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F Brunner

Publications and source records attributed to F Brunner.

At least 19 recordsLinked to original sources
PubMed1992

Endothelin release during ischaemia and reperfusion of isolated perfused rat hearts.

The hypothesis tested was that release of endogenous endothelin plays a role in events associated with or leading to myocardial ischaemia and/or post-ischaemic reperfusion damage. Release of endogenous endothelin into the coronary perfusate of isolated perfused rat hearts during ischaemia and reperfusion was measured with a sensitive radioimmunoassay using a polyclonal antibody with 100% cross-reactivity for all three endothelin isomers. Basal endothelin release was 0.69 +/- 0.02 pg/min/g wet heart weight (n = 35) and was constant up to 180 min. During low-flow hypoxic ischaemia for 180 min (PO2 approximately 250 mmHg) and in the presence of 1% foetal calf serum, the release rate was reduced to below 10% of controls (P < 0.01) and increased four-fold on reperfusion (P = 0.05). The influence of endothelin on vascular and myocardial reperfusion damage was studied with exogenous endothelin-2. After 1 h of low-flow ischaemia, endothelin-2 increased the coronary perfusion pressure to a similar extent as in non-ischaemic hearts, but with a 30-times higher potency. The threshold dose for the constrictive effect was approximately 100 to 300 pg per heart, about ten times more than was recovered in the coronary effluent upon reperfusion. The influence of endothelin on myocardial reperfusion mechanical function (stunning) was assessed with 100 ng endothelin-2, a dose some 3500-fold higher than the amount released during 30 min reperfusion. This dose, given at the onset of reperfusion, improved post-ischaemic aortic output recovery during the first 20 min of reperfusion, but worsened it thereafter (up to 40 min). These data indicate that, in the isolated perfused rat heart model, (1) endothelin is released in measurable amounts into the coronary circulation, (2) the release is much reduced during ischaemia and increased on early reperfusion following prolonged ischaemia, (3) based on the amounts released and the post-ischaemic sensitization of the coronary vasculature to endothelin, the peptide could contribute to reperfusion vascular damage, and (4) endothelin is unlikely to influence stunning owing to the extremely high dose necessary to alter reperfusion mechanical function.

Animals↗
PubMed1992

Racemic (R,S)-propranolol versus half-dosed optically pure (S)-propranolol in humans at steady state: Hemodynamic effects, plasma concentrations, and influence on thyroid hormone levels.

In a randomized, double-blind, crossover study in 10 healthy volunteers the hemodynamic effects, drug plasma concentrations, and thyroid hormone profiles were compared after oral administration for 1 week of 40 mg t.i.d. racemic (R,S)-propranolol versus 20 mg t.i.d. optically pure (S)-propranolol. During exercise, both substances decreased heart rate (-14%, p less than 0.01), as well as the overall rate pressure product (-19%, p less than 0.01) to the same extent, indicating similar beta-blocking effects. After oral application of (R,S)-propranolol the maximal plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of (S)-propranolol were higher than those of (R)-propranolol (eudismic ratios (S)- over (R)-propranolol Cmax, 1.36 [p less than 0.01] and AUC, 1.42 [p less than 0.01]) despite dose-equivalence of both enantiomers in the administered racemic (R,S)-propranolol preparation indicating different pharmacokinetic properties. Mean values of Cmax and the AUC of (S)-propranolol did not differ significantly after 1 week of oral administration of 40 mg (R,S)-propranolol and 20 mg (S)-propranolol t.i.d., respectively. The ratio of triiodothyronine to thyroxine was decreased by (R,S)-propranolol (-25%, p less than 0.01) but not by (S)-propranolol, suggesting that only the (R)-enantiomer inhibits the conversion of thyroxine to triiodothyronine. Thus, half-dosed optically pure (S)-propranolol is an equally effective beta-adrenergic receptor antagonist compared with currently used racemic (R,S)-propranolol. By contrast, the conversion of thyroxine to triiodothyronine is inhibited by (R)-propranolol only.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Construction of antagonist dose-response curves for estimation of pA2-values by Schild-plot analysis and detection of allosteric interactions.

