Renal effects of atrial natriuretic peptide during dopa-decarboxylase inhibition in patients with essential hypertension

Summary To assess whether intrarenal dopamine synthesis could contribute to the renal response to ANP in essential hypertension, the effects of -human ANP influsion (50 ng·min^–1·kg^–1 b.w. for 30 min) on the urinary excretion of dopamine and sodium, urine flow rate and arterial pressure were evaluated in 7 patients with mild-moderate essential hypertension before (control period) and during DOPA-decarboxylase inhibition with carbidopa (carbidopa period).In the control period, urinary dopamine excretion was 400 pg·min^–1 in baseline conditions and 340 pg·min^–1 during ANP infusion. Carbidopa significantly decreased urinary dopamine excretion both before (210 pg·min^–1) and during ANP (99 pg·min^–1). In contrast, carbidopa did not affect sodium excretion (control from 184 to 460 Eq·min^–1; carbidopa period from 140 to 390 Eq·min^–1) or urine flow rate (control from 5.35 to 11.21 ml·min^–1; carbidopa period from 4.29 to 11.54 ml·min^–1).Arterial pressure fell significantly during ANP infusion in both periods, and no significant difference was observed between the two study days, i.e. in the absence of and during carbidopa administration.We conclude that DOPA-decarboxylase inhibition does not influence the diuretic and natriuretic response to -human ANP infusion in patients with essential hypertension.     

Pharmacokinetics of quinine in patients with chronic renal failure

Methods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (t_max 4.5 vs 1.6 h, C_max 6.17 vs 3.45 g·ml^–1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min^–1·kg^–1, whereas V_z/f remained unchanged (1.82 vs 2.78 1·kg^–1). This resulted in the increased values of AUC and prolongation of the t_1/2z and MRT in the patients (AUC 181.5 vs 61.8 g·min^–1·ml^–1, t_1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.     

Pharmacokinetics of ibuprofen in febrile children

Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC.The maximum observed serum concentrations of ibuprofen ranged from 17–42 m·ml^–1 at 5 mg·kg^–1 and 25–53 m·ml^–1 at 10 mg·kg^–1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean t_max, oral clearance and elimination half life were 1.1 h, 1.2 ml·min^–1·kg^–1, and 1.6 h, respectively in patients at 5 mg·kg^–1 doses; the corresponding values were 1.2 h, 1.4 ml·min^–1·kg^–1, and 1.6 h in those receiving 10 mg·kg^–1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients.These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.     

Pharmacokinetics of exogenous adenosine in man after infusion

Summary The plasma kinetics of adenosine was investigated in healthy volunteers after a 1 minute infusion of 2.5, 5 and 10 mg (38, 79 and 148 g·kg^–1 respectively) and after infusion of 200 g·kg^–1 in 10 min followed by 400 g·kg^–1 in 10 min.As the dose in the 1 min infusion study was increased the mean CL of adenosine decreased (10.7, 4.70 and 4.14 l·min^–1, respectively), its mean half-life increased (0.91, 1.24 and 1.86 min, respectively), and the mean volume of distribution did not show any clear trend (8–13 l).After the 20 minute infusion the plasma level of adenosine reached a peak value comparable to that observed after infusion of 5 mg in 1 min (about 0.5 g·ml^–1), but the mean clearance and half-life were significantly different (12.1 l·min^–1 and 0.63 min respectively).In all the subjects the plasma concentration of adenosine had returned to the baseline value in 5–15 min after the end of the infusion.     

The pharmacokinetics ofα-human atrial natriuretic polypeptide in healthy subjects

Summary We have analysed the pharmacokinetics of-human atrial natriuretic polypeptide (-hANP) in healthy subjects, using a two-compartment open model following bolus intravenous injection. The plasma half-times for the fast and slow components were 1.7±0.07 min and 13.3±1.69 min respectively. V₁ (the volume of the central compartment), V_z (volume of distribution) and V_ss (volume of distribution at steady-state) were 5370±855 ml (89.5±14.3 ml·kg^–1), 32000±4620 ml (533±77.0 ml·kg^–1), and 11900±1530 ml (198±25.5 ml·kg^–1) respectively. The mean plasma clearance was 1520±121 ml·min^–1 (25.4±2.0 ml·min^–1·kg^–1.     

