Role of Ca channel in the renal autoregulatory vascular response analysed by the use of BAY K 8644

Summary The role of Ca channel and extracellular Ca²⁺ on autoregulation of renal blood flow was investigated in the perfused kidney of the anesthetized dog. The perfusion pressure was changed in the range between 60 and 200 mm Hg. Intra-arterial infusion of nifedipine (5 g/min) increased renal blood flow at a perfusion pressure above 100 mm Hg and inhibited autoregulation. Simultaneous infusion of 5 g/min of BAY K 8644 antagonized the effect of nifedipine. Renal blood flow was increased and autoregulatory relationship between flow and perfusion pressure was inhibited by EDTA (30 mg/min) infusion. The inhibitory effect of EDTA on renal autoregulation was counteracted by simultaneous infusion of CaCl₂ at 30 mg/min, but not counteracted by that of BAY K 8644 (5 g/min). BAY K 8644 also could not antagonize the inhibitory effect of a vasodilator, papaverine (5 mg/min) on renal blood flow autoregulation. These results provide the evidence that the renal autoregulation involves the process of Ca²⁺ influx into the vascular smooth muscle cell through the Ca channels. Send offprint requests to N. Ogawa at the above address     

Comparison of the effects of intravenous and intrasplenic infusions of glucagon on cardiac output and its distribution in the rat

Summary In order to determine whether or not glucagon released from the pancreas might have local vascular effects, the actions upon regional haemodynamics in the anaesthetised rat of two doses of glucagon (2 and 10 g kg^–1 min^–1) infused intrasplenically (and thus into the portal vein) were compared with those of a single dose (2 g kg^–1 min^–1) infused i. v. Infusion of glucagon i. v. produced a significantly increased heart rate (by 6%) and cardiac output (by 23%) in the experimental animals compared to those receiving saline by the same route. Total peripheral resistance fell by 24%. A greater proportion of the cardiac output passed to the coronary and renal vascular beds and blood flow was increased in the spleen, testes, pectoral skeletal muscle, stomach and small intestine as well as the heart and kidneys.The lower dose infused intrasplenically had no significant effect on cardiac output or total peripheral resistance but significantly increased the proportion of cardiac output passing both to the stomach and the small intestine such that the percentage of cardiac output flowing through the portal vein increased from 19.1 ± 1.1% to 23.8 ± 1.7%.Intrasplenic infusion of 10 g kg^–1 min^–1 significantly increased cardiac output (by 29%) but reduced total peripheral resistance by 37%. Greater fractions of the cardiac output were received by the spleen, small intestine and epididymides. Blood flow was increased in these organs and the skin, kidneys, stomach, large intestine and the mesentery.It is concluded that pharmacologically effective amounts of glucagon only passed into the systemic circulation with the higher dose infused intrasplenically. Thus the redistribution of cardiac output in favour of the splanchnic bed with the lower dose of glucagon infused into the portal region is most likely the result of local mechanisms rather than a direct effect of the hormone on the inflow vasculature resulting from recirculation. Send offprint requests to C. R. Hiley at the above address     

Drug-induced intrahepatic cholestasis: characterization of different pathomechanisms

The pathogenesis of intrahepatic cholestasis in rats was studied using isolated perfused livers as an experimental model. Three basic mechanisms were differentiated: 1. Permeabilization of the bilio-sinusoidal barrier associated with electron microscopic alterations of the tight junctional complexes was found in livers of rats treated with -naphthylisothiocyanate (ANIT, 250 mg/kg body weight). Consequences of these alterations were: reflux of bile constituents such as taurocholate and sulfobromophthalein and increased access to the biliary space of paracellular markers such as inulin and sucrose. The clear-cut mechanism of ANIT cholestasis was used to distinguish other mechanisms of intrahepatic cholestasis. 2. Inhibition of the basic process of fluid secretion was found to be the primary event in the development of cholestasis induced by estrogens. After 5 days of treating rats with ethinyl estradiol (5 mg/kg/day), bile flow was diminished in isolated livers while the permeability of the biliary tract to sucrose and inulin was not affected. Accordingly, the maximal concentration of taurocholate in bile was increased, indicating that its secretion was sustained. The same effect was observed after 1 week of treatment with the depot estrogen estradiol valerate (1 mg/kg/week). After 3 weeks of treatment, however, the taurocholate concentration in bile was lowered and the clearance of sucrose was increased. Bile flow remained at the same cholestatic level for 20 weeks. These results suggest that estrogens have the potency to increase tight junctional permeability only in a second step in the development of cholestasis, following the inhibition of bile flow. 3. An additional mode of secretory inhibition was induced by lowering the concentration of Ca²⁺ in the perfusate of isolated liver. Using ANIT-pretreated livers, i. e., livers with very low capacity to secrete foreign dyes, a high rate of efflux of sulfobromophthalein into the perfusate of preloaded livers suggests stimulation of the efflux of cholephilic solutes across the sinusoidal membrane of liver cells.The results demonstrate that the term intrahepatic cholestasis comprises a number of different sites of interference with the complex process of bile secretion.Dedicated to Professor Dr. med. Herbert Remmer on the occasion of his 65th birthday     

