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Biomedical subjects

A Knorr

Publications and source records attributed to A Knorr.

At least 73 records · Page 4Linked to original sources
PubMed1989

Alpha and beta-adrenoceptors in hypertension. I. Cardiac and renal alpha 1-, beta 1-, and beta 2-adrenoceptors in rat models of acquired hypertension.

To determine whether adrenoceptor changes in genetic hypertension occur primary or secondary to blood pressure elevation, we measured cardiac and renal alpha 1- (by [125I]Be 2254 binding) and beta 1- and beta 2-adrenoceptors (by (-)-[125I]iodocyanopindolol binding) densities in various rat models of acquired hypertension (Dahl S rats on a high-sodium diet, 1-clip-1-kidney (1C-1K) renal hypertensive and DOCA-salt hypertensive rats) in comparison with genetically identical age-matched untreated rats. In addition, alpha 1-adrenoceptors were assessed in spontaneously hypertensive rats (SHR) and in SHR treated with the immunosuppressant cyclosporin A. In heart, no clear pattern of changes in alpha 1- or beta 1- and beta 2-adrenoceptors was obtained. In kidney, however, beta 1- and beta 2-adrenoceptors were increased in all models of hypertension, and a good correlation between renal beta-adrenoceptors and systolic blood pressure was found. In contrast, renal alpha 1-adrenoceptors were only increased in SHR but not in any form of acquired hypertension. Thus, renal beta-adrenoceptor increases probably occur secondary to blood pressure elevation, whereas alpha 1-adrenoceptor increases appear to be associated with genetic hypertension. Because renal alpha-adrenoceptors are linked to tubular sodium reabsorption, we suggest that an increase in renal alpha 1- (and alpha 2)-adrenoceptors may be a very early step in the development of genetic hypertension.

Animals↗
PubMed1989

[Phospholipase C hypersensitivity in hypertensive rats results from innate and acquired factors].

In spontaneously hypertensive rats (SHR), enhanced activity of phospholipase C (PLase C) has been reported in various cells and tissues. In particular, the increased PLase C activity of platelets has been described as being involved in the hyperactivity to thrombin exhibited by these cells in SHR and in some patients with essential hypertension. In order to determine the relationship between such an enzymic abnormality and hypertension, the PLase C activity of platelets was investigated in various models of experimental hypertension, i.e. Dahl rats and DOCA-salt hypertensive rats. PLase C activity was determined by measuring the thrombin-induced 32P-phosphatidic acid (32P-PA) formation from 32P-prelabeled platelets. In parallel, experiments on the platelet reactivity was assessed by measuring the thrombin-induced serotonin secretion from 3H-serotonin prelabeled platelets. In Dahl salt-resistant rats (DR), the blood pressures were 123 +/- 6 and 118 +/- 7 mmHg for animals fed a low (0.3 p. 100) and high (4 p. 100) salt diet, respectively; the blood pressures of Dahl salt-sensitive rats (DS) were 159 +/- 6 and 202 +/- 11 mmHg, respectively. Hypertensive rats of the DOCA/salt--treated group exhibited a blood pressure of 210 +/- 8 mmHg compared with 137 +/- 4 mmHg for those of the control group. At rest (ie before stimulation) the platelets of all groups of animals behave similarly with respect to the incorporation of 32P and its metabolism into phospholipids as well as the uptake of serotonin. These data indicate therefore that platelets were in a similar quiescent status.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

The pharmacology of nisoldipine.

Nisoldipine is a calcium antagonist that specifically blocks the slow or voltage-dependent calcium channel up to the highest concentrations. This mode of action has been confirmed in pharmacological studies on isolated organs, electrophysiological and binding studies, and by the measurement of transmembrane calcium transport. As with other dihydropyridine calcium antagonists, an interaction with intracellular calcium reservoirs and calmodulin seems to be of minor importance. The drug exhibits higher potency, longer duration of action, and a higher binding affinity in vitro and in vivo than nifedipine. In contrast to its vasodilating and spasmolytic activity, its negative inotropic effect occurs in vitro only after higher concentrations than after nifedipine. In whole animals a secondary positive inotropic effect occurs regularly owing to sympathetic counter-regulation. The influence of nisoldipine on cardiac stimulus formation and conduction is also very slight in anesthetized animals, and is completely eliminated in awake animals and humans by counter-regulation up to very high doses. The cardiac anti-ischemic action of nisoldipine has been demonstrated in various ischemia models and is probably based predominantly on its afterload-reducing properties in addition to its spasmolytic effect on the coronary arteries. Various other suspected effects, for which there are isolated indications, e.g., inhibition of thromboxane synthesis, preload reduction, interaction with the transport of adenosine, and normalization of the sarcolemmal Na+, K(+)-ATPase activity, are probably of subordinate importance. Its antihypertensive effect is explained primarily by lowering of the peripheral resistance. There are, however, some indications that nisoldipine exerts certain effects over and above pure vasodilation. The prevention of postischemic calcium overloading in the renal tubule epithelium and the natriuretic effect are probably of importance in the therapeutic action. Clinically, nisoldipine was found more potent and prolonged in its action in comparison with nifedipine. In comparative studies, nisoldipine, 10 mg once a day, was found equieffective with nifedipine 10 mg three times or 20 mg twice a day in angina or hypertension, respectively.

