RENAL DENERVATION POTENTIATES THE NATRIURETIC AND DIURETIC EFFECTS OF ATRIAL NATRIURETIC PEPTIDE IN ANAESTHETIZED RABBITS

1. The role of the renal nerves in modulating the action of atrial natriuretic peptide (ANP) in the kidney was studied by comparing the responses to ANP in innervated and surgically denervated kidneys in anaesthetized rabbits. 2. A low dose of ANP (0.05 μg/kg per min, i.v.) was used to minimize the confounding effects of systemic hypotension. 3. The natriuretic and diuretic responses to ANP were significantly greater in denervated kidneys than in kidneys with intact innervation. Sodium excretion from denervated kidneys rose by 7.49 ± 3.11 μmol/min in response to ANP (-55%, P<0.05) compared to 0.84 ± 0.59 μmol/min (-28%, NS) in innervated kidneys. Urine flow increased markedly in denervated kidneys by 73.2 ± 29.9 μmol/min (-60%, P<0.05) but not in innervated kidneys. 4. Fractional sodium excretion increased significantly in denervated kidneys in response to ANP (median 2.3% to median 3.0%, P<0.05). 5. Renal blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure were unchanged in response to ANP in either denervated or innervated kidneys. Pre-glomerular vascular resistance fell in denervated kidneys during ANP infusion. 6. The natriuresis and diuresis observed in the denervated kidneys, due to an increased fractional excretion of sodium without increases in GFR or glomerular capillary pressure, is consistent with effects of ANP on tubular reabsorption of sodium. 7. Thus, ANP produced a natriuresis and diuresis at a low dose in denervated but not in innervated kidneys. This indicates that reflex activation of renal nerves may antagonize the renal effects of ANP.     

Pharmacokinetics and renal excretion of sulfamethoxazole in sheep

Pharmacokinetics and urinary excretion of sulfamethoxazole were investigated in healthy sheep. From the plasma disappearance curves after intravenous bolus injection (50 mg/kg), the half-life and volume of distribution were found to be 76±14 min and 0.41±0.18 lit/kg respectively. Body clearance was 4.06±1.03 ml/kg/min. Very low Concentration of drug was present in plasma after 3 hours of administration and plasma level at 6 hour was only 4.4±2.0 μg/ml. The renal clearance of sulfamethoxazole (22±2.17 ml/min/10 kg) exceeded the creatinine clearance (9.78±1.57 ml/min/10 kg) which may be due to involvement of active tubular secretion and pH dependent back diffusion. Half of the dose of sulfamethoxazole was excreted as unchanged free drug while acetylated amine comprised of 20 percent within the first 6 hours of drug administration.     

Effect of Prenalterol,a β-1-Adrenoceptor Agonist,on Renin Secretion Rate in the Anaesthetized Dog

Abstract: The effects of the β-1-adrenoceptor agonist, prenalterol, 20 μg/kg intravenously on renin secretion rate (RSR), renal haemodynamics and sodium excretion were examined in anaesthetized dogs with innervated or denervated kidneys. In dogs with innervated kidneys, prenalterol increased RSR from 1.1±0.2 to 7.9±0.1 unitsXmin.^?1Xg^?1 (P<0.01). Prenalterol did not affect mean arterial pressure, renal blood blow, glomerular filtration rate or sodium excretion. Heart rate was increased by 53±17 beats/min. (P<0.01). The increase in RSR produced by prenalterol was independent of intact renal innervation as RSR increased to the same extent in dogs with denervated kidneys. Pretreatment with the β-1-adrenoceptor antagonist, metoprolol 0.5 mg/kg intravenously, abolished the increase in RSR produced by prenalterol. These findings suggest that prenalterol directly activates renal β-1-adrenoceptors to increase RSR.     

