Renal kallikrein‐kinin system,but not renal dopamine system,mediates the natriuretic response to intravenous saline infusion in healthy Chinese subjects

1 To assess the role of renal dopamine (DA), sympathetic nervous system (SNS) activity and the renal kallikrein‐kinin system in sodium excretion in Chinese subjects, we studied the effects of intravenous saline infusion on the urinary excretions of sodium, free DA, free noradrenaline (NA) and kallikrein in eight healthy males aged 23–25 years.
2 After a baseline period of 1 h (hour 0), these subjects received 1 l of 0.9% saline over 2 h (hours 1 and 2), followed by a 4‐h recovery period (hours 3–6). From hours 0–4, subjects remained in the supine position, except to void urine. Distilled water was given orally throughout the study to ensure an adequate diuresis.
3 A 31–39% increase in sodium excretion (P<0.05) was seen during hours 2 and 3. Urinary DA did not change throughout the study period. Urinary free NA showed no changes while the subjects remained supine, but an increase of 91–105% (P<0.02) was seen after the subjects became ambulatory. However, there was a 103–140% increase in urinary kallikrein excretion (P<0.05) during the saline infusion. Urinary kallikrein was still much higher (by 74%) than the basal level 1 h after the completion of the saline infusion.
4 There is no evidence from the present study that renal DA or SNS play any role in the natriuretic response to saline infusion in Chinese subjects. The brisk urinary kallikrein response, despite a relatively small salt load, suggests that the renal kallikrein‐kinin system may play an important role in extracellular fluid volume and sodium homeostasis in Chinese subjects.     

Renal response to infusion of dopamine precursors in anaesthetized rats

In the present study the renal response to intravenous infusion of the catecholamine precursors l-dihydroxyphenylalanine (l-DOPA) or l-tyrosine was investigated in thiopentone sodium-anaesthetized Sprague-Dawley rats. Glomerular filtration rate (GFR) was assessed by renal clearance of inulin, urinary concentration of dopamine (U_DAV) by HPLC and sodium excretion (U_NaV) by flame photometry. We found that basal U_DAV was 6.5 ± 0.5 pmol/min per 100 g body weight (mean ± SEM). Intravenous infusion of l-tyrosine at 0.1–3.0 μmol/min dose dependently enhanced U_DAV (17 ± 3 to 144 ± 14 pmol/ min respectively) with higher doses of l-tyrosine resulting in no further increase in U_DAV. Compared with l-tyrosine administration significantly lower doses of l-DOPA (0.07 to 35 nmol/min) caused increases in U_DAV which were orders of magnitude higher (18 ± 1 to 7800 ± 470 pmol/min, respectively) and did not show saturation characteristics. GFR did not change in response to l-tyrosine or l-DOPA infusion. No variations in urinary flow rate or in U_NaV could be observed which were significantly correlated to changes in U_DAV. In contrast, intravenous infusion of dopamine at a dose of 6 nmol/min significantly increased GFR by 35 ± 6.2% and urinary flow rate by over 2-fold. Immunohistochemistry with light microscopy revealed no tyrosine hydroxylase in the kidney. Therefore, dopamine synthesis in the tubular cells mainly depends on the renal supply of l-DOPA. The unchanged GFR and U_NaV in spite of large variations of U_DAV argue against the hypothesis that intratubular dopamine plays a functional role in the regulation of hemodynamics or sodium transport in the kidney. Renal dopamine excretion may rather represent an effective pathway for the elimination of catecholamine precursors from the plasma. Received: 5 February 1997 / Accepted: 24 July 1997     

Role of prostaglandin, the kallikrein-kinin system and renal dopamine receptors in the mechanism of the natriuretic action of the beta-adrenoblocker obzidan

It has been established in experiments on anesthetized rats that the beta-adrenoblocker obsidan inhibiting tubular sodium reabsorption in the kidneys provokes the natriuretic reaction which correlates with the increased blood flow in the cortex and in the external medullary substance. pO2 in these zones of the renal tissue remains unchanged. The inhibitor of prostaglandin biosynthesis indomethacin and the inhibitor of the kallikrein-kinin system contrykal did not affect the renal response to the drug under study. The dopamine blocker haloperidol prevented the hemodynamic shift in the cortical and in the external medullary layers and interfered with the inhibitory action of obsidan in tubular sodium transport. It is inferred that the natriuretic response to the action of beta-adrenoblockers is not linked with the increased prostaglandin biosynthesis in the kidneys or with activation of the kallikrein-kinin system but is partially governed by stimulation of dopamine receptors of the kidneys.     

A comparison of the effects of intravenous propranolol and nadolol on the renal response to hypertonic saline infusion.