Animals↗
PubMed1987

[Repair mechanisms of the lung--experimental and clinical results].

The effect of dose and time and of the RBE on the pulmonary reaction to radiation has been studied by means of trials with young pigs. 70 animals received a fractionated (five and 15 fractions) telecobalt irradiation of the right lung over total treatment periods T of five, 23, and 35 days. The influence of dose and time on the pulmonary reaction to radiation is defined at the ED50 level (effective dose, after which 50% of animals will suffer from radiopathy) by a proportionality of D approximately N0.32 X T0.05. An alpha/beta value of 3.7 Gy is calculated according to the LQ model. An RBE value of 4.0 to 4.1 was determined in 38 animals treated over five and 35 days with the 6.2 MeV neutrons of the cyclotron Rossendorf. The experimentations on animals allow to classify the lung reaction as late effect. The clinical results found in literature show that this classification is also valid for human lung reaction to fractionated radiotherapy. So it is not possible to achieve a considerable increase of the pulmonary tolerance dose by increasing the total treatment period. The best sparing of the respiratory organ is obtained by an application of small single doses which allows to profit from the large repair capacity of pulmonary tissue. These results, as well as our considerations regarding the latent time between therapy and lung reaction, and some trials on laboratory rodents allow to speak of a radiogenic pneumopathy with the proprieties of a late reaction characterized by a pneumonitis appearing previously and changing into pulmonary fibrosis.

Animals↗
PubMed1986

Fractionated lung irradiation in young pigs with 6.2 MeV neutrons and cobalt-60.

Irradiations of the right lung with 6.2 MeV neutrons (38 test animals) and 60Co photons (34 test animals) were made using young pigs. Twenty animals were used as controls. Five fractions were administered in an overall treatment time of 5 or 35 days. The radiogenic pneumopathy was monitored with clinical, radiological and histological investigations, and by determining the hydroxyproline content in the lung tissue. The pneumopathy in pigs given neutrons developed after a shorter latency period and followed a more rapid and serious course than that in animals given gamma rays. While after photons the extension of the overall treatment time from 5 to 35 days led to a measurable but low increase of the ED50 this was not true for neutrons. The relative biological effectiveness (RBE) for the 6.2 MeV neutrons compared with 60Co photons was 4.0 for an overall treatment time of 5 days and 4.1 for 35 days.

Animals↗
PubMed1986

The time-dose relationship for radiation-induced lung damage in pigs.

The dose-time relationship of radiogenic pneumopathy was studied in 68 young pigs. The right lungs of the animals were irradiated by means of a telecobalt unit. Dose distribution calculations and the preparation and execution of irradiation were chosen to largely parallel the treatment of patients. The radiation response of the lungs was quantified by chest-X-rays, functional studies and histological and biochemical investigations of the autopsy specimens. The dose which produced unambiguous signs of radiation pneumopathy in at least 50% of the individuals (ED50), was used to draw an iso-effect plot. A steep slope of the iso-effect line was found when the number of fractions was increased from 5 to 15. In contrast, the iso-effect line showed only a small slope when the influence of overall time was investigated. Significant differences between doses for early and late reactions of the lungs could not be detected. The radiogenic lung reaction in pigs is adequately described by the relation D approximately N0.32 X T0.05 and an alpha/beta value of 3.7 Gy. These results are in a good agreement with those derived for mice by other investigators. The good comparability of the biological findings obtained with pigs to man points to the application of this dose-time relation in radiotherapeutical practice.

Animals↗
PubMed1986

[Dose-time correlation in the irradiation of the lung of piglets for evaluating a model of human radiogenic pneumopathy].

Dose-time relationships with respect to a pulmonary radiogenic reaction were studied in 62 improved-breed pigs aged 3 mos. with the mass of 20-30 kg. The animals received fractionated irradiation with 60Co. Irradiation and its doses were computed in a way similar to that used in clinical practice. Clinical evidence, respiration rate, chest x-ray, histological and biochemical investigations of pulmonary tissue served as quantitative criteria of pulmonary lesion. ED50 was determined, i.e. a dose at which 50% of the experimental animals fell ill. The number of fractions produced a greater effect on an isoeffect curve than the entire period of irradiation. The pulmonary radiogenic reaction in pigs could be expressed by the calculation D approximately N0,32 T0,05. A possibility to introduce the results of the experiments on pigs into clinical practice allows practical use of the dose-time relationships obtained in the experimental studies.

Animals↗
PubMed1985

Interference of the calcium antagonist nisoldipine with the abnormal response of vessels from hypertensive rats to alpha-adrenergic stimulation.