The availability of inorganic sulphate as a rate limiting factor in the sulphate conjugation or xenobiotics in the rat?: Sulphation and glucuronidation of phenol

Phenol is converted by the rat in vivo into the sulphate and glucuronide conjugates. When the intravenously administered dose of ¹⁴C-labelled phenol was increased from 13 to 266 μmol/kg the percentage glucuronidated increased from 28 to 60 per cent of the dose; the percentage sulphated decreased from 72 to 40 per cent. In rats with intact kidneys the conjugates were almost completely excreted in the urine: when the kidneys were ligated phenylglucuronide was excreted in bile to a high extent, but biliary excretion of phenylsulphate was still very low. Using ³⁵S-labelled sodium sulphate, incorporation of [³⁵S]-sulphate into phenylsulphate could be observed; phenol enhanced the disappearance of [³⁵S]-sulphate from plasma. No significant depletion of inorganic sulphate was found when a high dose of unlabelled phenol (266 μmol/kg) was injected. The literature data on sulphate depletion by substrates of phenolsulphotransferase are critically reviewed; from our data is concluded that the relative decrease of phenol sulphation at high phenol doses is not due to sulphate depletion.     

Effect of chronic chlorpromazine administration or prior treatment with reserpine on brain apomorphine concentrations and apomorphine-induced sterotyped behaviour in the rat

The effect of bradykinin on the renal medullary osmotic gradient was evaluated in anesthetized dogs which were undergoing water diuresis and which received a unilateral renal arterial infusion of bradykinin. The effect of the peptide on the medullary osmotic gradient was determined by analysis of medullary tissue electrolyte and urea concentrations and by analysis of changes in urine osmolality induced by vasopressin. Bradykinin decreased the total osmalality per kg H₂O in tissue from inner medulla and papilla (?18.7 ± 6% and ?19.3 ± 8%) and increased fractional water excretion (3.8±1.3%). Furthermore, a direct relationship between changes in free water clearance and changes in papillary tissue osmalality was found. Finally, the increase in urine osmolality after ADH was signifacantly less in vasodilated than in control kidneys. These results indicate that bradykinin can diminish the medullary osmotic gradient during water diuresis in the dog. Thus, a bradykinin-induced increase in free water clearance may be accounted for by other than an inhibition of proximal tabular sodium reabsorption.     

Indomethacin and diclofenac sodium increase sodium and water excretion after extracellular volume expansion in the rabbit

The renal effects of an acute extracellular fluid volume expansion (50 ml Ringer/kg body weight/60 min) were studied in aldosterone-treated (100 μg/kg), anesthetized rabbits with and without pretreatment with either indomethacin (3.0 mg/kg) or diclofenac sodium (3.0 mg/kg), two different inhibitors of renal prostaglandin (PG) biosynthesis. In controls (n = 7), the volume expansion increased urine flow from 1.5 ± 0.24 to 6.1 ± 0.5 (S.E.) ml/min/100 g kidney weight and sodium excretion from 0.15 ± 0.03 to 0.99 ± 0.10 mmol/min/100 g. PAH and insulin clearance increased by 42 and 58%, respectively, while plasma renin activity and urinary excretion of PGF_2α-like immunoreactivity were reduced (P < 0.05). In aninals pretreated with indomethacin (n = 6) or diclofenac sodium (n = 6), the diuresis and the natriuresis following volume expansion were significantly increased about two-fold over controls, whereas PAH and inulin clearance, plasma renin activity and hematocrit did not differ from controls. Both drugs were found to reduce urinary excretion of PGF_2α-like immunoreactivity by 75–95% throughout the experiment. The results indicate that diclofenac sodium, indomethacin and extracellular volume expansion enhance sodium and water excretion partly by suppression of a PG sensitive reabsorption process in the kidney.     