Intravenous loading with 500 ml of 2.7% saline increased the clearance of PAH and inulin and urine sodium excretion in 14 healthy subjects. Intravenous propranolol (0.075 and 0.15 mg/kg) did not alter PAH or inulin clearance at rest but abolished the increase expected during saline infusion. There was no consistent effect on urinary sodium excretion. Intravenous nadolol (0.05 and 0.75 mg/kg) reduced resting PAH and inulin clearances by up to 25%. Both clearances fell significantly during saline infusion but natriuresis was not significantly reduced in spite of the changes in renal function. There was no evidence from these studies in normal volunteers that nadolol confers any advantages over propranolol in its effects on renal function.     

Increased activity of the renal kallikrein-kinin system in autosomal dominant polycystic kidney disease in rats,but not in humans

The kallikrein-kinin system (KKS) was investigated in autosomal dominant polycystic kidney disease (ADPKD)-affected rats (PKD) and compared to unaffected controls (SD) and 5/6 nephrectomized rats (5/6 Nx). In addition, patients with ADPKD compared to patients with nonpolycystic kidney disease and healthy controls have been investigated. Plasma and urine samples for determination of creatinine, protein, kallikrein (KAL) and bradykinin (BK) were taken in male 3- and 9-month-old PKD, SD and 9-month-old 5/6 Nx. The same parameters were determined in young (age: 20-40 years) and old (41-65 years) male patients with ADPKD and compared to age-matched patients with nonpolycystic kidney disease and age-matched healthy controls. Plasma and urine KAL were measured by chromogenic peptide substrate, and kininswere determined by radioimmunoassay. Urine KAL and BK levels were increased i n PKD compared to age-matched SD. No differences with respect to serum KAL were found between PKD and SD. In 5/6 Nx, urinary BK levels showed a trend towards higher compared to old SD (p = 0.06). KAL and BK were not increased in serum and urine of patients with ADPKD, in contrast to rats. Urinary KAL excretion was reduced in patients with ADPKD and advanced renal failure. Our results demonstrate an age-dependent activation of the renal KKS in rats with ADPKD, whereas the KKS is not activated in patients with ADPKD and advanced renal failure. These data indicate that there are fundamental differences in the factors influencing the course of the disease in human and rat ADPKD.     

Impaired renal response to portal infusion of hypertonic saline in adriamycin-treated rats

1. The hepatorenal reflex plays an important role in water and salt homeostasis by matching renal excretion to gastrointestinal absorption. This homeostatic mechanism is impaired in nephrotic rats. The present study tested the hypothesis that, in nephrotic rats, the renal sodium excretion response to hypertonic saline infusion is impaired due to decreased sensitivity of the hepatoportal sodium-sensing mechanism. 2. The present study was performed in control and adriamycin (ADR)-induced nephrotic syndrome rats. After baseline data collection, urinary sodium (U(Na)V) and potassium (U(K)V) excretion responses were tested following continuous infusion of hypertonic NaCl solution (20 μL/min for 30 min) into either the femoral or mesenteric vein. A second series of experiments tested hepatic and renal nerve responses to continuous mesenteric vein infusion of hypertonic NaCl (10 μL/s for 30 s). 3. Compared with control rats, nephrotic rats displayed significantly lower baseline U(Na)V and U(K)V excretion. In control rats, mesenteric compared with femoral vein infusion of hypertonic NaCl produced a more rapid and greater increase in U(Na)V. In contrast, in nephrotic rats, femoral and mesenteric vein infusion caused similar increases in U(Na)V and the maximum increases in U(Na)V to either route of infusion were much lower in nephrotic than control rats. Furthermore, portal hypertonic saline infusion caused greater increases in hepatic nerve activity and greater decreases in renal nerve activity in control compared with nephrotic rats. 4. These data suggest that, in rats, adriamycin treatment decreases hepatoportal sodium-sensing sensitivity, leading to marked impairment of hepatorenal reflex responses, potentially contributing to salt and water retention.     

