Effect of isradipine on renal haemodynamics and systemic blood pressure changes induced by intravenous infusion of endothelin in healthy humans

BACKGROUND: In some vascular beds calcium-channel-blocking agents have beenshown to posses some antagonism to endothelin-1 (ET-1)-inducedvasoconstriction. This issue has not been well investigatedin humans, however. METHOD: The study had a double-blind cross-over design. In 12 healthyhuman volunteers we investigated the effect of pretreatmentwith either isradipine 10 mg daily for 1 week or placebo onchanges in (i) systemic and renal haemodynamics and (ii) renalhandling of sodium and water induced by intravenous infusionof ET-1 at a rate of 1 pmol/min/kg for 60 mm. RESULTS: Infusion of ET-1 affected systemic haemodynamics. The increasein diastolic blood pressure was similar after pretreatment withplacebo (+6.8%) or isradipine (+5.3%). The changes in renalhaemodynamics in response to ET-1 infusion were also familiar,e.g. renal plasma flow (–32.1% versus –31.2%), glomerularfiltration rate (–8.8% versus –10.9%) and renalvascular resistance (+55.1% versus +52.7%). Likewise the changesin renal handling of sodium and water in response to ET-1 infusionwere unaffected by pretreatment with placebo or isradipine,e.g. sodium excretion (–44.6% versus –40.8%), urineflow rate (–49.8% versus –38.9%) and clearance oflithium (–32.0% versus –29.1%). CONCLUSION: Intravenous infusion of ET-1 in healthy humans discretely increasesdiastolic blood pressure and profoundly decreases renal haemodynamicsand excretion of sodium and water. Pretreatment with the calcium-channelblocking agent isradipine for 1 week in a clinically relevantdose does not interfere with the action of ET-1.     

Urinary and plasma endothelin 1 in essential hypertension and in hypertension secondary to renoparenchymal disease

An alteration in renal metabolism of endothelin may contributeto hypertension in the SHR and it has been shown that the excretionrate of endothelin is reduced in patients with essential hypertension. We measured plasma and urinary endothelin 1 (ET-1) in 20 untreatedessential hypertensives with normal renal function, in eightnormotensive healthy subjects, and in 13 hypertensive patientswith primary renoparenchymal disease. Plasma ET-1 was higher (P</italic><0.01) in essentialhypertensives (median 1.69, interquartile range 1.2–3.3pg/ml) than in normal subjects (0.84, 0.37–1.10 pg/ml)but significantly less (P</italic><0.01) than in hypertensiveswith renoparenchymal disease (3.57, 1.45–9.52 pg/ml).ET-1 levels slightly correlated with diastolic pressure in essentialhypertensives (r=0.43, P<0.05) and tended to be correlatedwith systolic pressure in hypertensives with renal disease (r=0.47,P=0.08). ET-1 excretion in essential hypertensives (137, 99–154ng/24 h) and in normal subjects (120, 62–150 ng/24 h)was significantly lower than in renal hypertensives (191, 123–241ng/24 h). The ET clearance/GFR ratio (C1ET/GFR) was markedlyreduced (30%, 21–67%) in essential hypertensives and substantiallyraised in renal hypertensives (164%, 86–314%) in comparisonwith normal subjects (83%, 35–94%). Since the Cl_ET/GFR ratio should be 100% if all filtered ET-1is excreted, the data indicate that ET-1 is synthesized at areduced rate and/or broken down at an enhanced rate by the kidneyin essential hypertension and confirm that there is a high ET-1generation rate in remnant nephrons in hypertension secondaryto renal disease.     

Prevention of acute cyclosporin nephrotoxicity by verapamil and atrial natriuretic factor in the rat