INTERACTION OF EXOGENOUS OUABAIN AND CHRONIC MINERALOCORTICOID TREATMENT IN THE KIDNEY OF THE CONSCIOUS SHEEP

1. Ouabain is known to have natriuretic effects only at high doses, and therefore if endogenously produced ouabain has a role in the regulation of sodium excretion, the renal response to ouabain must be increased substantially in certain physiological situations. The aim of this study is to determine whether treatment with the mineralocorticoid, aldosterone, potentiates that natriuretic response to ouabain. 2. Six conscious sheep received renal arterial infusion of either vehicle or aldosterone (3 μg/h). Forty hours after commencement of infusion ouabain was infused into the renal artery at 400 μg/h for 60min. A second infusion of ouabain was administered on the 6th day of aldosterone treatment. 3. In the absence of aldosterone, the effects on sodium excretion produced by ouabain infusion at 400 μg/h into the renal artery were variable and not statistically significant. Ouabain infusion after 40 h of aldosterone treatment increased sodium excretion from 40 ± 14 to 676 ± 69 μmol/min in the second hour following cessation of ouabain infusion (P< 0.001). Ouabain infusion after 6 days of aldosterone treatment increased sodium excretion similarly. Ouabain-stimulated sodium excretion was significantly greater during aldosterone treatment compared to vehicle treatment (P<0.05). In contrast, no enhancement of effect was observed after acute treatment with aldosterone. 4. These results demonstrate potentiation of the natriuretic response to ouabain infusion by chronic mineralocorticoid treatment and suggest a potential role of endogenous digitalislike factor in the physiological control of sodium homeo stasisaldo sterone, endogenous digitalis-like factor, ouabain, sodium excretion.     

Enterohepatic Circulation,Urinary Excretion and Laxative Action of Some Bisacodyl Derivatives after Intragastric Administration in the Rat

Abstract: Bisacodyl (BIS), the parent diphenol (DES) and its sulphuric acid di-ester (picosulphate = PICO) were given by stomach tube to fasted rats at a dose of 3.1 μmol/100 g rat. Bile was sampled in the periods 0–6, 6–12 and 12–18 hrs after drug administration, and assayed for total diphenol (= free + conjugated) by HPLC. Mean fractions (% of dose±S.E.M.) excreted in 5 rats per compound and period were: BIS 74.0±4.7, 51.9±7.9 and 30.8±2.5; DES 41.2±4.3, 46.8±4.7 and 25.1±2.5; PICO 9.0±0.9, 26.0±5.4 and 19.6±3.1. Only minor amounts were excreted as free diphenol. Urine samples taken by bladder puncture and assayed as above furthermore showed that the renal excretion of total diphenol was insignificant compared to the amounts excreted in bile. Practically no diphenol was present in urine 0–6 hrs after the administration of PICO. In experiments with BIS and DES at 0.85 μmol/100 g, total diphenol excreted in bile during 0–6 hrs was: BIS 67.1±2.6 (n = 5); DES: 55.4±3.0 (5). - The latency time for laxative effect was studied in groups of 10 unfasted rats per compound. Cumulative time response curves showed that PICO caused diarrhoea more promptly at 0.85 μmol/100 g than either BIS or DES. In most rats, this delayed action of BIS and DES persisted also at 1.7 μmol/100 g. At 3.1 μmol/100 g, however, the majority of the rats reacted as promptly to these two compounds as to PICO. These results are discussed in relation to the biliary excretion experiments, and interpreted in terms of the relative importance at the different dose levels of: 1. The enterohepatic recirculated fraction, and 2. The non-absorbed fraction, which passes directly to the large intestine. For PICO, the latter fraction is the single determinant of the effect, which is triggered when the di-ester is being hydrolyzed to active diphenol in this part of the GI-tract.     