1. One aim of this paper is to show an alternative approach for the determination of antagonist affinity estimates, KB and pA2, by construction and evaluation of antagonist dose-response curves (DRCs), using the curve-fitting programme, ALLFIT. 2. Parallel antagonist DRCs were derived by vertical analysis of families of conventional agonist DRCs in the presence and absence of an antagonist at a certain agonist concentration above its ED50. The latter represents a chosen, i.e. fixed dose-ratio (DR). The antagonist concentration that reduces an agonist effect to its Emax/2 was termed Bx. It corresponds to B, the fixed antagonist concentration, tested to obtain DR-1, conventionally. 3. The dissociation constant was calculated as KB = Bx/DR-1, analogous to the conventional approach (KB = B/DR-1). Likewise, pA2-values were estimated by plotting log Bx, obtained by the alternative approach, vs log (DR-1) in an 'alternative Schild plot'. 4. Experimental agonist DRCs from our laboratory and from the literature were analysed and KB- and pA2-values obtained by the alternative approach were compared with those obtained by the conventional method. The results showed a very good agreement (correlation) between the pA2-values obtained by either method (slope = 1.02, r = 0.99, n = 9), in agreement with theoretical DRCs. 5. Besides estimation of KB and pA2, antagonist DRCs were also evaluated qualitatively. The most important finding was that allosteric antagonists or competitive antagonists with an allosteric component, such as gallamine, showed a significant reduction in the maximum of the antagonist DRCs (Imax). The evaluation of antagonist DRCs appears to be a sensitive procedure to detect allosteric interactions.6. This alternative approach can supplement or replace the conventional approach for the evaluation of antagonists on a quantitative and qualitative basis. The alternative approach appears of special advantage where the supply and/or the solubility of the agonist is limited, resulting in incomplete agonist DRCs.7. For rapid screening of potential antagonists, a single antagonist DRC at the maximum effective agonist concentration may be constructed to calculate KB reliably.

Allosteric Regulation↗
PubMed1992

Recurrence of primary renal disease on kidney graft: a European pediatric experience.

Of the 4,776 first grafts recorded in the pediatric European Dialysis and Transplant Association (EDTA) registry, 2,113 were reported to have failed and 5.6% of graft failures were related to a recurrence of primary renal disease. Nephrotic syndrome with focal and segmental glomerulosclerosis was the main renal disease prone to recur because recurrence represented 20% of the causes of graft failure in these patients; an even higher proportion was reported in a single-center experience in Europe. Other glomerulonephropathies, such as membranoproliferative glomerulonephritis and Berger's disease, were also reported to be the cause of graft failure by means of recurrence in a proportion similar to focal and segmental glomerulosclerosis. The usual recurrence of primary oxaluria was the cause of close to 50% of graft failure in this disease. Finally, hemolytic uremic syndrome recurred rarely with the graft in the EDTA registry, which is the opposite of what was reported in the United States.

Adolescent↗
PubMed1991

Characterization of muscarinic receptors mediating endothelium-dependent relaxation of bovine coronary artery.