Neuroendocrine response to intravenous citalopram in healthy control subjects: pharmacokinetic influences

Rationale The neuroendocrine response to intravenous citalopram may provide an acute, functional, in vivo measure of the neural serotonin (5-HT) system.Objective To refine the quantification of acute neuroendocrine responses following intravenous citalopram in studies of 5-HT function.Methods In 75 adult healthy subjects taking part in four similar protocols, we measured plasma prolactin and cortisol, as well as serial citalopram concentrations following intravenous citalopram (10 mg, 20 mg, 40 mg, 0.33 mg/kg) and placebo. The relationship between the AUC for intravenous citalopram during the first 150 min (AUC₁₅₀) and the magnitude of the neuroendocrine response was determined. The role of pharmacokinetic (PK) parameters, as well as sensitivity to placebo injections, in influencing the neuroendocrine response to citalopram was then evaluated.Results Citalopram produced a dose-dependent increase in cortisol and prolactin. The maximal increase from baseline correlated significantly but modestly with citaloprams AUC₁₅₀ (prolactin r²=0.23, P<0.0001; cortisol r²=0.3, P<0.0001). Additionally, citaloprams AUC₁₅₀ was affected by between-subject differences in both the peripheral and central volume of distribution. However, the neuroendocrine responses to citalopram did not correlate with the responses to placebo.Conclusions The parenteral citalopram challenge test is characterized by a modest concentration-response relationship, with concentration influenced by variable PK factors. Accounting for individual differences in drug distribution may improve the power of the citalopram challenge test, when used as an in vivo measure of central 5-HT function.     

Renal response to infusion versus repeated bolus injections of atrial natriuretic factor in man

Summary In 7 healthy humans consuming a 170 mmol sodium diet the effect of the mode of administration of atrial natriuretic factor (human ANF 99–126) on renal function has been investigated, using conventional clearance studies during maximal water diuresis. ANF was administered as four repeated bolus (0.4 μg/kg) injections and, after a 2-day interval, as a one-hour infusion (0.02 μg/kg/min) preceded by a 0.4 μg/kg bolus injection. In the two experiments ANF caused comparable elevations in glomerular filtration rate, free water clearance, and lithium excretion. No change in blood pressure or heart rate was observed in either study, and plasma renin activity and aldosterone fell by a similar extent. As expected, the time course of plasma ANF concentrations was markedly different during the two studies. It is concluded that with those doses of ANF the changes in renal haemodynamics and sodium handling were essentially similar after bolus injections and a constant infusion.     

Gender-dependent dissociation between oxytocin but not ACTH, cortisol or TSH responses to m-chlorophenylpiperazine in healthy subjects

m-chlorophenylpiperazine (m-CPP), a serotonin (5-HT) agonist with some selectivity for the 5-HT_2C receptor subtype, which is widely used to examine 5-HT receptor function in human subjects, has been found to induce oxytocin and thyrotropin (TSH) responses in rodents. This study examined whether m-CPP had any effect on plasma oxytocin, TSH and aldosterone concentration in healthy volunteers using a double-blind, placebo-controlled crossover design. Plasma adrenocorticorticotropic hormone (ACTH) and cortisol responses, two generally accepted markers of m-CPP-induced 5-HT receptor activation, were measured in parallel. Male subjects (n = 7) received placebo, 0.25 and 0.5 mg/kg oral m-CPP. In female subjects (n = 5), the effects of placebo and 0.25 mg/kg m-CPP were studied. After placebo, given in the morning, ACTH, cortisol, TSH and aldosterone concentrations decreased over time. m-CPP 0.25 mg/kg avoided decreases in ACTH, cortisol and TSH concentrations; these responses were significant. At the dose of 0.5 mg/kg, m-CPP caused increase in ACTH, cortisol, TSH and aldosterone concentrations. Significant plasma oxytocin responses were found in female subjects only; thus this effect of m-CPP was statistically significantly gender dependent. Other responses to m-CPP were similar in male and female subjects. The present results suggest that there are clear differences, including dose and gender-dependent dissociations, among the 5-HT receptor agonist m-CPP-induced neuroendocrine responses. Received: 6 June 1997/Final version: 27 October 1997     

Effect of intravenous dopamine infusion on plasma concentrations of dopamine and dopamine sulfate in men, during and up to 18 h after infusion

Objective: We investigated whether sulfoconjugation contributes to the inactivation of intravenously infused dopamine (DA) in low concentrations with a predominant action on the kidney. Methods: Plasma DA and dopamine sulfate (DA-S) concentrations were determined during 4 h of intravenous infusion of DA (2 μg/kg/min) and up to 18 h after cessation of infusion. Twenty-seven healthy young subjects participated in the placebo controlled, randomised and double-blind study. Results: Intravenously administered DA was sulfoconjugated rapidly and to a great extent. After starting the infusion, DA levels rose within minutes and reached a steady state after 30–60 min. The steady-state levels averaged 151.3 ± 8.2 nmol/l. DA-S levels also increased markedly with infusion from 16.7 ± 9.9 nmol/l at the start of infusion up to 261.2 ± 24.2 nmol/l at 30 min after cessation of infusion. Plasma DA concentrations after cessation of the infusion decreased rapidly with an initial half-life of elimination of 4.8 min. Concentrations of plasma DA-S declined with a half-life of 4.5 h. Persistent elevations of free and conjugated DA compared with pre-treatment levels were observed even 18 h after cessation. Heart rate and blood pressure remained unchanged both during DA and saline infusion. Conclusion: Findings indicate that the sulfoconjugation pathway contributes markedly to the inactivation of intravenously infused DA and seems not to be saturable by DA infusion in low doses. Received: 8 March 1999 / Accepted in revised form: 21 September 1999     