MECHANISMS UNDERLYING THE DECREASE IN CIRCULATING ANGIOTENSIN II CONCENTRATION AFTER SODIUM LOADING

1. Acute sodium loading causes a rapid decrease in the circulating concentration of angiotensin II (AngII), which is apparent from 5 min after sodium administration. This could result from an increase in AngII catabolism and/or a decrease in AngII synthesis/secretion. However, the major determinant of AngII synthesis is thought to be a change in plasma renin activity, which occurs over a longer time frame (15 min). 2. To investigate the mechanisms underlying the rapid decrease in plasma AngII engendered by sodium administration, we performed metabolic clearance studies in male New Zealand white rabbits before and after a hypertonic sodium load of 1.5 mmol/kg as 0.513 mol/L saline i.v. bolus. 3. The metabolic clearance rate of AngII increased significantly from 42.2 ± 9.0 mL/min per kg before sodium to 110.8±33.7 mL/min per kg after sodium administration (P<0.05). The calculated or theoretical secretion rate decreased from 1470.7±404.2 to 573.5 ± 139.5 fmol/min per kg (P<0.025) in response to sodium. 4. We conclude that an increase in AngII metabolism and a decrease in synthesis/secretion contribute to the reduction in circulating AngII, which occurs in the first 60–90 min after sodium loading.     

Effect Of Age On Renal Functional And Orthostatic Vascular Response In Healthy Men

1. Few studies have been reported concerning the effect of ageing on renal functional and vascular responses to various stresses during ordinary life. In the present study, we examined the effect of age on changes in renal sodium handling and renal vascular resistance (RVR) in response to standing from a supine position in subjects with normal renal function. 2. We selected 43 healthy males in the second through to the seventh decade of life and gave them a constant dietary sodium intake before the study period. Renal function was estimated by standard clearance methods with the subject in a state of euvolaemia. 3. The mean daily urinary excretion of sodium was 236 ± 22 mEq. Standing from a supine position was associated with significant decreases (P < 0.0001) in creatinine clearance (from 125 ± 18 to 117 ± 19 mL/min per 1.73 m ² ), sodium excretion (from 178 ± 29 to 97 ± 23 μ Eq/min) and fractional excretion of sodium (from 1.02 ± 0.19 to 0.60 ± 0.13%). A significant increase (P < 0.0001) in the RVR index (from 0.11 ± 0.03 to 0.14 ± 0.04 units) was noted. Univariate analysis indicated that while the change in RVR associated with standing was significantly diminished (P < 0.05) in older subjects, orthostatic changes in other parameters associated with standing were minimally influenced by age. 4. In conclusion, although the renal vascular response is impaired in advanced age, the renal functional response to orthostasis is otherwise maintained in healthy elderly subjects under conditions of normal sodium intake and clinical euvolaemia.     

Renal,Biliary and Intestinal Clearance of a Quaternary Ammonium Compound,Emepronium in the Dog

Abstract Different routes of elimination of emepronium have been quantitated in conscious and anaesthetized dogs. Smoothed plasma concentration time curves and urinary excretion data obtained following intravenous bolus injection of 5 mg/kg indicate at least four different phases with the following half-lives: 5 min., I hour, 10 hours and 9 days. The initial dilution space, 0.2-0.6 l/kg, is rather similar to the extracellular volume (0.20-0.35 l/kg). From infusion experiments plasma clearance of emepronium have been found to be 33±2 ml. min^-1.kg^-1 (meani ± S.E.M., n = 14). The drug is secreted by the renal tubules at a maximum rate of 20 μg/min. at a plasma concentration of about 200 μg/l. Compared with other quaternary ammonium compounds, this is an easily saturated mechanism with a low capacity. The renal clearance constitutes about 30 % of the plasma clearance at a plasma concentration of 200 μg/l. The biliary excretion rate increases proportionally to a plasma concentration up to 100 μg/l and then reaches a maximal rate which is dependent on the bile flow. The biliary clearance decreases from 7 to 2 ml.min.^-1.kg^-1 when the bile flow changes from 7 to 4 g/ hour and the plasma concentration is 200 μg/l. Experiments with bile diversion and saline perfusion of isolated intestinal segments reveal an intestinal route of elimination of both emepronium and metabolites. The bile diversion experiments indicate that about 5-15% of an intravenous dose is excreted through the gastrointestinal epithelium. Perfusion of isolated intestinal loops indicates an apparent clearance of 4-5 ml. min^-1.m^-1 over a wide range of steady state plasma concentrations (20-1200 μ/l). An apparent total intestinal clearance could be calculated to about 7 ml. min.^-1.kg^-1. The remaining part of the plasma clearance (about 8 ml. min.^-1. kg^-1 in an anaesthetized dog) is accounted for by metabolism. The degree of protein binding has been shown to be low, about 20 per cent, and the red blood cell penetration in vitro is only 1-10% of the total amount present in whole blood.     