In order to identify the receptor subtype responsible for acetylcholine (ACh)-induced relaxation of bovine coronary artery, we determined the affinity of six subtype-selective muscarinic antagonists and compared them with affinity estimates obtained for bovine left atria. At low concentrations, ACh potently relaxed circular strips of coronary artery with endothelium (EC50 0.15 microM), but contracted them at higher agonist concentrations with potencies that depended on the presence or absence of endothelium: EC50 1.8 microM (without endothelium); 4.6 microM (with endothelium). The pA2 values obtained for antagonism of relaxant responses to ACh were: pirenzepine (M1-selective) 7.38 +/- 0.12; AF-DX 116 (11-[2-(diethylamino-methyl)-1-piperidinyl-acetyl]-5,11- dihydro-6H-pyrido(2,3-b)1,4-benzodiazepine-6-one; M2-selective) 5.79 +/- 0.09; and 4-diphenylacetoxy-N-methyl-piperidine-methobromide (4-DAMP; M3/M1-selective) 9.07 +/- 0.12. The corresponding Schild slopes were 0.98 +/- 0.07 for pirenzepine, 1.17 +/- 0.09 for AF-DX 116 and 1.01 +/- 0.04 for 4-DAMP. For the following three antagonists, pKB values were determined at two different antagonist concentrations: dicyclomine (M1-selective) 7.49 +/- 0.10, cyclohexylphenyl-(2-piperidinoethyl)-silanol (CPPS; M3-selective) 8.0 +/- 0.10, and parafluoro-hexahydrosila-difenidol (pFHHSiD; M3-selective) 7.87 +/- 0.10. For comparison, the antagonism of methacholine-induced negative inotropy in left atria was determined for three antagonists, yielding the following pA2 values: pirenzepine 5.98 +/- 0.14; AF-DX 116 6.81 +/- 0.14 and 4-DAMP 7.99 +/- 0.14. The slopes of the corresponding Schild plots were 1.05 +/- 0.10, 1.14 +/- 0.12 and 1.08 +/- 0.08, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Characterization of muscarinic receptors of bovine coronary artery by functional and radioligand binding studies.

The nature of the muscarinic receptor subtype mediating contraction of the endothelium-denuded bovine coronary artery was investigated in vitro by functional measurements and radioligand binding studies. The acetylcholine (ACh)-induced isotonic contraction of circularly cut muscle strips was recorded and expressed as a percentage of the maximum contraction obtained with 80 mM K+. In order to distinguish between M1, M2 and M3 receptors, the potency of the five subtype-selective antagonists, 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP), parafluor-hexahydro-siladifenidol (pFHHSiD), pirenzepine, AF-DX 116 and methoctramine, to block the ACh-induced contraction was estimated. All the antagonists competitively inhibited the responses induced by ACh, with one exception, namely, 4-DAMP, whose Schild plot had a slope greater than one. The low affinity of pirenzepine (pA2 7.14 +/- 0.14) excluded an action at the M1 subtype. The low affinity of AF-DX 116 (pA2 6.49 +/- 0.18) and methoctramine (pA2 5.88 +/- 0.07) suggest that the bovine coronary artery smooth muscle receptor is not of the M2 (cardiac) subtype. In contrast, 4-DAMP (pA2 9.04 +/- 0.03) and pFHHSiD (pA2 7.64 +/- 0.04) potently inhibited the ACh-induced contraction with affinities similar to those reported for the M3 (glandular) receptor. In addition, the muscarinic receptors mediating coronary artery contraction were characterized in antagonist/[3H]N-methyl-scopolamine ([3H]NMS) competition binding studies. With the exception of AF-DX 116, all antagonists bound to a homogeneous population of receptors with pseudo-Hill slopes not different from unity. The pKi values, albeit somewhat lower, essentially substantiated the functional affinity estimates.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Radioligand binding to muscarinic receptors of bovine aortic endothelial cells.