Pretreatment with corticosterone attenuates the nucleus accumbens dopamine response but not the stimulant response to cocaine in rats

It has been suggested that stress, via corticosterone secretion, can modulate some of the behavioural responses to cocaine. In particular, we have demonstrated that daily exposure to electric footshock stress or daily pretreatment with corticosterone shifts the ascending limb of the dose-response curve for the acquisition of cocaine self-administration upwards and to the left. It has been suggested that this corticosterone-induced increase in sensitivity to low doses of cocaine is associated with an enhancement of dopaminergic neurotransmission. The present study was designed to test this hypothesis. Adult male rats were pretreated with corticosterone (2.0 mg/kg intraperitoneally) 15 min prior to an injection of cocaine (5.0, 10.0 or 20.0 mg/kg intraperitoneally), and motor activity and extracellular dopamine concentrations in the nucleus accumbens were monitored. Cocaine administration resulted in dose-related increases in motor activity that were unaffected by pretreatment with corticosterone. However, rather than augmenting cocaine-induced increases in dopamine in the nucleus accumbens, corticosterone pretreatment actually caused attenuation at the two highest doses of cocaine tested. These data suggest dissociation between locomotor activation and nucleus accumbens dopamine responses to cocaine, and indicate that other brain regions and/or mechanisms may be involved in the changes in sensitivity to cocaine induced by corticosterone.     

Renal response to amino acid infusion in rats: effect of dopamine receptor antagonists and benserazide

Previously, we have found that feeding is a dominant factor controlling urinary dopamine excretion (U_DA) in conscious rats (Mühlbauer and Osswald 1992). Since the renal response to feeding is also characterized by an increase in glomerular filtration rate (GFR), we wanted to investigate in a first step whether the feeding-induced elevations of GFR and U_DA could be causally related phenomena. Therefore, we studied the influence of dopamine synthesis and dopamine receptor blockade on the renal response to amino acid infusion (AA) in thiopental anesthetized rats. AA infusion (n = 7) increased GFR by 33±7% (P<0.001) and U_DA by 87±19% (P<0.001). In the presence of benserazide (BZD, n = 5), an inhibitor of dopamine synthesis, infused i.v. at a dose of 30 g/min/kg, U_DA was suppressed to values below detection limit and the AA-induced GFR increase was abolished. Continuous intravenous infusion of the DA₁ receptor antagonist SCH 23390 (SCH, n = 7) in a dose of 4.0 g/kg/min did not prevent the AA-induced increase in GFR (33±3%, P<0.001) and U_DA (97±12%, P< 0.001). In contrast, S-sulpiride (SUL), a specific DA₂ receptor antagonist, infused continuously i.v. in a dose of 5 g/kg/min, completely abolished the AA-induced GFR increase, while U_DA was increased 1.6-fold (P<0.01). Like BZD, both dopamine receptor antagonists did not affect renal sodium excretion substantially.Our results suggest, that endogenous dopamine could act as a mediator in the renal response to amino acid infusion in the rat, most likely by activation of DA₂ receptors. Correspondence to:B. Mühlbauer at the above address     

Pharmacokinetics and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, following chronic infusion in healthy subjects

AIMS: The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, during chronic infusions in healthy male subjects. METHODS: Tezosentan was infused at a rate of 100 mg h(-1) for 6 h (study A, six subjects) and at a rate of 5 mg h(-1) for 72 h (study B, eight subjects). Both studies had a randomized, placebo-controlled, double-blind design. Tolerability and safety were monitored by the recording of vital signs, ECG, adverse events and clinical laboratory parameters. Blood samples were collected frequently for pharmacokinetic determinations and measurement of plasma endothelin-1 concentrations. RESULTS: In both studies tezosentan was well tolerated with headache the most frequently reported adverse event (incidence of 75-100% for tezosentan and 50% for placebo). Plasma concentrations of tezosentan rapidly approached steady state (3000 and 125 ng ml(-1) in study A and B, respectively) and did not change upon prolonged infusion. A two-compartment model could describe its pharmacokinetic profile. The half-lives of the two disposition phases were approximately 0.10 and 3.2 h. Endothelin-1 concentrations increased rapidly 11- and 2-fold compared with pre-dose values in study A and B, respectively, during infusion of tezosentan and did not change during the 72 h infusion. CONCLUSIONS: On the basis of these results, dose finding studies with tezosentan in acute heart failure can be initiated in the dose range 5-100 mg h(-1).     