Nephrotexicity is the most common and important side-effectof cyclosporin (CsA) therapy. CsA alters renal haemodynamicswith a reduction in renal blood flow (RBF) and glomerular filtrationrate (GFR) and a significant increase in renal vascular resistances(RVR). The present experimental study investigates whether verapamilor atrial natriuretic factor (ANF) are able to prevent the nephrotoxicityof CsA. All studies were conducted in an in-situ autoperfused rat kidneymodel which allows continuous measurement of renal blood flowwithout dissection of the renal artery. CsA as a 40 mg/kg bolus dose significantly decreased RBF (from2.15±0.1 and 2.19±0.1 before CsA, to 1.29±0.16ml/min/100 g BW, 60 mm after CsA administration) (P<0.05),and GFR (from 0.14±0.1 and 0.13±0.01 before CsA,to 0.08±0.01 ml/min/100 g BW, 60 min after CsA administration)(P<0.05). CsA significantly increased RVR (from 9.5±0.73and 9.8±0.78 before CsA, to 16.7±2.9 mmHgxmin/ml60 min after CsA administration) (P<0.05). Verapamil pretreatment(as continuous intrarenal infusion at the rate of 1.25 µg/kg/min)attenuated the fall in GFR (from 0.16±0.01 and 0.19±0.03ml/min/100 g before CsA to 0.20±0.05 ml/min/100 g BW,60 mm after CsA administration) (NS) and in RBF (from 2.42±0.2and 2.6±0.22 ml/min/100 g before CsA to 1.79±0.17ml/min/100 g BW, 60 min after CsA administration (P<0.05).Pretreatment with ANF (as continuous intrarenal infusion atthe rate of 2.5 µg/kg/min) protected GFR (from 0.11±0.02and 0.18±0.03 ml/min/100 g before CsA, to 0.11±0.03ml/min/100 g BW, 60 min after CsA administration) (NS) and RVR(from 9.53±0.6 and 8.95±0.74 mmHgxmin/ml beforeCsA to 11.93±1.19 minHgxmin/ml, 60 min after CsA administration)(NS)and attenuated the fall in RBF (from 2.17±0.11 and 2.2±0.14ml/min/100g before CsA to 1.56±0.25 ml/min/100 g BW 60mm after CsA administiation)(P<0.05) when compared with initialvalues. These studies suggest that verapamil and ANF can prevent CsA-inducedrenal toxicity. Further studies should evaluate their usefulnessin clinical practice.     

Effects of Cyclosporin on Renal Microcirculation

To evaluate renal microcirculation during acute cyclosporin(CsA) administration (50 mg/kg, i.v.), seven euvolaemic Munich–Wistarrats were studied. CsA infusion caused a significant decreasein total glomerular filtration rate (GFR) (0.96±0.04vs 0.47±0.07 ml/min) and in single-nephron GFR (SNGFR)(27.90±3.4 vs 14.02±3.5 nl/min). The efferentarteriolar resistance increased substantially (P<0.05) whilethe afferent resistance rose moderately. Consequently, therewas an increase (P<0.05) in mean glomerular capillary hydraulicpressure (_GC), from 45±1to 55±4 mmHg, together with an important decrease inmean glomerular plasma flow rate (Q_A), from 100±17 to44±13 nl/min. Since tubular hydraulic pressure was maintainedunaltered, an elevated transglomerular hydraulic pressure differencewas observed (P<0.05). The lower values of SNGFR were accountedfor by both the decrease in Q_A and in the glomerular ultrafiltrationcoefficient (K_f). The latter was reduced from 0.096±0.03to 0.031±0.010 nl/sec per mmHg(P<0.05) by CsA Additionally, three groups of Munich–Wistar rats werepreviously treated with captopril (2 mg/kg per h, i.v.), verapamil(20 µg/kg per min, i.v.) or indomethacin (2 mg/kg, i.v.).Both captopril and verapamil minimised the renal effects ofCsA, with a decline of 25% instead of 50%on GFR and RPF. Thus CsA infusion caused a decline on SNGFR due to an importantreduction in Q_A and K_f with an impressive increase on arteriolarresistance, a mark of angiotensin II stimulation. However, indomethacinwas unable to prevent glomerular haemodynamic changes, suggestingthat prostaglandins have a minor effect, if any, in impairingglomerular haemodynamics during acute CsA treatment.     