1. Muscarinic receptors on endothelial cells of bovine thoracic aorta were characterized by binding assays in which (-)-[3H]-N-methyl quinuclidinyl benzilate ([3H]-NMeQNB) was used as radioligand. 2. Binding of [3H]-NMeQNB to crude membranes of freshly isolated endothelial cells was atropine-displaceable and of high affinity (KD = 0.48 nM) to a single class of sites (maximum binding capacity: 14 +/- 3 fmol mg-1 protein). Stereospecificity of the binding sites was demonstrated in experiments in which [3H]-NMeQNB binding was inhibited by dexetimide in the nanomolar range (KI = 0.63 nM) and by levetimide, its stereoisomer in the micromolar range (KI = 3.2 microM) (selectivity factor: approximately 5000). 3. Drug competition curves indicated a single class of binding sites for antagonists and the following apparent affinities (KI, nM): methyl atropine: 1.1: 4-diphenylacetoxy N-methyl piperidine methyl bromide (4-DAMP): 3.4; pirenzepine: 16; 11-[2-diethylamino-methyl)-1-piperidinyl- acetyl]-5,11-dihydro-6H-pyrido(2,3-b)1,4-benzodiazepine-6-one (AF-DX 116); 2.500. Competition of acetylcholine with [3H]-NMeQNB was best described by two affinity sites (or states) (KH = 0.82 microM, KL = 1.6 microM). In the presence of guanylimido diphosphate [Gpp(NH)p] (100 microM), acetylcholine affinity (IC50) was slightly, but significantly reduced (factor approximately 4). 4. Binding of [3H]-NMeQNB to freshly harvested intact cells was also atropine-displaceable, stereospecific (selectivity factor: approximately 3500) and of high affinity (KD = 0.35 nM). The maximum binding capacity (9 +/- 2 fmol mg-1 total cell protein) was comparable to that of membranes and corresponded to approximately 900 binding sites per endothelial cell. Binding to enzymatically harvested and cultured endothelial cells, or membranes derived therefrom, showed no atropine-displaceable binding. 5. The results suggest that (1) bovine aortic endothelial cells contain muscarinic binding sites with all necessary criteria of functional muscarinic receptors; (2) the receptor most closely corresponds to the M1 subtype and is of comparatively very low density, and (3) cultured endothelial cells lose their receptors during isolation or culture procedures.

Animals↗
PubMed1990

Evidence for muscarinic receptors in endothelial cells from combined functional and binding studies.

The aim of this study was to characterize muscarinic receptors of the bovine coronary artery by means of a combination of mechanical relaxation and contraction responses and radioligand binding data. Fresh helical strips of bovine coronary artery with intact endothelium relaxed in response to low concentrations (0.03-1 microM) of acetylcholine (ACh) and contracted at higher concentrations while endothelium-denuded strips only contracted. The ED50 for relaxation was 0.13 microM and that for contraction 1.8 microM (without endothelium); in the presence of endothelium, contraction dose-response curves were shifted to the right and the maximum contraction was reduced. In order to determine the location of the receptors mediating vasorelaxation, apparent affinity constants (KA) of ACh for relaxant and contractile effects were determined by irreversible blockade of a fraction of receptors with propyl benzilylcholine mustard (PBCM). The affinity constants (KA) were 0.22 microM for relaxation and 13 microM (with endothelium) and 20 microM (without endothelium) for contraction. In competition binding experiments against the muscarinic antagonist, [3H]N-methylscopolamine ([3H]NMS), the apparent affinity (KI) of ACh for binding sites in homogenates of endothelium-free coronary artery was 16 microM which was not different from the affinity constant determined in functional contraction experiments. Thus, the affinity constant of ACh determined for relaxation responses with endothelium-preserved vessels had no correlate in the binding affinity as determined with endothelium-free arteries. These findings indicate that bovine coronary arteries are relaxed by ACh through muscarinic receptors located on the endothelium whereas contractions are mediated by receptors on smooth muscle cells.

Acetylcholine↗
PubMed1990

The arc operon for anaerobic arginine catabolism in Pseudomonas aeruginosa contains an additional gene, arcD, encoding a membrane protein.

The arginine deiminase (ADI) pathway in Pseudomonas aeruginosa serves to generate ATP. The three enzymes involved, ADI, catabolic ornithine carbamoyltransferase and carbamate kinase, are induced by oxygen limitation and encoded by the contiguous arcABC genes. A 1.5-kb region upstream from arcABC was sequenced and found to contain an open reading frame, arcD, coding for a hydrophobic polypeptide of 52 kDa. The content and distribution of hydrophobic amino acids suggest that the arcD gene product may be a transmembrane protein. When arcD was fused to an Escherichia coli promoter, the ArcD protein was synthesized in E. coli maxicells and detected in the membrane fraction. In sodium dodecyl sulfate-polyacrylamide-gel electrophoresis the ArcD protein migrated like a 32-kDa protein; such anomalous electrophoretic mobility is known for other highly hydrophobic proteins. Mutations in arcD rendered the cells unable to utilize extracellular arginine as an energy source. Since anaerobic arginine consumption and ornithine release are coupled in P. aeruginosa, it is proposed that arcD specifies an arginine: ornithine antiporter or a part thereof. Insertions of IS21 or Tn1725 in arcD had a strong polar effect on the expression of the arcAB enzymes, indicating that the arc genes are organized as an arcDABC operon.