Renal response of ethanol-treated dogs to increased filtered loads of sodium, bicarbonate, and chloride

Twenty, male, mongrel dogs were given either 3 g/kg (33% $\text{v}\text{v}$ solution) of ethanol or an isovolumetric quantity of water by oral intubation. Sixteen hours later the animals were anesthetized and after a control renal clearance, infused with either a hypertonic sodium chloride or sodium bicarbonate solution for an additional three clearance periods. The rate of infusion of solutions was increased progressively prior to each of the next periods. At each new rate, 45 min was permitted for equilibration before the clearance period. The hypertonic NaCl infusion produced similar increases in GFR, the filtered loads of Na and Cl, and the excretory rates of Na and Cl in both the water and ethanol groups. Although the hypertonic NaHCO₃ infusion produced equal increases in GFR and filtered loads of Na and HCO₃, there were dissimilar increases in Na and HCO₃ excretions. Sodium excretion increased by 17.1 ± 1.1 μeq/min/kg and percentage reabsorption decreased by 3.5 ± 0.3% in the water group while in the ethanol group, U_Na · V increased by 10.0 ± 1.4 μeq/min/kg (p < 0.01) and %R_Na decreased by 1.9 ± 0.2% (p < 0.01). In the ethanol group, bicarbonate excretion increased by 8.1 ± 1.3 μeq/min/kg and in the water group by 12.3 ± 1.1 μeq/min/kg (p < 0.05). The reduction in %R_HCO3 was significantly less in the ethanol group in comparison to the water group (8.1 ± 1.0 vs 12.1 ± 0.8%). Known effectors of sodium bicarbonate reabsorption, i.e., volume status, pCO₂, potassium stores, and filtration rate were not different between groups. It is concluded that ethanol pretreatment ameliorated the depressant effect of the NaHCO₃ infusion on tubular reabsorption.     

METABOLIC STUDIES OF URIDINE IN RATS WITH DOCA-SALT HYPERTENSION AND ON HIGH SODIUM DIET

1. The steady-state metabolic clearance and calculated secretion rate of the pyrimidine nucleoside uridine were studied by equilibrium infusion in normal rats, rats on a high sodium diet, rats made hypertensive by subcutaneous injection of deoxycorticosterone acetate (DOCA), unilateral nephrectomy and high sodium drinking fluid, and two control groups of rats for the hypertensive group. 2. Basal plasma uridine concentration in DOCA-salt hypertension rats was found to be significantly reduced to 3.99 ± 0.31 pmol/L (mean ± s.e.m.) compared with control rats (11.98 ±1.64 μmol/L). Metabolic clearance (MCR) in DOCA-salt hypertensive rats was significantly raised (200.54±10.77 mL/kg per min) compared with control rats (65.17 ± 1.99 mL/kg per min). No difference was found in plasma uridine concentration and MCR among the other two control groups and high sodium diet rats. Calculated secretion rate was unchanged in all animals. No significant differences were found between different groups of rats in blood pressure responses to uridine. 3. The raised metabolic clearance and reduced plasma uridine concentration in DOCA-salt hypertension may be consistent with increased intracellular transport and phosphorylation of uridine to the physiologically active compound uridine monophosphate (UMP) which would lead to arteriolar constriction, hypertension and natriuresis. The results contrast with those in humans with extracellular fluid (ECF) expansion from endstage renal failure and rats with one-kidney, one-clip (1K1C) hypertension but are not due to the pharmacological effects of deoxycorticosterone. The difference may be due to the haemodynamic consequences of reduced renal perfusion pressure or reduced renal mass compared with DOCA-salt model.     