Acute systemic and renal haemodynamic effects and long-term antihypertensive action of cadralazine in patients pretreated with β-blockers and diuretics

Summary The antihypertensive effects of the hydralazine-related compound cadralazine (2-{3-[6-(2-hydroxypropyl)ethylamino]pyridazinyl}ethyl carbazate, ISF 2469), were investigated in 16 patients with primary hypertension concurrently treated with -blockers and diuretics. The protocol included a double-blind placebo controlled haemodynamic evaluation after the first tablet and two 4-week double-blind placebo controlled cross-over periods followed by an open evaluation during 2 months. Cadralazine induced a moderate, prolonged fall in blood pressure that was associated with vasodilatation and slight increases in cardiac output (dye-dilution) and heart rate. Renal plasma flow (PAH) and glomerular filtration rate (⁵¹Cr-EDTA) were not significantly influenced, but the filtration fraction was reduced. Plasma concentrations of noradrenaline and adrenaline rose, whereas plasma renin activity was unchanged. The haemodynamic parameters were not correlated with the plasma concentrations of cadralazine. During chronic cadralazine treatment the supine blood pressure was significantly lower than during the double-blind placebo phase (160/93 vs 174/102 mmHg). The compound was generally well tolerated but the body weight increased slightly (1.1 kg), probably because of fluid retention. Several patients who had previously experienced side effects with hydralazine, including one with hydralazine-syndrome, tolerated cadralazine well. This suggests that cadralazine does not cross-react with hydralazine.     

Thoracic duct lymph and PEEP studies in anaesthetized dogs

PEEP impedes thoracic duct drainage (LF). This can be counteracted by a thoracic duct fistula. Consequently, lung oedema (LOE) should develop during PEEP more slowly with LF at atmospheric pressure (LF_AP) than with LF against jugular venous pressure (LF_JVP). In 12 anaesthetized dogs LOE was produced by Ringer's solution i.v. (2.5 ml/min per kg) for 6 h during PEEP (10 mmHg) with either LF_AP or LF_JVP. Ringer's+PEEP greatly increased aortic, pulmonary artery and wedge pressures, JVP, and cardiac output. Colloid osmotic pressures in plasma and lymph were drastically reduced, pulmonary effective filtration pressure (EFP) rose by about 20 mmHg. LF_JVP increased 7-fold, LF_AP about 19-fold, the respective loss of plasma proteins was 1.83 and 1.06 g/kg during 6 h. Thermal-dye extravascular lung water showed an increment of 68 with LF_JVP versus 43 l/h/g per mmHg with LF_AP. Final lung water content was at any EFP (12.8–31.9 mmHg) lower with LF_AP than with LF_JVP amounting 512 with LF_JVP versus 377 l/g/per mmHg with LF_AP. LF_AP decreased the development of LOE during PEEP by bypassing the PEEP-induced high JVP and thus facilitating the removal of interstitial fluid. It is hypothesized that a thoracic duct fistula might aid the treatment of patients with LOE due to ARDS and therefore requiring high levels of PEEP.     

Prostaglandins: Antiproliferative effect of PGD 2 on cultured human glioma cells

Summary Five cultured human glioma cell lines were investigated for their reaction to prostaglandin (PG) D 2 and E 2. In all cases a suppressive effect on DNA synthesis as assessed by³H-thymidine incorporation was seen with all test substances as early as six hours after the addition of the compounds in doses of usually 10^–5 M. A dose response curve was generated in four cases and showed an estimated ED 50 of about 5 · 10^–6 M. The effect was most pronounced at 12 hours after which the cultures began to recover except those which had been incubated with PGD 2. In those cultures which had been exposed to PGD 2 virtually no thymidine incorporation was seen after 24 hours and as long as 72 hours.In another set of experiments, the effect of PGD 2, PGE 2, two synthetic PGD 2 analogues, with a chlorine substitution in position 9 (DACl) or with a fluoride substitution in position 9 (DAF) and a synthetic prostacyclin-analogue (Iloprost) was investigated after single and repeated addition of the compounds. A second administration after 12 hours of incubation did not result in a further decrease in³H-thymidine incorporation like that observed during that first incubation period. In general the cells recovered after 24 hours total incubation time except those which had received PGD 2 or repeated doses of PGE 2. Only in those cells which had been treated with PGD 2, an almost complete blockade of³H-thymidine incorporation was seen even after the single administration. Parallel evaluation of the cells by flow cytometry showed effects on cell cycle distribution at different times of the incubation. After 12 hours cells began to accumulate in G2/M at levels of approximately twice control, the effect being the least pronounced for PGD 2. For this compound we observed a threefold increase in cells in the S phase. After 24 hours the cell cycle distribution had normalized for all compounds except PGD 2 where the arrest of cells in G2/M persisted to be about 2–3-fold control level until the end of the experiment.Our data suggest, that also in cultured human glioma cells, prostaglandins are effective in suppressing cellular DNA synthesis.Although the effect of PGD 2 can be achieved to some extent by PGE 2 and the analogues which are more stable to dehydrogenases and the metabolic conversion into other biologically active homologues, PGD 2 appears to have a unique quality of action, becoming apparent 24 hours after administration.Abbreviations PG prostaglandin - DME Dulbecco's modified Eagle medium - STV trypsin in phosphate buffered saline EDTA (versene) - PBS phosphate buffered saline - ICP impulse cytophotometry - TCA trichloroacetic acid - DACl 9-chloro-15-cyclohexyl-11,15-dihydroxypentanor-5,13-prostadienoic acid- and DAF=9-Fluoro-15-cyclohexyl-11,15-dihydroxypentanor-5,13-prostadienoic acid Dedicated to Prof. Dr. Friedrich Loew on the occasion of his 65th birthday and the 25th anniversary of the Homburg Neurosurgical University Clinic, which has been founded and built up by him.     