Amino Acid Sequence↗
PubMed1990

Five-year survival for end-stage renal disease patients in the United States, Europe, and Japan, 1982 to 1987.

We compared the 5-year survival for new end-stage renal disease (ESRD) patients accepted for renal replacement therapy (RRT) between 1982 and 1987 in the United States (n = 150,862), Europe (European Dialysis and Transplant Association [EDTA]) (n = 124,796), and Japan (n = 66,244). Given these large samples that approach a census in each of the three regions, all results are statistically significant. Our analysis showed that the US patients were older and more likely to be diabetic than the patients in either EDTA or Japan. After correction for patient differences in age composition and the percent diabetic, Japan had the highest survival, followed by EDTA, and then the US. Overall, the US 5-year survival was 40%. When comparison is done by age, only the youngest patients in the US (less than 15 years) have longer survival than their counterparts in Europe and Japan. For ages greater than 14 years, the survival differences between the US and EDTA and between the US and Japan grow larger with higher patient age. The comparisons of mortality by diagnosis showed that the differences between the US and EDTA and between the US and Japan were least for diabetes. For non-diabetic patients, the age adjusted relative risk (RR) of mortality for the US compared with EDTA was 1.22, ie, 22% higher in the US; for the US compared with Japan, the RR was 1.40. In contrast, the RR for diabetic patients in the US compared with EDTA was 1.07, and 1.23 for the US compared with Japan.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Bretylium tosylate binds preferentially to muscarinic receptors labelled with [3H]oxotremorine M (SH or 'high affinity' receptors) in rat heart and brain cortex.

Bretylium tosylate is an antiarrhythmic agent. In guinea pig atria it showed the properties of a competitive muscarinic (cholinergic) antagonist and could distinguish between two muscarinic receptor classes or states in cardiac membranes. We decided to further investigate its binding properties at muscarinic cholinergic receptors of the rat heart and brain (cortex), keeping in mind the recently discovered heterogeneity of muscarinic receptor protein. Bretylium tosylate recognized two receptor classes or states in the heart with Ki values of 0.9 and 11 microM. All cardiac membrane receptors showed a homogeneous (11 microM) Ki value for the drug in the presence of GTP in the incubation medium, or after in vivo pretreatment with islet activating protein (IAP). Bretylium tosylate was able (but only at a high concentration, 1 mM) to slow the dissociation kinetics of the tracer, which suggests that it also bound to an allosteric site on the muscarinic receptor, or that it affected the receptor environment. In the brain cortex, as in the heart, bretylium tosylate displayed a high affinity for receptors labelled with the agonist [3H]oxotremorine M (Ki value: 0.8 microM for the SH-or cardiac-type high-affinity receptors), and a 8- to 10-fold lower affinity for cortex M and L receptors. These data suggest that the antagonist bretylium tosylate had binding properties in rat cardiac membranes analogous to those of the partial agonist pilocarpine and that it interacted with a single type of receptor.

Animals↗
PubMed1989

Interaction of DPI 201-106 with cardiac muscarinic receptors.

The effects of the new cardiotonic compound, DPI 201-106, on muscarinic responses and muscarinic receptor binding were studied in the guinea pig heart. DPI 201-106 exerted a pronounced anticholinergic action in isolated auricles and a moderate one in papillary muscles, which resembled the pattern of a functional antagonism. However, in competition binding experiments, DPI 201-106 inhibited binding of the specific muscarinic antagonist [3H]NMS with equal potency in atrial and ventricular homogenates (apparent KI = 0.7 mumol/l in atria and 1.2 mumol/l in ventricles). At higher concentrations (greater than 3 mumol/l), DPI 201-106 slowed the dissociation of [3H]NMS from cardiac muscarinic receptors, indicating that DPI 201-106 affects in addition a site allosteric to the muscarinic receptor. It is concluded that DPI 201-106 is able to inhibit cholinergic responses in the heart, not only by a functional antagonism but also by direct interaction with muscarinic receptors.

