterized by a succession of aerobic and anaerobic efforts), for engaging a new competition. At day 0, total cholesterol (TC = 4.4 +/- .04 mmol/l), triglycerides (TG = .6 +/- .04 mmol/l), and LDL-TC (2.54 +/- .18 mmol/l) were significantly decreased versus sex and age matched sedentary subjects (TC = 5.13 +/- .2 mmol/l, P less than .02; TG = .99 +/- . mmol/l, P less than .01; LDL-CT = 3.26 +/- .2 mmol/l, P less than .02). HDL-TC was increased (1.50 +/- .06 vs 1.30 +/- .05 mmol/l, P less than .05). The apoprotein A1 (apoA1) was higher in football-players (1.5 +/- .06 vs 1.16 g/l, P less than .001), while the apoprotein B (apoB) was lower (.6 +/- .03 vs .88 +/- .04 g/l, P less than .001). Even after 3 weeks of rest, the football-players lipoproteins were still identical to aerobic elite-athletes. At day +30, after a daily training involving 2 anaerobic sequences, the maximal aerobic capacity was increased by 21%, without any change in nutritional, plasmatic and hepatic status. Weight was diminished (-0.8 kg, P less than 0.05). TC (4.14 +/- .2 mmol/l), TG less than .64 +/- .08 mmol/l), LDL-TC (3.37 +/- .17 mmol/l), apo B (.64 +/- .05 g/l) were unchanged. HDL-CT fell to controls values while apoA1 increased (1.66 +/- .06 mmol/l, P less than .001). Thus, HDL-CT/apoA1 ratio (indicating the TC content of HDL) was decreased, whereas apoB/apoA1 ratio was unchanged. The decrease of TC content of HDL was not related to dietary change nor to weight decrease. As TG were stable, the lipoprotein lipase activity could not be modified.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of changes in plasma hepatic-portal and systemic osmolality on plasma concentrations of arginine vasopressin in conscious newborn calves

Systemic plasma concentrations of arginine vasopressin (AVP) were studied in three groups of 10-15 day-old conscious newborn calves. Animals in the first group (control group) and in the second group (systemic-hypertonic-injected group) received respectively isotonic and hypertonic (8 mmol NaCl/kg body weight) saline injection into the right jugular vein. Animals in the third group were fitted with chronic mesenteric and hepatic-portal catheters and received a 1 h-hypertonic saline infusion (2 mmol NaCl/kg body weight) into the main mesenteric vein. In animals in the second group there were parallel increases in systemic plasma concentration of Na+ (from 148.0 +/- 2.6 to 177 +/- 8 mmol/l; P less than 0.01), osmolality (from 289 +/- 2 to 319 +/- 4 mOsmol/kg H2O; P less than 0.01) and systemic plasma concentrations of AVP (from 4.2 +/- 0.4 to 11.1 +/- 0.6 pmol/l; P less than 0.01) 10 min after the injection. There were no significant changes in control animals. Hypertonic saline infusion into the main mesenteric vein in the third group induced an increase in concentration of Na+ (from 147.3 +/- 2.0 to 165.0 +/- 5.0 mmol/l; P less than 0.01) and osmolality (from 288 +/- 5 to 315 +/- 10 mOsmol/kg H2O; P less than 0.01) in hepatic-portal vein plasma but did not alter systemic plasma osmolality or concentrations of Na+ and AVP. This study demonstrates that the relationship between plasma concentrations of AVP and systemic osmolality is operative in the newborn calf but does not support the hypothesis that hepatic portal osmo-receptors sensitive to hyperosmolality influence AVP release.     

Role of muscle mass and mode of contraction in circulatory responses to exercise

The roles of the mode of contraction (i.e., dynamic or static) and the active muscle mass as determinants of the cardiovascular responses to exercise were studied. Six healthy men performed static handgrip (SHG), dynamic handgrip (DHG), static two-knee extension (SKE), and dynamic two-knee extension (DKE) to local muscular fatigue in approximately 6 min. Increases in mean arterial pressure were similar for each mode of contraction, 29 +/- 5 and 30 +/- 3 mmHg in SHG and DHG and 56 +/- 2 and 48 +/- 2 mmHg in SKE and DKE (P greater than 0.05) but larger for KE than HG (P less than 0.001). Cardiac output increased more for dynamic than for static exercise and for each mode more for KE than HG (P less than 0.001). Systemic resistance was lower for dynamic than static exercise and fell from resting levels by approximately 1/3 during DKE. The magnitude of the pressor response was related to the active muscle mass but independent of the contraction mode. However, the mode of contraction affected the circulatory changes contributing to the pressor response. Equalization of the pressor responses was achieved by proportionately larger increases in cardiac output during dynamic exercise.     