Prolactin response following intravenous and oral sulpiride in healthy human subjects in relation to sulpiride concentrations

Sulpiride (100 mg) was administered intravenously and orally to healthy human subjects. Serum concentrations of sulpiride and prolactin were followed for 36 h. Both routes of drug administration resulted in a pronounced and sustained increase in serum prolactin concentration. The prolactin response was positively correlated to the prolactin baseline value. The concentrations of prolactin remained at an elevated plateau for 9–36 h after drug treatment despite low drug concentrations. The level of this plateau was directly related to the normal circadian secretion of prolactin. The sustained prolactin elevation may be due to high affinity and strong binding of the compound to the regulating receptors or the formation of an active sulpiride metabolite.Prolactin and sulpiride concentrations were significantly correlated during the initial phase after intravenous sulpiride. Following intravenous and oral sulpiride the area under the concentration-time curve (AUC) for prolactin was similar despite a considerable difference in the sulpiride concentration.     

Pressor response to intravenous tyramine is a marker of cardiac,but not vascular,adrenergic function

Intravenous injections of the indirect sympathetic amine, tyramine, are used as a test of peripheral adrenergic function. The authors measured the time course of increases in ejection fraction, heart rate, systolic and diastolic pressure, popliteal artery flow, and greater saphenous vein diameter before and after an injection of 4.0 mg/m(2) body surface area of tyramine in normal human subjects. The tyramine caused moderate, significant increases in systolic pressure and significant decreases in total peripheral resistance. The earliest changes were a 30% increase in ejection fraction and a 16% increase in systolic pressure, followed by a 60% increase in popliteal artery flow and a later 11% increase in greater saphenous vein diameter. There were no changes in diastolic pressure or heart rate. These results suggest that pressor responses during tyramine injections are primarily due to an inotropic response that increases cardiac output and pressure and causes a reflex decrease in vascular resistance. Thus, tyramine pressor tests are a measure of cardiac, but not vascular, sympathetic function.     

Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Cranberry juice has a significant inhibitory effect on CYP2C9 activity in vitro , whereas it shows a minimal effect on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate in vivo .
• Information regarding the interaction between cranberry juice and other medications metabolized by CYP2C9 is limited.
WHAT THIS STUDY ADDS
• Cranberry juice suppressed the metabolism of diclofenac, another CYP2C9 substrate, by human liver microsomes.
• Pharmacokinetic parameters of diclofenac were not altered by cranberry juice consumption in human subjects.  

AIM

To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9.  

METHODS

The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics.  

RESULTS

Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects.  

CONCLUSIONS

Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro , it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations.     

Metformin improves performance in high‐intensity exercise,but not anaerobic capacity in healthy male subjects

The aim of this study was to determine the ergogenic effects of metformin in high‐intensity exercise, as well as its effects on anaerobic capacity, in healthy and physically active men. Ten subjects (mean (± standard deviation) maximal oxygen uptake (_2max) 38.6 ± 4.5 mL/kg per min) performed the following tests in a cycle ergometer: (i) an incremental test; (ii) six submaximal constant workload tests at 40%–90% (_2max); and (iii) two supramaximal tests (110% (_2max). Metformin (500 mg) or placebo was ingested 60 min before the supramaximal test. There were no significant differences between the placebo and metformin groups in terms of maximum accumulated oxygen deficit (2.8 ± 0.6 vs 3.0 ± 0.8 L, respectively; P = 0.08), lactate concentrations (7.8 ± 2.6 vs 7.5 ± 3.0 mmol/L, respectively; P = 0.75) or O₂ consumed in either the last 30 s of exercise (40.4 ± 4.4 vs 39.9 ± 4.0 mL/kg per min, respectively; P = 0.35) or the first 110 s of exercise (29.0 ± 2.5 vs 29.5 ± 3.0 mL/kg per min, respectively; P = 0.42). Time to exhaustion was significantly higher after metformin than placebo ingestion (191 ± 33 vs 167 ± 32 s, respectively; P = 0.001). The fast component of recovery was higher in the metformin than placebo group (12.71 vs 12.18 mL/kg per min, respectively; P = 0.025). Metformin improved performance and anaerobic alactic contribution during high‐intensity exercise, but had no effect on overall anaerobic capacity in healthy subjects.