Animals↗
PubMed1989

Comparative effects of haemodialysis and haemofiltration on plasma atrial natriuretic peptide.

The effects of 4 h haemodialysis (15 patients) or 4 h haemofiltration (five patients) on plasma concentrations of atrial natriuretic peptide (ANP) were compared by means of a sensitive radioreceptor binding assay, and related to accompanying changes in body weight, blood pressure and plasma renin activity. Before dialysis, plasma ANP concentrations were considerably elevated: haemodialysis group 10-484 pmol/l (mean 156 pmol/l); haemofiltration group 72-320 pmol/l (mean 170 pmol/l). Although plasma concentrations of ANP fell markedly with treatment in both groups: post-haemodialysis 2-187 pmol/l (mean 67 pmol/l); post-haemofiltration 47-135 pmol/l (mean 79 pmol/l), after treatment it remained above the normal range in 14 of the 20 patients. Pretreatment plasma ANP was related to systolic blood pressure (r = 0.459; P less than 0.05) but bore no relationship to mean or diastolic blood pressure, or plasma renin activity. The fall in plasma ANP concentration during treatment correlated with the postural blood pressure drop after dialysis (r = 0.505; P less than 0.05), but was unrelated to changes in weight or plasma renin activity with haemodialysis or haemofiltration. Plasma ANP concentrations rose rapidly again in the 60 min after dialysis treatment, without change in body weight. These results show that high levels of biologically active ANP circulate in end-stage renal disease. The fact that these are not reduced to normal by haemodialysis or haemofiltration, despite restoration to normovolaemic or hypovolaemic state, suggests that the increased levels of ANP in end-stage renal failure are due to both hypervolaemia and other factors, which may include occult cardiac dysfunction and loss of renal clearance.

Adult↗
PubMed1989

Subclassification of atrial and intestinal muscarinic receptors of the rat--direct binding studies with agonists and antagonists.

1. Although extensively investigated, the extent of differences between receptors mediating negative inotropic and chronotropic responses is still unclear. In the present study atrial and intestinal muscarinic receptors were identified by [3H]-N-methyl-scopolamine ([3H]-NMS) binding and the affinities of some presumably inotropy- or chronotropy-selective agonists and several antagonists determined. 2. All the agonists tested showed similar affinity for right and left atrial receptors. Accepting an affinity difference of 0.4 log units as experimental error, none of the agonists tested was selective for either atrium. 3. Affinity differences of the cardioselective antagonists himbacine, AF-DX 116 and methoctramine and the M1-selective antagonist dicyclomine for right and left atrial muscarinic receptors were also minimal (less than 2 fold selective). When compared to intestinal receptors, AF-DX 116 was 3 to 4 fold, methoctramine 10 to 13 fold selective and himbacine and dicyclomine non-selective. 4. These data provide evidence for differences between atrial and intestinal but not between right and left atrial muscarinic receptors.

Acetylcholine↗
PubMed1989

Incidence of arrhythmias and myocardial ischaemia during haemodialysis and haemofiltration.

Thirty-two patients (10 male, 22 female; age 37-82 years) undergoing maintenance haemodialysis or haemofiltration were studied by means of Holter device capable of simultaneously analysing rhythm and ST-changes in three leads. Twenty-five patients were on haemodialysis, seven on haemofiltration, mean duration of haemodialysis/haemofiltration being 3.4 +/- 3 years. Incidence of ventricular tachycardia was low, being detected only in 1 of 32 patients. Ventricular premature beats in excess of 10/h during a period of 2 h were found in 8 of 32 patients and 100 supraventricular premature beats for 2 h or more in 4 of 32 patients. Both ventricular premature beats and supraventricular premature beats were most frequently recorded during the last hour of haemodialysis/haemofiltration. ECG signs of ischaemia were detected in eight patients, four of whom were asymptomatic. Ischaemia also occurred predominantly during the last hour of haemodialysis/haemofiltration. Two symptomatic patients displayed neither arrhythmias nor ST-changes while being monitored. The study shows that silent ischaemia and arrhythmias in patients undergoing chronic haemodialysis/haemofiltration may not be infrequent. Recognition of these events could be of importance in the management of these patients.