SODIUM LOADS ENHANCE THE NATRIURETIC RESPONSES TO ATRIAL NATRIURETIC PEPTIDE AND NEUTRAL ENDOPEPTIDASE INHIBITORS IN CONSCIOUS CYNOMOLGUS MONKEYS

1. The effects of sodium supplements on the renal responses to human atrial natriuretic peptide (hANP 99–126) and to the selective inhibitors of neutral endopeptidase 3.4.24.11 (NEP) SQ 28 603 and candoxatrilat were determined in conscious monkeys. 2. When the monkeys’ diet was changed from 0.55% sodium to 1.1% sodium, the natriuretic response to 100 μmol/kg intravenous of SQ 28603 increased from 665 ± 64 to 1015 ± 224 μEq/3h. An acute oral load of 25 mEq sodium significantly increased the natriuresis stimulated by 300 pmol/kg, P.o., of SQ 28603 from 700 ± 332 μEq/3h in normal monkeys to 2437 ± 841 μEq/3h. Therefore, the non-human primate model was appropriate for investigating the effects of sodium loads on the urinary ANP and cGMP responses to exogenous ANP in the presence and absence of NEP inhibitors. 3. Graded intravenous infusions of saline increased basal urine volume and excretion of sodium and ANP. Salt supplements enhanced the diuretic, natriuretic and ANP responses to 0.3 nmol/kg intravenous of hANP 99–126 in monkeys treated with vehicle or 10 μmol/kg intravenous of candoxatrilat. The sodium and ANP excretions stimulated by hANP 99–126 were positively correlated with each other and with the calculated intravenous sodium load in the presence or absence of candoxatrilat. 4. SQ 28 603 and candoxatrilat (0.3 to 10 μmol/kg intravenous) each produced significant, dose-related potentiation of the natriuretic, cGMP and ANP responses to 0.3 nmol/kg intravenous of hANP 99–126 in monkeys receiving 5 mL/kg + 0.2 mL/min saline. In addition, the highest dose of SQ 28 603 produced significant depressor activity. 5. In conclusion, the increased natriuretic activity of hANP 99–126 in sodium loaded monkeys was mediated, in part, by increased ANP delivery to the guanylate cyclase linked ANP receptors in the distal renal tubules.     

Pharmacokinetics and Biliary Excretion of Mitoxantrone in Rats

The objective of this investigation was to compare the observed biliary clearance (CL_b) and % of dose excreted in the bile (PD_b) of mitoxantrone with the predicted values obtained from quantitative structure pharmacokinetic relationship (QSPKR) models. Blood and bile samples were collected from bile duct cannulated rats after an intravenous bolus dose of 0.5 or 2 mg/kg mitoxantrone, and the concentrations were measured by HPLC. Mitoxantrone plasma concentrations exhibited a tri‐exponential profile with systemic clearance of 118 ± 6.8 mL/min/kg. After dosing, 6.08 ± 2.32% and 5.69 ± 0.59% of the dose were excreted into bile in unchanged form after a 3‐h collection. CL_b was 7.20 ± 4.54 and 7.46 ± 0.62 mL/min/kg after the two doses. With the co‐administration of 10 mg/kg GF‐120918, a P‐glycoprotein and BCRP inhibitor, PD_b was reduced to 0.69 ± 0.07%, suggesting that BCRP or P‐glycoprotein may play an important role in the biliary elimination of mitoxantrone. Using QSPKR models developed for the biliary excretion of cations/neutral compounds in rats, CL_b and PD_b of mitoxantrone were predicted as 5.18 mL/min/kg and 7.21%, respectively, suggesting that the models could be used to predict the biliary excretion of mitoxantrone. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2502–2510, 2010     