The pharmacokinetics and haemodynamic effects of continuous nicorandil infusion in healthy volunteers

Summary We have studied the pharmacokinetics and haemodynamic effects of nicorandil after a 12-h infusion. Nicorandil is a mixed vasodilator combining the actions of a nitrate and a potassium channel opener.Nicorandil was infused for 12 h in 21 healthy volunteers at rates of 0.05, 0.10, and 0.20 g·kg^–1·min^–1 using a placebo controlled, crossover design. Systemic blood pressure, heart rate, electrocardiographic (ECG) intervals, and cardiac output (impedance cardiography) were measured supine and standing.Dose-related, steady-state plasma nicorandil concentrations occurred within 3 to 4 h. Nicorandil's pharmacokinetics were linear with dose.Four 0.20 g·kg^–1·min^–1 nicorandil infusions were terminated early primarily because of moderate or severe headaches. There were no safety concerns (ECG intervals, laboratory assays).Blood pressure fell versus placebo only in the standing position and heart rate increased slightly (not significant). That is, standing blood pressure in the 6 to 12 h interval fell from baseline 8.0*/6.8, 1.6/5.1, and 9.8*/7.9* mmHg (systolic/diastolic, *=P<0.05 versus placebo) at 0.05, 0.10, and 0.20 g·kg^–1·min^–1 respectively. Cardiac output increased slightly above placebo at lower doses. Haemodynamic changes correlated poorly with plasma nicorandil concentrations. Similar total doses were less well-tolerated when extended over 12 h. We saw no evidence of pharmacodynamic tolerance to nicorandil within 12 h.     

Pharmacokinetics of cimetidine after subchronic administration

Summary The influence of cimetidine on its own pharmacokinetics after subchronic administration was assessed in 8 healthy volunteers, aged 26–29 years. On control Day 1, each subject received cimetidine 300 mg i.v., and serum and urine samples were obtained. Each subject was initiated on cimetidine 600 mg b.i.d. orally for 2 weeks. There were 3 further study days repeated after 1 and 2 weeks of cimetidine dosing and 1 week after stopping cimetidine. There was no significant difference in the mean total body clearance of cimetidine among the 4 study days. Mean elimination t_1/2 and V were similarly unchanged. However mean renal clearance (CL_R) and f_e were significantly increased following 2 weeks of drug dosing (CL_R 5.41 ml·min^–1 kg^–1; f_e 0.61) compared to control (CL_R 4.00 ml·min^–1·kg^–1; f_e 0.48). Although the non renal clearance was reduced from control values of 4.29 to 3.51 ml·min^–1·kg^–1 following 2 weeks of dosing the difference was not significant. Dosage adjustment of cimetidine appears unnecessary after short-term dosing in the presence of normal renal function.     

Bioavailability and pharmacokinetics of oxazepam

Summary Six healthy volunteers received oxazepam 15 mg i.v. and orally at an interval of at least one week. The kinetic variables of i.v. oxazepam were: elimination half-life (t_1/2) 6.7 h, total clearance (CL) 1.07 ml·min^–1·kg^–1, volume of distribution (V_c) 0.27 l·kg^–1 (0.21–0.49) and volume of distribution at steady-state (V_ss) 0.59 l·kg^–1. The intravenous disposition of unbound oxazepam was characterized by a clearance of 22.5ml·min^–1·kg^–1 and a distribution volume of 12.3 l·kg^–1. After oral oxazepam the peak plasma level was reached in 1.7 to 2.8 h. The plasma t_1/2 at 5.8 h was not significantly different from the i.v. value. Absorption was almost complete, with a bioavailability of 92.8%. Urinary recovery was 80.0 and 71.4% of the dose after intravenous and oral administration, respectively. Renal clearance (CL_R) of the glucuronide metabolite was 1.10 ml·min^–1·kg^–1 (0.98–1.52). Oxazepam was extensively bound to plasma protein with a free fraction of 4.5%.     