Experimentelle Bedingungen zur Reproduktion eines submucösen Steal-Phänomens am Hundemagen

Zusammenfassung Der Einfluß von Pentagastrin auf die Durchblutung des Hundemagens wurde mit 9-Mikrosphären untersucht. Schon 6 min nach dem Beginn der Pentagastrin-Infusion nimmt bei nüchternen Tieren der Fluß in allen Magenarealen zu. Mißt man die Änderung der Durchblutung zwei Stunden postprandial, so findet sich ein Durchblutungsanstieg lediglich im Bereich der Corpusmucosa, während die Antrummucosadurchblutung unter den Ausgangswert abfällt. Dieses intragastrale Steal-Phänomen findet auf der Ebene des submucösen Plexus statt.

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Experimental conditions for the reproduction of a submucous steal-phenomenon in the dog stomach

Summary The influence of pentagastrin on gastric blood flow has been investigated using 9-microspheres in dogs. As soon as 6 min after the onset of a pentagastrin infusion blood flow rises in all gastric probes in fasted animals. In dogs, fed two hours previously, such a response can only be seen in the corpus-mucosa areas. Blood flow in the antrum mucosa specimen falls beneath its initial value. This gastric steal-phenomenon takes place at the level of the submucous plexus, as has been shown earlier.

     

Blood loss during and following transurethral resection

Blood loss measurement in transurethral prostatic surgery (TUR) has been studied with the following objectives: (1) to measure the total lost volume (during surgery and 48 hours postoperatively); (2) to compare surgical bleeding and coagulogram alterations in benign prostatic hypertrophy (BPH) and prostatic carcinoma (CaP); (3) to establish the relationship between blood loss, duration of the procedure, and amount of resected tissue. The method of Jansen was used to measure blood loss, and the "coagulogram" included the following parameters: hematrocrit; prothrombin, recalcification, thrombin, and partial thromboplastin times; fibrinogen; platelets and fibrin split products. The study is based on TUR performed on 75 patients from whom a mean weight of 25.68 grams was resected resulting in a mean total bleeding volume of 305 ml. Blood loss over 400 ml was associated with surgical durations of 60 minutes or with resection of over 40 grams of tissue. There was a slight tendency for fibrinolysis in prostatic cancer, which could explain the relatively higher amount of blood loss observed in these cases.     

Lead in finger-bone analysed in vivo in active and retired lead workers

In 75 active lead workers the median lead level in finger-bone (bone-Pb), as determined in vivo by an X-ray fluorescence method, was 43 micrograms/g (range less than 20-122). In 32 retired workers the median level was even higher, 59 micrograms/g (range less than 20-135), which indicates a slow turnover rate of lead in finger-bone. This was confirmed in 18 of the "active" workers, in whom bone-Pb was studied in connection with an exposure-free period. In spite of a significant decrease in blood-lead levels (B-Pb), no systematic change of bone-Pb occurred. There was an increase of bone-Pb with time of employment, but with a large interindividual variation. No association was found between bone-Pb and present B-Pb in the active lead workers. However, in the retired ones, B-Pb rose with increasing bone-Pb. The bone-lead pool thus causes an "internal" lead exposure.     

Effects of fenflumizole on aggregation ex vivo of human platelets and formation of thromboxane B2 and 6-keto-prostaglandin-F_{1\alpha }

Summary Fenflumizole (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)imidazole), a new non-steroidal anti-inflammatory drug, was given to healthy subjects in single oral doses of 0.1, 1 and 2 mg/kg. The effect of the drug was followed for up to 8 h by repeated tests of arachidonic acid-induced platelet aggregation and was related to its concomitant plasma concentration. Fenflumizole reversibly inhibited platelet aggregation and the degree of inhibition was found to be linearly correlated with the log plasma concentration. There was depression of the formation of thromboxane B₂ and 6-keto-prostaglandin F₁ (the stable metabolites of thromboxane A₂ and prostacyclin) in clotted whole blood measured by radioimmunoassay after fenflumizole 1 mg/kg. This effect was directly related to the concentration of the drug in plasma, the maximum effect being reached at fenflumizole concentrations >200 ng/ml. EC₅₀-values for inhibition of the formation of thromboxane B₂ and 6-keto-prostaglandin were approximately 20 and 40 ng/ml, respectively. The results suggest that orally administered fenflumizole is a potent inhibitor of platelet aggregation and prostanoid formation.