Disposition kinetics of cyclohexanone in beagle dogs

The disposition kinetics of cyclohexanone, a commonly used industrial solvent, was studied in beagle dogs following intravenous administration of a 284 mg/kg dose at various rates for 18 or 21 days. The major metabolite of cyclohexanone was identified as cyclohexanol. Plasma and urine concentrations of the compound and the metabolite were determined using a newly developed gas chromatographic procedure. A two-compartment open model was used to analyze plasma concentration-time data of cyclohexanone. The distribution half-life, biological half-life, and clearance values for cyclohexanone were 6.6 ± 3.6 min, 81.0 ± 22.5 min, and 27.4 ± 4.3 ml/kg/min, respectively. Between 74 and 100% of the administered dose of cyclohexanone was converted to cyclohexanol and approximately 60% of the dose was excreted in the urine as the glucuronide conjugate of cyclohexanol. Peak cyclohexanol concentrations in plasma following intravenous bolus administrations of 284 mg/kg of cyclohexanone ranged from 140 to 220 μg/ml and occurred between 5 and 30 min after cyclohexanone administration. Apparent plasma elimination half-life of the metabolite was 99 min. Urinary excretion data suggested that less than 1% of the dose was excreted as cyclohexanol and cyclohexanone. Under the dosage schedule employed in the present study, there was neither any accumulation of cyclohexanone nor any evidence of enzyme induction on repeated administrations. The data gathered in the present investigation are useftul in calculations of cyclohexanone peak or steady-state levels during comparative toxicological studies involving different dosage regimens.     

Elimination kinetics and urinary excretion of disopyramide in human healthy volunteers

Elimination kinetics and the renal handling of disopyramide was examined in 8 healthy volunteers. Approximately 50% of the administered disopyramide undergoes hepatic metabolism (metabolic clearance = 116.1 +/- 42.2 ml/min.), while the rest is excreted by the kidneys (renal clearance = 101.9 +/- 21.6 ml/min.). Total renal excretion rate of disopyramide was 0.676 +/- 0.188 mumol/min. and 0.258 +/- 0.029 mumol/min. was excreted by glomerular filtration leaving a net tubular secretion of 60% of the total renal elimination. A significant positive correlation was observed between total serum concentrations and renal clearance values of disopyramide while no significant correlation could be obtained between serum concentrations of the unbound drug and renal clearance values of disopyramide, implying a constant value of unbound renal clearance. Hepatic blood flow was significantly (P less than 0.005) decreased following disopyramide infusion.     

Pharmacokinetics of dihydroquinidine in congestive heart failure patients after intravenous quinidine administration

Summary The pharmacokinetics of dihydroquinidine were studied in 8 patients with congestive heart failure following a 22 min intravenous infusion of a quinidine preparation that contained 5.9% dihydroquinidine as an impurity. Using a thin layer chromatography-fluorometric assay procedure for dihydroquinidine, the post-infusion plasma dihydroquinidine concentrations declined biexponentially. The half-life of the fast and slow dispositional processes was 4.42±1.81 min and 6.52±2.40 h, respectively. The central compartment volume for dihydroquinidine in these patients was 0.44±0.11 l/kg with an overall apparent volume of distribution of 1.14±0.38 l/kg. The computed values of total body plasma clearance of dihydroquinidine ranged from 1.29 to 2.69 ml/min/kg with a mean value of 1.94±0.60 ml/min/kg. In these patients, approximately 16% of the administered dihydroquinidine dose was excreted intact into the urine in 48 h. The estimated value of renal clearance was 0.314±0.129 ml/min/kg. When compared to control cardiac patients, the data showed that the apparent volume of distribution for dihydroquinidine is smaller in patients with congestive heart failure and as a result of this diminished volume, the clearance rate of dihydroquinidine was slower. The net effect of these differences was the production of higher plasma concentrations of dihydroquinidine in the heart failure group.     