Stimulatory effect of insulin on tubular sodium reabsorption in normotensive subjects with a positive family history of hypertension

BACKGROUND: Insulin resistance and hyperinsulinaemia has been suggestedas a pathogenetic mechanism in hypertension. METHODS: In this investigation the renal response to insulin was studiedin normotensive subjects with a positive family history of hypertensionin two generations (n = 14), in one weight-matched (n = 11)and one lean (n = 13) control group. During hyperinsulinaemia(euglycaemic hyperinsulinaemic clamp technique) we determinedrenal haemodynamics (clearances of ⁵¹Cr-EDTA and PAH) and urinarysodium excretion. Lithium clearance was used to estimate thesegmental tubular reabsorption of sodium. RESULTS: In subjects with a positive family history of hypertension,hyperinsulinaemia did not influence renal plasma flow (RPF)or glomerular filtration rate (GFR) but urinary sodium excretiondecreased by 50%. Estimated proximal tubular sodium reabsorptionwas unaffected by insulin while estimated distal fractionalsodium reabsorption increased, P<0.01. At the end of theclamp a low-dose infusion of angiotensin II (0.1 ng/kg per min)was superimposed. GFR and RPF then decreased significantly concomitantwith urinary excretion of sodium. In control subjects hyperinsulinaemia caused an unchanged GFRin both groups, increased RPF in the lean control group and15–25% reduction in sodium excretion. No alteration wasseen in estimated proximal tubular sodium reabsorption, butestimated distal tubular sodium reabsorption increased (P<0.05)in the lean control group. Angiotensin II elicited a furtherincrease in distal fractional tubular sodium reabsorption inboth control groups (P<0.05). CONCLUSIONS: In normotensive subjects with a positive family history of hypertension,in contrast to control subjects without such history, hyperinsulinaemiacaused a marked decrease in urinary sodium excretion in presenceof unchanged RPF and GFR indicating a renal tubular effect ofinsulin located at a distal site of the renal tubules. AngiotensinII caused further sodium retention, probably due to an effecton renal haemodynamics.     

Effects of AM281, a cannabinoid antagonist, on systemic haemodynamics, internal carotid artery blood flow and mortality in septic shock in rats

Introduction. The purpose of this study was to examine the effectsof AM281, a cannabinoid receptor antagonist, on systemic haemodynamics,internal carotid artery blood flow and mortality during septicshock in rats. Methods. The study included three sets of experiments: measurementsof changes in systemic haemodynamics and left internal carotidartery flow (30 animals divided into three groups of 10); measurementsof biochemical variables (n=30); assessment of mortality (n=30).Male Wistar rats (7 weeks old) were randomly divided into threegroups: group 1, control; group 2, lipopolysaccharide (LPS)i.v., Escherichia coli endotoxin 10.0 mg kg^–1 i.v., bolus;group 3, LPS 10.0 mg kg^–1 i.v.+AM281 1 mg kg^–1 i.v.Systemic haemodynamics, carotid artery flow changes and biochemicalvariables were assessed at pretreatment and 1, 2 and 3 h afterthe treatment was performed. Results. Administration of AM281 could prevent the haemodynamicchanges induced by sepsis. Tumour necrosis factor-     

Renal responses to nifedipine and captopril in hypertensive insulin-dependent diabetic men: a randomized cross-over study

The effects of nifedipine retard and captopril on renal haemodynamicparameters have been examined in a double blind randomised cross-overtrial in 10 insulin-dependent diabetic males with hypertension(systolic pressure>150 mmHg or diastolic pressure>90 mmHg).The acute renal haemodynamic response to nifedipine retard 20mg and captopril 25 mg was monitored at the start of therapyand again after 8 weeks treatment with nifedipine retard 20mg b.d. and captopril 25 mg b.d. Blood pressure fell from 148/97±4/2(SEM) during the run-in phase to 135/87±4/1.5 on nifedipineretard and to 131/83±5/1 on captopril. There was no differencebetween the initial renal response to the two agents; an increasein renal plasma flow and a non-significant decline in glomerularfiltration rate resulted in similar decreases in filtrationfraction. After 8 weeks therapy, neither drug had a significanteffect on urinary albumin excretion. Baseline renal functiondid not differ and no acute changes in renal haemodynamics wereseen after nifedipine. Following captopril there was no acutechange in systemic blood pressure but RPF rose from 572±41to638±42ml/min per 1.73 m² (P<0.05) and filtrationfraction fell from 0.21 to 0.16 (P<0.02). This sustainedacute response of the renal circulation to angiotensin-convertingenzyme (ACE) inhibition after chronic therapy may be relevantto the apparent renal protection afforded by ACE inhibitorsin experimental nephropathies.     