Adult↗
PubMed1989

Pharmacokinetics and metabolism of the antiarrhythmic agent [3H]-diprafenone in the rat.

After acute intravenous (i.v.) administration of 3 mg/kg of 3H-labelled 2'[2-hydroxy-3-(1,1-dimethylpropylamino)propoxy]-3-phenylproiop henon hydrochloride ([3H]-diprafenone), plasma radioactivity levels declined biphasically with half-lives of 0.2 h (alpha-phase) and 1.5 h (beta-phase), respectively. After acute oral administration of 9 mg/kg, absorption was prompt but continued, similar to a zero-order process, over many hours resulting in plateau-like plasma levels up to 5-6 h and a subsequent slow decline with a beta-half-life of 6-8 h. Absorption varied between 50 and 80%. Distribution of [3H]-diprafenone was rapid and tissue levels in general paralleled blood levels. After i.v. dosing highest levels of radioactivity were found in the lung; after oral application in the gastrointestinal tract. Radioactivity was distributed into subcellular organelles and the cytosol resulting in an apparent volume of distribution (Varea) of 4-5 l/kg. About 95% of the 3H-activity given was excreted in urine (20%) and faeces (75%) within 48 h after i.v. administration. After oral application, total 3H-recovery was substantially lower. After i.v. dosing most of the 3H-label found in faeces originated from biliary excretion and was almost completed within 4 h after administration. After oral application, biliary excretion varied between about 5 and 35% indicating protracted absorption. 3H-radioactivity was reabsorbed and subject to extensive enterohepatic cycling. After repetitive oral administration, total radioactivity reached a steady state after 4-5 days. The corresponding cumulation factors R ranged between 2 and 3. A decline in elimination rate is likely. [3H]-Diprafenone was metabolized rapidly and quantitatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Characterization of guinea-pig cardiac muscarinic receptors by radioligand dissociation kinetics.

The question of cardiac muscarinic receptor heterogeneity was studied in guinea-pig auricles and ventricle. Radioligand dissociation kinetics were analyzed in the absence and presence of alinidine and AQ-A 39, two muscarinic agents and allosteric modulators of radiotracer dissociation. The dissociation kinetics were monophasic with all 3 radiotracers used and in both auricles and ventricle. [125I]3-Quinuclidinyl 4-iodobenzilate ([125I]QNB) dissociated with an identical half-life (t1/2 off) in ventricle and in left and right auricle, respectively. Alinidine (1 mM) decreased t1/2 off by 50% in ventricle but had no significant influence in auricles. AQ-A 39 (= falipamil) uniformly increased t1/2 off 4-fold in all 3 tissues. The binding of tritium-labelled quinuclidinyl benzilate ([3H]QNB) dissociated equally rapidly from both ventricular and auricular receptors under control conditions but was not affected by alinidine. AQ-A 39 (1 mM) slowed [3H]QNB dissociation 6.5-fold in ventricle but only 3-fold in both auricles. [3H]N-Methyl scopolamine ([3H]NMS) dissociation was uniform in both auricles but was somewhat slower in the ventricle, both in the absence and presence of alinidine. AQ-A 39 was without effect. These results demonstrate differences in ventricular versus auricular receptors detected by [125I]QNB in the presence of alinidine and by [3H]QNB in the presence of AQ-A 39. The quaternary ligand [3H]NMS was unable to detect receptor heterogeneity. No differences were found between right and left auricular receptors. The results presented provide no evidence for the existence of different subtypes of muscarinic receptors for the negative chronotropic and inotropic actions of muscarinic agonists.

Allosteric Site↗