The effects of dopamine and a low protein diet on glomerular filtration rate and renal plasma flow in the aged kidney

Summary The aims of this study were to determine the effects of dopamine and a low protein diet on glomerular filtration rate and effective renal plasma flow in the aged kidney. Effective renal plasma flow was measured using ¹²⁵I-labelled hippuran and glomerular filtration rate using ⁵¹Cr-labelled EDTA.Low-dose continuous intravenous dopamine 3 g·kg^–1·min^–1 in 10 healthy elderly volunteers caused a significant increase in effective renal plasma flow but not in the mean glomerular filtration rate when compared with baseline. However, glomerular filtration rate did increase substantially in 5 subjects (mean 14.4, SD 1.3). This implied that the elderly kidney was working maximally without reserve capacity in half the elderly. Since renal function is likely to be even more reduced in elderly patients with congestive cardiac failure, dopamine infusions may have little place in this condition in some older patients.A low protein diet (0.69 g·kg^–1) in the same volunteers reduced glomerular filtration rate, suggesting that protein restriction may help to reduce the increased filtration rate in the remaining nephrons, thereby leading to structural and functional preservation in the aged kidney.     

The activity of the neuronal and extraneuronal catecholamine-metabolizing enzymes of the perfused rat heart

Summary In a comparative study the neuronal and extraneuronal metabolism of several ³H-catecholamines (all of which were tritiated in the C-7 position of the side chain only) was determined in isolated rat hearts perfused at a concentration of the 3H-amines of 50 nmol/1. While the neuronal MAO activity was determined after inhibition of extraneuronal uptake (100 mol/1 OMI) and COMT (10 mol/1 U-0521), the extraneuronal MAO activity was estimated after inhibition of neuronal uptake (30 mol/1 cocaine) and COMT. The extraneuronal COMT activity was determined under conditions of inhibition of both neuronal uptake and MAO (pretreatment with pargyline). Hearts were perfused with the 3H-catecholamines until the rate of appearance of the various ³H-metabolites in the venous effluent has reached a steady state. From these rates (v _st-st) and the steady-state content of the unchanged ³H-catecholamines in the tissue (S _i), the rate constants (V _max/K _m) for the unsaturated intracellular enzymes COMT (_COMT) and MAO (_MAO) were calculated. The _COMTvalues for all four catecholamines, (–)-noradrenaline, dopamine, (–)-adrenaline and (±)-isoprenaline exhibit a range from 0.24 to 0.78 min^–1; the metabolism of the catecholamines by the COMT differs: (-)-noradrenaline = dopamine < (–)-adrenaline < (±)-isoprenaline. The extraneuronal MAO activity was low for all three catecholamines, (–)-adrenaline, (–)-noradrenaline and dopamine (range of _MAOfrom 0.05 to 0.28 min^–1) and declined in the order: (–)-adrenaline < (–)-noradrenaline < dopamine. The neuronal MAO activity for (–)-adrenaline, (–)-noradrenaline and dopamine was slightly higher than that in the extraneuronal cells (range of kMAO from 0.08 to 0.35 min^–1), but the ranking order showed the same pattern: (–)-adrenaline < (–)-noradrenaline = dopamine.Abbreviations MAO monoamine oxidase - COMT catechol-Omethyltransferase - NMN normetanephrine - MN metanephrine - MT 3-methoxytyramine - OMI 3-O-methyl-isoprenaline - DOPEG dihydroxyphenylglycol - DOPET dihydroxyphenylethanol - DOMA dihydroxymandelic acid - DOPAC dihydroxyphenylacetic acid - U-0521 3,4-dihydroxy-2-methyl propiophenone     

Catecholamine release in the locus coeruleus is modified by experimentally induced changes in haemodynamics

Summary The involvement of catecholaminergic neurons of the locus coeruleus in central cardiovascular control was investigated in the anaesthetized cat. Push-pull cannulae were bilaterally inserted into the LC and the release of noradrenaline and dopamine was determined radioenzymatically in the superfusate. The effects of experimentally induced changes in blood volume and vascular resistance on catecholamine release in the locus coeruleus were studied.Hypervolaemia strongly inhibited the release of noradrenaline in the locus coeruleus. Intravenous infusion of noradrenaline (5 g·kg^–1·min^–1) elicited a pronounced pressor response which was also associated with a decrease in the release of noradrenaline in the locus coeruleus. Conversely, a fall of blood pressure caused by a controlled haemorrhage enhanced the release of noradrenaline. A profound fall in blood pressure caused by infusion of nitroprusside (8 g·kg^–1·min^–1) did not modify the release rate of noradrenaline. Dopamine release rate was not significantly influenced by these cardiovascular alterations.The results demonstrate that increases in blood pressure elicited by vascular constriction or hypervolaemia inhibit the release of noradrenaline in the locus coeruleus. Decreases in blood pressure elicited by hypovolaemia enhance the release of noradrenaline, but lowering blood pressure by vasodilatation is ineffective. Hence, the release of endogenous noradrenaline in the locus coeruleus is responsive to haemodynamic signals, thus supporting the suggested integrative role of the locus coeruleus in central cardiovascular control.Correspondence to N. Singewald at the above address     