Renal effects of maintenance low-dose cyclosporin A treatment in psoriasis

The renal effects of low-dose cyclosporin A (CsA) treatmentin severe psoriasis was investigated in 10 patients treatedwith a mean CsA dose of 3.23 (range 1.94–4.10) mg/kg/dayfor 12 months. The psoriasis area and severity index was reducedby 63–76%. Ambulatory GFR (iothalamate-¹²⁵I) ERPF (hippuran-¹³¹),RVR and MAP were examined at 3-months intervals. A control renalbiopsy was performed shortly before treatment start and a secondbiopsy was taken after 12 months of therapy. GFR was slightlybut significantly reduced after 6 and 9 months; after 12 monthsthe decrease was not significant (121.0±7.6 versus 115.2±7.8ml/min/l.73M P>0.10). After 12 months serum creatinine increasedfrom 82±4 to 94±7 µmol/litre (P<0.05while an insignificant increase of ERPF was seen and FF decreasedfrom 0.29±0.01 to 0.26±0.01 (P<0.05). MAP remainedunchanged. GFR and serum creatinine correlated significantlywithin each 3-month interval. A slight de novo interstitialfibrosis was seen in the second biopsy in 4 of 10 patients receivinga mean CsA dose of 3.2–4.1 mg/kg/day. In three of thesepatients a concomitant rise in serum creatinine was seen. In conclusion, low-dose CsA was associated with reversible fallin GFR and potentially progressive structural changes not alwaysaccompanied by corresponding functional alterations. One shouldconsider reducing the daily dose of CsA to 3.0 mg/kg body- weightor less in CsA therapy up to 1 year.     

Borderline hypertensive autosomal dominant polycystic kidney disease patients have enhanced production of renal dopamine. Normalization of renal haemodynamics by DOPA infusion

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD) thepathophysiology of hypertension, which is frequently observedbefore loss of renal function, is not well understood. We investigatedintrarenal dopamine, the renin-angiotensi n-aldosterone system(RAAS), and plasma endothelin in relation to sodium homeostasisas potential hypertensive factors in this disease. METHOD: Eight borderline hypertensive ADPKD patients with (near) normalrenal function and seven matched healthy control subjects wereinvestigated at three levels of daily dietary sodium intake:150, 50 and 450 mmol. In the 450-mmol sodium intake period westudied the effects of renally formed dopamine by infusing itsprecursor DOPA (DOPA_i.v., 7 µg kg^–1 min^–1).In the 50-mmol sodium intake period we studied the influenceof the RAAS by administering enalaprilate (42 µg kg^–1followed by angiotensin II (12 ng kg^–1 min^–1) intravenously.GFR and ERPF were measured by continuous infusion of inulinand PAH. RESULTS: At all levels of sodium intake sodium balances were equal, butdaily urinary excretions of dopa mine and DOPA were higher (P<0.01)in the ADPKD patients than in the controls. Renal vascular resistance,filtration fraction and blood pressure were higher in the ADPKDpatients (all P<0.05) while plasma renin activity was similar.DOPA^i.v. normalized renal haemodynamics and increased plasmaendothelin in ADPKD patients (all P<0.05), while stimulationof natriuresis was equal in both groups. Enalaprilate increasedplasma endothelin in the ADPKD patients and only partially normalizedrenal haemodynamics. CONCLUSION: In borderline hypertensive ADPKD patients: (1) urinary dopamineexcretion is increased at all levels of sodium intake, suggestingthat this may be needed to maintain sodium balance; (2) stimulationof renal dopamine production is able to normalize renal haemodynamics,making dopamine receptor agonism a potential therapeutic option;(3) the activity of the RAAS is not clearly enhanced; (4) renalvasodilatation increases plasma endothelin levels.     

Enhanced plasma endothelin in healthy uninephrectomized subjects during basal conditions and after indomethacin