Steroid antagonism of the ‘hypertensinogenic’ activity of 9α-fluoroprednisolone

We have previously reported that adrenocortical steroids raise blood pressure by a ‘hypertensinogenic’ mechanism of action which is not simply related to their classical ‘mineralocorticoid’ or ‘glucocorticoid’ actions. This study presents evidence for specific antagonism of this ‘hypertensinogenic’ activity. The effects of separate IV infusions of prednisolone (P) 100 mg/d and 9α-fluoro-prednisolone (9αF-P) 0.6 mg/d on mean arterial pressure (MAP), plasma [K], plasma [glucose] and urinary NA excretion (UNaV) after 2 days were studied in sheep. In the same group of sheep which received P alone for 2 days, 9αF-P was given for a further 2 days while continuing the P infusion (P + 9αF-P). P alone had no effect on MAP or plasma [K] or U_NaV but increased plasma [glucose], effects which are characteristic of ‘glucocorticoid’ activity. 9αF-P alone increased MAP by 14 mmHg (P<0.001) and reduced plasma [K] and U_NaV but had no effect on plasma [glucose]. Thus 9αF-P exhibited both ‘hypertensinogenic’ and ‘mineralocorticoid’ activity. In the sheep which received the combined P + 9αF-P infusion, the increase in MAP normally produced by 9αF-P was blocked. Although pretreatment with P blocked the pressor effect of 9αF-P, it did not alter the ‘mineralocorticoid’ effects, namely hypokalaemia and urinary Na retention, produced when 9αF-P was infused alone. These results provide further evidence for our concept of a ‘hypertensinogenic’ class of steroid activity and are the first demonstration of specific antagonism of steroid induced hypertension.     

Reversal of fatigue during prolonged exercise by carbohydrate infusion or ingestion

Seven cyclists exercised at 70% of maximal O2 uptake (VO2max) until fatigue (170 +/- 9 min) on three occasions, 1 wk apart. During these trials, plasma glucose declined from 5.0 +/- 0.1 to 3.1 +/- 0.1 mM (P less than 0.001) and respiratory exchange ratio (R) fell from 0.87 +/- 0.01 to 0.81 +/- 0.01 (P less than 0.001). After resting 20 min the subjects attempted to continue exercise either 1) after ingesting a placebo, 2) after ingesting glucose polymers (3 g/kg), or 3) when glucose was infused intravenously ("euglycemic clamp"). Placebo ingestion did not restore euglycemia or R. Plasma glucose increased (P less than 0.001) initially to approximately 5 mM and R rose (P less than 0.001) to approximately 0.83 with glucose infusion or carbohydrate ingestion. Plasma glucose and R then fell gradually to 3.9 +/- 0.3 mM and 0.81 +/- 0.01, respectively, after carbohydrate ingestion but were maintained at 5.1 +/- 0.1 mM and 0.83 +/- 0.01, respectively, by glucose infusion. Time to fatigue during this second exercise bout was significantly longer during the carbohydrate ingestion (26 +/- 4 min; P less than 0.05) or glucose infusion (43 +/- 5 min; P less than 0.01) trials compared with the placebo trial (10 +/- 1 min). Plasma insulin (approximately 10 microU/ml) and vastus lateralis muscle glycogen (approximately 40 mmol glucosyl U/kg) did not change during glucose infusion, with three-fourths of total carbohydrate oxidation during the second exercise bout accounted for by the euglycemic glucose infusion rate (1.13 +/- 0.08 g/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ascorbic acid does not affect large elastic artery compliance or central blood pressure in young and older men

Large elastic artery compliance is reduced and arterial blood pressure (BP) is increased in the central (cardiothoracic) circulation with aging. Reactive oxygen species may tonically modulate central arterial compliance and BP in humans, and oxidative stress may contribute to adverse changes with aging. If so, antioxidant administration may have beneficial effects. Young (Y; 26 +/- 1 yr, mean +/- SE) and older (O; 63 +/- 2 yr, mean +/- SE) healthy men were studied at baseline and during acute (intravenous infusion; Y: n = 13, O: n = 12) and chronic (500 mg/day for 30 days; Y: n = 10, O: n = 10) administration of ascorbic acid (vitamin C). At baseline, peripheral (brachial artery) BP did not differ in the two groups, but carotid artery compliance was 43% lower (1.2 +/- 0.1 vs. 2.1 +/- 0.1 mm(2)/mmHg x 10(-1), P < 0.01) and central (carotid) BP (systolic: 116 +/- 5 vs. 101 +/- 3 mmHg, P < 0.05, and pulse pressure: 43 +/- 4 vs. 36 +/- 3 mmHg, P = 0.16), carotid augmentation index (AIx; 27.8 +/- 7.8 vs. -20.0 +/- 6.6%, P < 0.001), and aortic pulse wave velocity (PWV; 950 +/- 88 vs. 640 +/- 38 cm/s, P < 0.01) were higher in the older men. Plasma ascorbic acid concentrations did not differ at baseline (Y: 71 +/- 5 vs. O: 61 +/- 7 micromol/l, P = 0.23), increased (P < 0.001) to supraphysiological levels during infusion (Y: 1240 +/- 57 and O: 1,056 +/- 83 micromol/l), and were slightly elevated (P < 0.001 vs. baseline) with supplementation (Y: 96 +/- 5 micromol/l vs. O: 85 +/- 6). Neither ascorbic acid infusion nor supplementation affected peripheral BP, heart rate, carotid artery compliance, central BP, carotid AIx, or aortic PWV (all P > 0.26). These results indicate that the adverse changes in large elastic artery compliance and central BP with aging in healthy men are not 1). mediated by ascorbic acid-sensitive oxidative stress (infusion experiments) and 2). affected by short-term, moderate daily ascorbic acid (vitamin C) supplementation.