Effects of altitude (4300 M) on the pharmacokinetics of caffeine and cardio-green in humans

The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardiogreen (ICG) were examined in eight healthy males (23–35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg · kg^–1) was administered as an intravenous bolus and caffeine (4 mg · kg^–1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in the caffeine half-life (t_1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g · 1^–1 · min^–1), and increased clearance (117 vs 86 ml · min^–1 · 70 kg^–1). In ALT the area under the curve of ICG significantly decreased (85 vs 207 mg · 1^–1 · min^–1) and the volume of distribution and clearance increased (5.2 vs 2.41 and 532 vs 234 ml · min^–1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.     

The pharmacokinetics of theβ 2-adrenoceptor agonist fenoterol in healthy women

Summary We have studied the pharmacokinetics of fenoterol in healthy women during and after a 3 h intravenous infusion of different doses within the therapeutic range for tocolysis (0.5 g·min^–1, 1.0 g·min^–1, and 2.0 g·min^–1). A specific and sensitive radioimmuno-assay was used for the determination of fenoterol. For compartmental analysis the plasma concentration time data were fitted with the TOPFIT program, assuming two exponentials.The total clearance of fenoterol increased with dose (1299 ml·min^–1 at 0.5 g·min^–1, 1483 ml·min^–1 at 1.0 g·min^–1, and 1924 ml·min^–1 at 2.0 g·min^–1), as did the apparent volume of distribution (from 491 at the lowest to 851 at the highest dose).In contrast, the apparent half-lives were not dose-dependent, with t_{1/2· 1} 4.8 min and t_{1/2· 2} 52 min.This paper is dedicated to Prof. Dr. Ellen Weber, Heidelberg, FRG     

Steady-state concentrations of choline and acetylcholine in rat brain parts during a constant rate infusion of deuterated choline

Summary An intravenous infusion of deuterated choline at constant rate for 6 min (5 or 25 moles kg^–1 min^–1) significantly increases the concentration of choline in plasma, occipital cortex and striatum. Both 5 and 25 moles kg^–1 min^–1 increase the concentration of acetylcholine in cortex but only 25 moles kg^–1 min^–1 increases the acetylcholine content in striatum. In contrast, 1 mole kg^–1 min^–1 does not change the choline or acetylcholine content in cortex or striatum. A single pulse injection of choline (200 moles kg^–1) causes a significant increase in the concentration of choline in striatum 30 sec following injection. The choline content returns to normal values within 2 min. These studies show that when a pulse injection of a non-tracer dose of radioactive choline is used to measure brain acetylcholine turnover rate the maintenance of steady state must be verified within seconds after the pulse injection of radioactive choline. When constant infusion of deuterated choline is used to measure turnover rate of acetylcholine in the brain of rats, a dose of 1 mole kg^–1 min^–1 appears to be a maximal infusion rate.     

Inhibitory effects of apomorphine and pergolide on neurogenic vasoconstriction in the hindquarters of the rat