Plasma levels of immunoreactive endothelin (ir-ET) at basalresting conditions and the effects of indomethacin (150 mg orally)on the plasma level of ir-ET and renal haemodynamics were evaluatedin 14 healthy uninephrectomized subjects (Unx) and in 14 sex-and age-matched healthy controls subjects (Cs). Glomerular filtrationrate (GFR) and renal plasma flow (RPF) were measured by theconstant infusion clearance technique using ¹²⁵iothalamate and¹³¹I-hippuran as references substances. Immunoreactive endothelinwas measured by radioimmunoassay after prior extraction. At basal resting conditions the plasma level of ir-ET was significantlyhigher in the Unx group. (Unx: 1.28 pmol/l versus Cs: 0.99 pmol/l,P=0.02, medians). After indomethacin the plasma level of ir-ETincreased significantly in both groups and the ir-ET level remainedsignificantly higher in the Unx group compared with the Cs group.Both GFR and RPF decreased significantly after indomethacin(after 120 min: Unx: GFR, –10.9%; RPF, –6.7%; andCs: GFR, –12.5%; RPF, –7.8%, medians). A negativecorrelation in the percentage decrease in GFR (= –0.58,P=0.03) and RPF =–0.61, P=0.03) and the percentage increasein ir-ET 2 h after indomethacin was only found in the Cs group. It is concluded that healthy uninephrectomized subjects havea higher level of ir-ET than healthy controls subjects bothduring basal conditions and after indomethacin. Indomethaciningestion resulted in comparable decreases in renal haemodynamicsin the two groups. It is suggested that the enhanced ir-ET inuninephrectomized subjects could be due to an abnormal renalmetabolism of endothelin in the remnant kidney.     

Correlation between glomerular morphology and renal haemodynamic response to amino-acid administration in patients with IgA nephropathy

RATIONALE.: To establish relationship, if any, between renal morphologyand renal haemodynamic response to amino acids. DESIGN AND METHODS.: We investigated the correlation between renal haemodynamic regulationand morphology in a group of 15 patients with primary IgA nephropathy(IgAN) (age 26±2 years, BMI 24.4±1, GFR 64±5ml/min, RPF 377±34 mI/mm, FF 0.17±0.02). Twelvenormal subjects (age 30±3 years, BMI 24±1, GFR82±6 ml/min, RPF421±42 ml/min, FF 0.19±0.02)were studied as controls. IgA patients were divided into twogroups according to the histological staging of glomerular lesions:group I (n=7) stage II, and group II (n=8) stage III–IV. RESULTS.: In the basal state GFR was similar in the two groups and averaged64±9 and 64±6 ml/mm respectively. In contrast,FF was significantly lower in group II(0.14±0.01) (P<0.05)in comparison to group I (0.21±0.03) and controls (0.19±0.02).In order to evaluate the renal functional reserve, all studygroups underwent to an intravenous amino-acid infusion designedto increase plasma amino acid levels twofold (total from 2096±145to 4301±221 µmol/l in IgA nephropathy patientsand from 2272±83 to 3844±238 µmol/l in controls).In response to amino-acid infusion, GFR rose significantly ingroup I (GFR 20±2% and RPF 37±4% versus basal)and controls (GFR 20±2% and RPF 20±3% versus basal)(both P<0.01 vs basal). In contrast, in patients with moresevere glomerular lesions (group II) neither GFR nor RPF rosesignificantly (GFR –1±4% and RPF –8±6%versus basal) (P NS versus basal, P<0.01 versus group I andcontrols). CONCLUSIONS.: The data show that in IgA nephropathy: severe forms of glomerularlesions are associated with a complex alteration of glomerularhaemodynamic regulation, characterized by lower basal FF andloss of haemodynamic response to hyperaminoacidaemia.     

Effects of endothelin-1 and endothelin-1-receptor blockade on renal function in humans.

BACKGROUND: In patients with renal or cardiac failure, renal function may be endangered by elevated plasma concentrations of the vasoconstrictor endothelin-1 (ET-1). To mimic effects of pathologically increased plasma ET-1, we gave intravenous ET-1 in healthy subjects and examined whether simultaneous infusion of the ETA-receptor antagonist VML 588 would prevent the effects of ET-1 on the kidney. METHODS: Nine healthy men received on four separate days intravenous infusion of ET-1 (2.5 ng/kg/min) superimposed on vehicle (saline) or on VML 588 infusion (0.05, 0.20 and 0.40 mg/kg/h) in randomized order to assess the effects on renal function and renal haemodynamics. RESULTS: At resting plasma ET-1, infusion of VML 588 alone had no significant effects on renal function. Infusion of ET-1 alone decreased glomerular filtration rate by 11% and this reduction was not reversed by co-infusion of VML 588. ET-1 reduced renal blood flow by 35% and VML 588 reduced this decrease by one-third, in a dose-independent fashion. ET-1 increased the filtration fraction by 34% and VML 588 reduced this increase dose-independently by one-half. ET-1 increased renal vascular resistance by 59% and VML 588 reduced this increase dose-independently by one-half. Finally, ET-1 decreased sodium excretion by 58% and VML 588 reduced this decrease dose-independently by two-thirds. CONCLUSIONS: ET-1-induced reductions in renal function were partially but not completely prevented in a dose-independent manner by the ETA-receptor antagonist VML 588.     