The effects of the calcium antagonist nisoldipine on contractions stimulated by phenylephrine and B-HT 920 (agonists of alpha 1- and alpha 2-adrenoceptors) in isolated aortic rings from stroke-prone spontaneously hypertensive rats (SHRSP) and from normotensive Wistar-Kyoto rats (WKY) were investigated in vitro. Phenylephrine and B-HT 920 produced concentration-dependent contractions of vessels from both groups of animals. The absolute force of the contractions was less in the aortae from hypertensive rats after all doses of both agonists. Nisoldipine inhibited the B-HT 920-induced contraction much more in vessels from SHRSP than in those from normotensive WKY rats (IC50 = 1.5 X 10(-10) versus 7 X 10(-9) g/ml). The phenylephrine contractions were inhibited in SHRSP aortae by higher concentrations (IC50 = 8.5 X 10(-8) g/ml) of nisoldipine; in WKY, nisoldipine only produced a slight inhibition of phenylephrine-induced contractions. The inhibitory concentrations of nisoldipine on BHT-920-induced contractions are similar to those for the inhibition of the calcium or depolarization-induced contractions in other experiments. The alpha 2-agonist-induced contractions of rat aorta are dependent on transmembrane calcium supply. The higher efficacy of nisoldipine in aortae from SHRSP suggests an increased transmembrane availability of calcium ions in hypertension.

Adrenergic alpha-Agonists↗
PubMed1985

Chronic treatment with nifedipine prevents development of hypertension and abnormal red cell Na+ transport in Dahl-S-rats.

Transmembrane Na+ transport was measured in erythrocytes of salt resistant (DR) and salt sensitive (DS) Dahl rats, fed either a standard (0.4%) or high (0.8%) NaCl diet, or a high NaCl diet containing 300 ppm of the calcium entry blocker nifedipine. Whereas salt-loaded DS became severely hypertensive, those treated with nifedipine remained normotensive. With a low NaCl diet, total Na+ efflux and Na+ pump activity was lower in DS than in DR. Cotransport was more active in DS than in DR. After excess Na+ intake, total Na+ efflux was markedly reduced in DS, but normal in nifedipine-treated DS. Cell Na+ content was increased by 52% in salt-loaded DS, but not so in DS chronically treated with nifedipine. Na+ pump was completely suppressed in salt-loaded DS, but normal in DR and rats treated with nifedipine. These results suggest that Na+ pump inhibition might be involved in the development of Dahl rat hypertension, and that prevention of salt-induced hypertension by chronic nifedipine treatment also prevents suppression of erythrocytic Na+ pump. This suggests a casual link between its biochemical and therapeutic action.

Animals↗
PubMed1985

Inhibition of human red blood cell Na+, K+-cotransport by various "high ceiling" diuretics.

The rank order of diuretic efficacy of furosemide analogs, e.g. bumetanide and piretanide, in humans is reflected better by their ability to inhibit Na+, K+-cotransport in human red blood cells than by their natriuretic activity in rats. High ceiling diuretics which are structurally unrelated to sulfamoyl diuretics, e.g. muzolimine, tizolemide, MK 447, may be similarly effective in rat and man, but by acting via other mechanisms cannot be detected by use of the Na+, K+-cotransport system. On the other hand, a possible conversion of such compounds to metabolites active in the cotransport system cannot be ruled out. In contrast to ethacrynic acid, the weak inhibitory activity of muzolimine on the Na+, K+-cotransport was not potentiated by cysteine. These results suggest that the diuretic activity of muzolimine is not caused by inhibition of Na+, K+-cotransport.

Adult↗
PubMed1985

Influence of muzolimine and other diuretics on human red cell Na+, K+-cotransport.

It is known that the diuretic activity of so-called loop diuretics is characterized by the ability of such compounds to inhibit the Na+, K+-cotransport system of the cell membrane. A good correlation has been demonstrated of the inhibitory activity of several furosemide- and ethacrynic acid-related compounds with their natriuretic activity in man. It was the aim of the study to examine, wether muzolimine has Na+, K+-cotransport inhibitory activity, and if so, if this occurs in a dose range which might be relevant for its natriuretic activity. For reasons of comparison, several other diuretics with high ceiling activity were studied. Cotransport inhibitory activities were compared with natriuretic activities in rats. Na+, K+-cotransport was measured by determination of furosemide-sensitive, ouabain-insensitive Na+-extrusion from Na+-loaded human red blood cells. Whereas the natriuretic activity of muzolimine is equal to that of furosemide in rats and superior in man, its cotransport inhibitory activity is merely 1/13 of that of furosemide. Additionally, only 50% inhibition is reached. The inhibitory activity of muzolimine, in contrast to ethacrynic acid, is not enhanced in the presence of equimolar cysteine. Muzolimine therefore appears to act via other mechanisms than furosemide-like diuretics. However, it cannot be excluded that muzolimine might act by an active metabolite.

Adult↗