Summary The effects of locally administered apomorphine and pergolide were studied in the isolated autoperfused hindquarters of the rat, in an attempt to assess the possible role of presynaptic dopamine receptors at the level in the hypotensive effect of these dopamine agonists.Local infusion of apomorphine (1g·kg^–1·min^–1 for 5 min) or pergolide (1g·kg^–1·min^–1 for 5 min) [into the hindquarters] did not alter perfusion pressure per se, but reduced the pressor response to electrical stimulation of the lumbar sympathetic chains for the whole frequency range used during a cumulative frequency-response curve (0.25–16 Hz, 1 ms, supramaximal voltage). Apomorphine and pergolide reduced the pressor response elicited by 4 Hz electrical stimulation (applied until maximum response was reached) to 54.8±7.1% and 53.9±1.7% respectively, but they did not modify similar increases of perfusion pressure produced by locally administered noradrenaline.The inhibition by apomorphine and pergolide of the 4 Hz stimulation-evoked pressor response was completely antagonized by local administration of the dopamine antagonist haloperidol (1g·kg^–1), but was not influenced by the ₂-antagonist rauwolscine (100g·kg^–1). This dose of rauwolscine antagonized the inhibitory effect of the ₂-agonist UK-14,304, which was not influenced by haloperidol.Local administration of rauwolscine increased the pressor response to stimulation at 4 Hz by 37.4–46.2%. In contrast, local administration of haloperidol did not influence the 4 Hz stimulation-evoked pressor response.These results indicate that dopamine receptors are pressent on the sympathetic innervation of the vascular bed in the rat hindquarters but do not provide evidence for a physiological role of these receptors in modulating peripheral sympathetic neurotransmission. Stimulation of these receptors, leading to a decrease of noradrenaline release and thus of vasomotor tone, might—at least in part—explain the blood pressure lowering effects of intravenous apomorphine and pergolide in the rat.     

Pharmacokinetics of ketorolac tromethamine in humans after intravenous,intramuscular and oral administration

Summary The pharmacokinetics of ketorolac tromethamine, a potent non-narcotic analgesic agent used for relief of moderate to severe pain, has been studied in 15 healthy volunteers who received single 10 mg doses intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.) in a three-way cross-over design.The kinetics of i.v. ketorolac were characterized by a terminal half-life of 5.09 h, a small plasma clearance (CL = 0.35 ml·min^–1·kg^–1) and a small tissue distribution (V_ss=0.111·kg^–1, V=0.17 l·kg^–1; mean (SD). Following i.m. and p.o. administration, peak levels of approximately 0.8 µg/ml were rapidly attained (t_max = 0.8 and 0.9 h, respectively) and the systemic bioavailability was essentially complete.     

Nicorandil-induced changes in the distribution of cardiac output and coronary blood flow in pigs

Summary The present investigation was conducted to study systemic and regional haemodynamic effects of nicorandil, a potent coronary vasodilator, after intravenous or local intracoronary administration in anaesthetized or conscious pigs. Intravenous infusions of nicorandil for 10 min in both anaesthetized (15, 30, 75 and 150 g · kg^–1 · min^–1) and conscious (20, 40 and 80 g · kg^–1 · min^–1) pigs reduced arterial blood pressure, stroke volume, left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance, but increased heart rate and maxLVdP/dt. Since nicorandil decreased LVEDP at doses which did not affect arterial blood pressure, the drug may be considered as a more potent venodilator than arterial dilator. Nicorandil increased cardiac output only in conscious animals due to a more marked tachycardia (85% after 80 g · kg^–1 · min^–1) than in anaesthetized animals (30% after 75 g · kg^–1 · min^–1). The nicorandil-induced increase in heart rate and maxLVdP/dt, being substantially attenuated in conscious pigs after treatment with propranolol, can be ascribed to a reflex activation of the sympathetic nervous system following the fall in arterial pressure. Although cardiac output did not change in anaesthetized animals, intravenous infusions of nicorandil did cause a redistribution of blood flow in favour of organs such as the heart, adrenals, spleen, small intestine and brain at the expense of that to the stomach and kidneys; hepatic artery and skeletal muscle blood flow did not change. The increase in myocardial blood flow, primarily to the subepicardial layers, was associated with an enhancement in coronary venous oxygen content and was also noticed after intracoronary infusions of nicorandil (0.6, 1.5, 3 and 6 g · kg^–1 · min^–1). The above cardiovascular profile suggests a possible usefulness of nicorandil in angina pectoris as well as congestive heart failure. However, caution is needed because the strong hypotensive action and reflex-mediated tachycardia may under certain conditions aggravate myocardial ischaemia, particularly in the subendocardial layers. Send offprint requests to P. D. Verdouw     