Single-dose Pharmacokinetics of Recombinant Human Erythropoietin in Patients with Various Degrees of Renal Failure

The pharmacokinetic profile of recombinant human erythropoietin(rHuEpo) was studied after a single intravenous dose of 150U/kg in ten patients with various degrees of renal function:group I, creatinine clearance >80 ml/min, n=2; group II,creatinine clearance 10–50 ml/min, n=6; group III, creatinineclearance <3 ml/min (patients undergoing haemodialysis) n=2.Erythropoietin concentrations in serum and urine samples obtainedover 48 h were measured by RIA. rHuEpo was cleared from circulationin an exponential fashion, the half-life ranged from 6.5 to12.7 h (mean 9.03 h) and was not different between the groups.The apparent volume of distribution varied from 0.041 to 0.0991/kg(mean 0.0701/kg) this corresponds to 1.5 times the plasma volumeand was unrelated to kidney function. Renal clearance (groupsI, II) accounted for less than 3% of total body clearance, bothparameters were unaffected by decreasing renal function. These results indicate that, in accordance with animal data,the elimination of rHuEpo occurs mainly through non-renal mechanisms.     

Impaired renal blood flow autoregulation in two-kidney, one-clip hypertensive rats is caused by enhanced activity of nitric oxide

Increases in renal perfusion pressure will induce shear stress-mediated nitric oxide (NO) release, which could oppose autoregulation of renal blood flow (RBF). Although cardiac, cerebral, and mesenteric autoregulation is enhanced during nitric oxide (NO) synthesis inhibition, this has not been reported for renal autoregulation of blood flow. In the present study, the lower limit and efficiency of RBF autoregulation (as assessed by the degree of compensation) were studied before and during NO inhibition in normotensive Sprague Dawley rats (control; n = 9) and in the non-clipped kidney of two-kidney, one-clip Goldblatt hypertensive animals (2K1C; n = 9; 3 wk; 0.25-mm silver clip). In both groups, renal autoregulation curves were obtained before and during infusion of N(G) -nitro-L-arginine (L-NNA) (bolus 1.5 mg/kg intravenously, infusion 10 microg/kg per min intravenously), using a transit-time flow probe around the left renal artery. In control rats, mean arterial pressure (MAP) increased, RBF decreased, and renal vascular resistance (RVR) increased in response to L-NNA infusion. The lower limit of autoregulation in control animals did not significantly change during L-NNA infusion (78 +/- 3 to 70 +/- 2 mmHg). The degree of compensation in these rats slightly increased during L-NNA infusion, however, this was only significant below 90 mmHg. The 2K1C rats had elevated MAP under baseline conditions. L-NNA infusion resulted in a decrease in RBF and an increase in MAP and RVR. During L-NNA infusion, RVR in 2K1C rats greatly exceeded RVR in control rats. A significant decrease was observed in the lower limit of autoregulation from 85 +/- 3 to 72 +/- 5 mmHg (P < 0.05). In the contralateral kidney of 2K1C rats, the degree of compensation was lower than in control rats under baseline conditions. L-NNA infusion resulted in significantly higher degrees of compensation compared to baseline. In conclusion, the contralateral kidney displayed a high NO dependency, as RBF greatly decreased and RVR dramatically increased in response to L-NNA infusion. The contralateral kidney of 2K1C rats exhibited impaired RBF autoregulation, which was improved by NO inhibition, as judged from a decrease in the lower limit of autoregulation and an increase in the degree of compensation. This study indicates that perfusion pressure-dependent NO release can oppose autoregulation in the kidney. However, the enhanced influence of NO on pressure-dependent RBF may facilitate the preservation of renal function in the nonclipped kidney of 2K1C rats.     