Comparison of biliary excretion of organic anions in mice and rats

Biliary excretion of cholephilic organic acids in anesthetized, male Swiss-Webster mice was compared to that in male Sprague-Dawley rats. The mouse excreted six of the eight compounds examined at a faster or equal rate than the rat. Indocyanine green, rose bengal, phenol-3,6-dibromsulphthalein disulfonate, and eosine were excreted in mice at a rate 120 to 460% higher than in rats. The excretion rates of bromcresol green and sulfobromophthalein glutathione conjugate were similar in the two species, whereas amaranth was excreted at a slightly lower rate in mice than in rats. Biliary excretion of sulfobromophthalein (BSP), especially its glutathione conjugate, was significantly lower in the mouse which corresponded to a difference in BSP-glutathione transferase activities between the two species (mouse, 0.97; rat, 1.35 μmol/min/g liver). The depression of bile production by cholestatic organic anions was stronger, and the stimulation of bile flow by choleretic acids was weaker in mice than in rats. Differences in biliary bile acid excretion (mouse, 3.62; rat, 1.42 μmol/kg/min), bile flow (mouse, 102; rat, 69 μl/kg/min), and liver weight (mouse, 57; rat, 38 g/kg) but not hepatic ligandin concentration (mouse, 132; rat, 214 nmol BSP/g liver) may explain the variations in the biliary organic anion excretion between mice and rats.     

INTERSTITIAL ADENOSINE AND FUNCTION IN RAT HEART IN VIVO: EFFECTS OF ADRENALINE AND 8-CYCLOPENTYL-1,3-DIMETHYLXANTHINE

1. Left ventricular interstitial adenosine and cardiac function were studied in open chest rats during adrenaline stimulation and P₁-purinoceptor antagonism with 8-cyclopentyl-1,3-dimethylxanthine (8-CPT). 2. Cardiac microdialysate adenosine concentration was 0.10±0.01 μmol/L (n= 24) under basal conditions, giving an estimated interstitial adenosine concentration of 0.27 μmol/L. Stimulation with 3.2 and 8.0 μg/kg per min adrenaline increased the rate-pressure product (heart rate X systolic blood pressure) by 72 and 157%, respectively, and increased dialysate adenosine to 0.26±0.04 and 0.65±0.11 μmol/L (n= 12), respectively (interstitial concentrations of approximately 0.70 and 1.76 μmol/L). 3. Treatment with 60 μg/kg per min 8-CPT did not alter basal adenosine concentrations, but potentiated elevations in dialysate adenosine during infusion of 3.2 and 8.0 μg/kg per min adrenaline to 0.54±0.10 and 1.30±0.22 μmol/L, respectively (n= 12). Basal function and the response to 8.0 μg/kg per min adrenaline were unaltered by 8-CPT, whereas elevations in heart rate and rate-pressure product during stimulation with 3.2 μg/kg per min adrenaline were enhanced by 8-CPT (by up to 30%). 4. Studies in isolated hearts confirmed the inhibitory potency of 8-CPT at A₁vs A₂ P₁-purinoceptors (e.g. pK_B of 7.7±0.2 and 6.4±0.1 for 5′-N-ethyl carboxamidoadenosine-mediated bradycardia and vasodilatation, respectively; n= 6). Studies in intact animals verified effective A₁ blockade by 60 μg/kg per min 8-CPT, but also revealed some inhibition of A₂-mediated responses. 5. In conclusion, the data show that cardiac interstitial adenosine levels exist within a physiologically active range in vivo and increase dose-dependently during graded adrenaline stimulation. Adenosine receptor antagonism enhances elevations in interstitial adenosine and modifies functional responses to moderate, but not high, doses of adrenaline. Whether 8-CPT-dependent elevations in interstitial adenosine are due to A₁ inhibition vs inhibition of A₂-mediated vasodilatation requires further investigation.