Variability of thiopental clearance in routine critical care patients

Thiopental was administered to neurosurgical patients as a drug for cerebral protection for up to 9 days either by continuous infusion (seven subjects) or repeated intravenous bolus (nine subjects). The efficient levels of thiopental measured at steady state ranged between 5 and 63 mg · l^–1. Steady-state clearance evidenced considerable interindividual variability. Overall mean plasma clearance was lower than 1 ml · min^–1 · kg^–1 for one subjects, ranged between 1 and 2 ml · min^–1 · kg^–1 for six subjects, between 2 and 3 ml · min^–1 · kg^–1 for seven subjects and was up to 5 ml · min^–1 · kg^–1 for one subject. Extreme values for apparent daily clearance were 0.268 ml · min^–1 · kg^–1 and 5.40 ml · min^–1 · kg^–1. Daily intersubject CV gradually increased from day to day, increasing from 37% on day 1 to 51% on day 7. During the treatment for seven subjects, variations were minimal and clearance was considered to be constant; the maximum variation of clearance expressed as a percentage of the initial value was lower than 21% over a period longer than 3 days. For the other subjects, clearance was not stable with time. A decrease in clearance was evidenced for four subjects over a period of 7 days and more; the maximum variation of clearance was greater than –35%. An increase in clearance was noted for three subjects after 2 days of treatment; the maximum variation of clearance was greater than +44%. Evaluation of clearance at steady state made it possible to analyse interindividual variability and its clinical implications.Professor Bernard Roquefeuil deceased on January 22nd, 1994     

Simvastatin reduces plasma lipid levels and improves insulin action in elderly,non-insulin dependent diabetics

Summary Twelve elderly non-insulin dependent diabetic patients took part in a double-blind, cross-over, randomized study comparing simvastatin 30 mg/day and placebo. Each treatment period lasted 3 weeks and was separated by a 3 week wash-out period. At the end of each treatment period all subjects underwent in randomized order an oral glucose tolerance test (OGTT; 75 g) and an euglycaemic hyperinsulinaemic (50 mU/kg·h) glucose clamp.Simvastatin compared to placebo significantly reduced plasma total cholesterol (7.9 vs 5.3 mmol·l^–1), LDL-cholesterol (7.2 vs 4.3 mmol·l^–1), triglycerides (2.9 vs 2.1 mmol·l^–1), free fatty acids (1106 vs 818 mmol^–1) and glucose (7.4 vs 6.6 mmol·l^–1) levels.After simvastatin, and in the last 60 min of the glucose clamp, there was an improvement in the action of insulin as demonstrated by stronger inhibition of hepatic glucose output (2.7 vs 5.2 mol·kg^–1·min^–1) and stimulation both of the glucose disappearance rate (26.3 vs 19.5 mol·kg^–1·min^–1) and glucose metabolic clearance rate (4.3 vs 3.6 ml·kg^–1·min^–1).The changes in glucose turnover parameters were significantly correlated with basal plasma free fatty acids and were independent of plasma glucoregulatory hormones. In conclusion, simvastatin seems to exert beneficial effects both on lipid and glucose metabolism.     

Low-dose Iloprost infusion improves insulin action and non-oxidative glucose metabolism in hypertensive patients

Fourteen hypertensive (174.3/98.3 mmHg) non-diabetic patients were given a euglyceamic glucose clamp along with infusion of 0.9% NaCl and the prostacyclin (PGI₂) analogue Iloporst (0.7 ng · kg · min^–1). Substrate oxidation was also determined by indirect calorimetry. Over the last 60 min of the clamp, Iloprost vs saline improved whole body glucose disposal (WBGD) (35 vs 28.3 mol · kg^–1 LBM) and non-oxidative glucose metabolism (24.7 vs 18.1 mol · kg^–1 LBM · min^–1). Iloprost delivery was associated with a significant decrease in membrane microviscosity (0.253 vs 0.205), but did not affect arterial blood pressure and heart rate. In nine patients, skeletal muscle blood flow (SMBF) and insulin-stimulated glucose uptake (GU) were also studied. At the end of the study, despite a similar SMBF (37 vs 38 ml · min^–1 · kg^–1), GU (0.55 vs 0.46 mmol · 1^–1) was significantly increased by Iloprost infusion. Percentage decrease in membrane microviscosity was correlated with percentage increase in WBGD (r=0.65) and non-oxidative glucose metabolism (r=0.68). In conclusion, low-dose Iloprost infusion improves insulin action and non-oxidative glucose metabolism in hypertensive patients.