Pharmacokinetic interactions between midazolam and propofol: an infusion study

We have tested the hypothesis that the synergistic interactionwhich occurs when midazolam and propofol are combined for i.v. sedation is caused by an increase in the free plasma concentrationof one of the drugs. Six patients undergoing general anaesthesiareceived an infusion of propofol with the addition of an infusionof midazolam commenced 30 min later. Another six patients receivedan infusion of midazolam with the addition of an infusion ofpropofol 30 min later. All infusions were administered via pharmacokineticmodel-controlled syringe pumps programmed to maintain a constantplasma concentration. Venous blood samples were taken beforeand after introduction of the second infusion for later analysis.Free plasma concentration of midazolam increased from 2.0 (SD1.5) ng mt^–1 to 2.2 (1.9) ng ml^–1 after introductionof the propofol infusion (P = 0.32). Free propofol plasma concentrationwas unchanged at 18.5 (5.3) ng ml^–1 before and 18.7 (7.8)ng ml^–1 after introduction of the midazolam infusion (P= 0.94). It was concluded that the observed synergism with thiscombination cannot be explained solely by alteration in freeplasma concentration of either of these drugs when they areadministered together. (Br. J. Anaesth. 1994; 72: 62–65)     

VARIATION IN THE DISPOSITION OF MORPHINE AFTER I.M. ADMINISTRATION IN SURGICAL PATIENTS

The disposition of morphine when administered by i.m. injectionwas studied in 36 patients receiving morphine as part of premedicationbefore general anaesthesia, and in five patients who receivedmorphine as a postoperative analgesic after median sternotomyfor coronary artery surgery (PCA group). Maximum plasma concentrationof morphine (Cp_max) was 75.3 ± 6.0 (mean±standarderror (SEM)) ng ml^–1 (range 30–160 ng ml(^–1),mean elimination rate constant (k) 4.85 x 10^–3 min^–1and half-life (T₁₂) = 143 min for the preanaesthetic group.The corresponding values for PCA group were Cp_max = 58.0 ±18.0 ng ml^–1 (range 30–130 ng ml^–1), k = 5.63x 10^–3 min^–1 and T₁₂ = 123 min. Analysis of varianceshowed no differences between the groups. Within the preanaestheticgroup, there was a significant difference in k between males(k = 4.01 x 10^–3 min^–1) and females (6.30 x 10^–3min^–1, P<0.01). The corresponding T₁₂ for males was173 min; and 110 min for females. The variation in the dispositionof morphine is thought to be the result of variations in restingmuscle blood flow and inadvertent injection into adipose tissue.There were no significant differences between males and femalesin the preanaesthetic group with respect to age, CP_max timefrom injection to Cp_max.     

Renal function on and off lithium in patients treated with lithium for 15 years or more. A controlled, prospective lithium-withdrawal study

BACKGROUND.: Controversy remains over the magnitude and reversibility ofreduced renal function in long-term lithium patients. METHOD.: Thirteen patients with 18 years (range 15–24) on lithiumdiscontinued the treatment, and were re-examined twice after5 and 9 weeks (4–16) off lithium. They were compared toa non-lithium psychiatric control group, matched for age andsex. RESULTS.: Glomerular filtration rate (GFR) tended to improve from 69 (39–96)to 74 (39–94) ml/min/1.73 m² BSA, P=0.057, which was notsignificantly different from 78 (61–106 ml/min per 1.73m² BSA in the controls. Reduced GFR was found in only two ofthe lithium patients off lithium, and in none of the controls.Maximal urinary concentrating capacity did not improve at all.It was 637 (130–875) mOsm/kg H₂O in the lithium patients,which was lower than 856 (705–1.035) mOsm/kg H₂O (P<0.01)in the controls. Two of the lithium patients had isosthenuria. CONCLUSIONS.: Lithium patients often have an irreversible, clinically importantreduction of Umax, sometimes progressing to nephrogenic diabetesinsipidus, while GFR is well preserved in most patients.     

The effect of α-human atrial natriuretic peptide on the incidence of acute renal failure in cadaveric kidney transplantation

In previous studies in humans, mannitol (20%, 250 ml) has been shown to reduce the incidence of acute renal failure (ARF) after transplantation from 54% to 19%. In rats, atrial natriuretic peptide appears to prevent ischemia-induced ARF. We therefore decided to evaluate the effects of α-human atrial natriuretic peptide (α-h-ANP) both alone and combined with mannitol during transplantation in humans. First, we demonstrated that systemic α-h-ANP infusion during kidney transplantation was safe in dosages up to 0.08 μg/kg per minute. In these patients the calculated metabolic clearance rate of α-h-ANP was relatively low ranging from 0.68 to 1.80 l/min. In a second study of 11 renal graft recipients, no mannitol was used and α-h-ANP (0.05 μg/kg per minute) was infused into the donor kidney artery during transplantation for 46±2 min, followed by IV administration for 71±2 min. Our aim was to reduce the incidence of ARF. Nevertheless, ARF occurred immediately after surgery in four of the patients (36%) in this group and, as a result, mannitol was reintroduced. A third group of nine renal graft recipients received α-h-ANP (total dose 400 μg) as five IV injections within 90 min after transplantation. ARF occurred in four of these patients (44%). We conclude that α-h-ANP, administered according to the aforementioned protocols in such small groups of patients, does not seem to be of value in the prevention of ARF after transplantation.     

CARDIOVASCULAR AND RENAL HEMODYNAMIC EFFECTS OF DOPEXAMINE: COMPARISON WITH DOPAMINE

We have studied the effects of dopexamine and dopamine on systemicand renal haemodynamics in 20 male patients undergoing electivecoronary artery bypass surgery. Patients were allocated randomlyto two groups (n = 10) who were treated with incremental dosesof either dopexamine 1, 2 and 4 µg kg^–1 min^–1,or dopamine 2.5 and 5 µg kg^–1 min^–1, eachdose being maintained for 15 min. Measurements were performedbefore administration of the drug and at the end of the infusionperiod at each dose. Fentanyl and midazolam were used as anaestheticagents. Renal blood flow was measured with the argon washintechnique. Dopexamine 4 µg kg^–1 min^–1 producedan increase in cardiac index of 117% caused by a 65% reductionin afterload and an increase in heart rate by 61%. Dopamine5 µg kg^–1 min^–1 caused a 40% increase in cardiacindex as a result of an increase in stroke volume. Renal vascularresistance decreased more than systemic vascular resistancewith dopamine. With dopexamine, the increase in renal bloodflow (66%) was less than the increase in cardiac index, whilerenal vascular resistance and systemic vascular resistance declinedto almost the same extent. The results show that dopexamineexerts systemic and renal effects mainly via stimulation ofß₂-receptors. An action of dopexamine at renal DA₁-receptorscould not be demonstrated in this study.     

Post-conditioning by a short administration of desflurane reduced renal reperfusion injury after differing of ischaemia times in rats

Background. ‘Anaesthetic post-conditioning’, thatis administration of anaesthetics during early reperfusion,is known to have positive effects on several organs. For thekidney, however, the effects of post-conditioning by volatileanaesthetics are not well researched. We examined renal functionand morphology after post-conditioning by desflurane. Methods. Anaesthetized rats were subjected to 30 or 45 min ofrenal ischaemia 14 days after contralateral nephrectomy. Post-conditioningwas achieved by administration of 1 MAC desflurane (6.7 vol%)for 15 min during early reperfusion (all groups n=8). CystatinC (CyC), creatinine clearance (Cl_Cr) and fractional sodium excretion(FE_Na) were measured in the awake rats over 3 days. Cell damagewas graded from 1 to 4 in histological sections. Functionalvariables [mean (SD)] were compared statistically by a one-wayANOVA followed by Bonferroni's multiple comparison test andhistological scores (median and range) by Kruskal–Wallistest followed by Dunn's multiple comparison test. Results. Pre-ischaemia function did not differ between the groups,but was markedly reduced after ischaemia. After 30 min ischaemia,the area under the curve (AUC) for Cl_Cr was smaller in the desfluranethan in the control group [21.5 (5.0) vs 31.6 (5.1) ml min^–1h, P<0.05]. After 45 min desflurane reduced the AUC comparedwith the control group for both CyC [15 (4) vs 21 (3) mg litre^–1h] and FE_Na [1054 (221) vs 1570 (572)% h, both P<0.05). Morphologicaldifferences were greater between the 30 min groups [control:2.75 (2.0–3.5) vs desflurane: 1.5 (1.0–2.5); P<0.05]than between the 45 min groups [control: 3.5 (3.0–4.0)vs desflurane: 3.0 (1.5–4.0)]. Conclusion. Desflurane post-conditioning protects renal functionand tissue. This protection was greater after the short episodethan after the long episode of ischaemia.