Biomedical subjects
Publications and source records attributed to A Fahr.
A simple method for the quantitation of 14C-whole-body autoradiograms by comparative densitometry is described. If processed under the same conditions as the samples of tissues to be investigated, a radioactive blood scale can be used as standard, with the exception of samples from bones, eyes and fat. This method is demonstrated to be simple, accurate, reproducible and precise.
The influence of trapidil on serum levels and cardiac effects of digoxin was investigated in 10 healthy men, intraindividually compared with placebo. Each subject took digoxin orally for 9 days (0.375 mg daily on days 1 to 8, 0.25 mg on day 9) either combined with trapidil (400 mg daily on days 1 to 8, 200 mg on day 9) or combined with placebo in a cross-over design. Trapidil failed to change significantly the steady-state serum digoxin concentrations on day 9 of treatment. It did also not alter significantly the following digoxin effects: shortening in QS2c time indicating the cardiotonic digoxin effect, shortening in QTc time, increase in PTQ index. But trapidil prevented the negative chronotropic digoxin effect.
Trapidil, a triazolopyrimidine, and its derivatives are coronary vasodilating drugs. Trapidil reduces the serum level of low density lipoprotein- and very low density lipoprotein-cholesterol and increases the serum level of high density lipoprotein-cholesterol in hyperlipemic patients. The present study demonstrates that trapidil and five different trapidil derivatives inhibit the proliferation of cells cultured from grossly normal intima and fatty streaks of human aorta. The inhibiting effect of trapidil derivatives is about 60%, similar to the standard substance 3-isobutyl-1-methyl-xanthine (MIX). In cells cultured from atherosclerotic plaques trapidil and trapidil derivatives reduced the content of cholesteryl esters by 36% for trapidil and between 47% and 68% for 4 of 5 trapidil derivatives, respectively. The trapidil derivative AR 12463 (5-piperidino-7-[N-(n-amyl)-N-(beta-hydroxyethyl)amino]-s-triazolo[1,5- a]pyrimidine) reduces the free cholesterol content by 29%, but the other trapidil derivatives are without effect on this parameter. Four of five derivatives decrease the content of triglycerides by 53 to 70%. The synthesis of collagen is inhibited by the trapidil derivative AR 12463 (25%). Trapidil and other derivatives have a smaller or no effect on the synthesis of collagen. These effects of trapidil derivatives point to potential antiatherosclerotic properties. The possible mechanisms are discussed.
A photoaffinity labeling method is described to label a protein covalently in various transient covalent states. The method uses a combination of an especially adapted stopped-flow apparatus with a Q-switched Nd: YAG DCR-2A laser (wavelength 266 nm, i.e. four-fold the primary frequency, pulse duration 4 ns, pulse energy 15 mJ). The construction of the mixing cell, the triggering device and the set-up for determining the dead time of the stopped-flow apparatus is described. The dead time is 2.4 ms. In combination with a specific photolabel the method has been used for labeling functional states (resting, activated, desensitized, antagonist-blocked) of the nicotinic acetylcholine receptor from Torpedo marmorata electric tissue.
The conditioning of the donor by 1.0 microgram/kg X min Iloprost over 15 minutes leads to a considerable inhibition of the aggregation of thrombocytes in the domestic pig. 160% more ADP had to be added than before the application of Iloprost. When 0.5 microgram/ml Iloprost are added to the perfusion fluid and to the reperfusion fluid 0.22 microgram/ml and 0.27 microgram/ml, respectively, are to be proved in the venous efflux. Whether or not the difference is absorbed or metabolized must remain open. During the 72-hour storage of the kidney in a Euro-Collins-solution with 0.5 microgram/ml Iloprost after 24 hours a decrease of 0.34 microgram/ml, after 48 hours to 0.33 microgram/ml and after 72 hours to 0.20 microgram/ml takes place. Thus Iloprost is present in an effective concentration also after 72 hours. The decrease to one plateau rather speaks for a consumption by active metabolic effect or absorption than for a chemical decomposition.
Intraindividually compared to placebo, the possible influence of an oral pretreatment with the cyclooxygenase inhibitor indometacin on serum concentrations and cardiac effects of digoxin, administered by a controlled intravenous infusion, was evaluated in 6 healthy male humans. A significant pharmacokinetic or pharmacodynamic interaction between both drugs could not be found. Indometacin only tended to elevate serum digoxin levels, to strengthen the digoxin induced decrease in the electrocardiogram parameters heart rate and QTc time as well as to reduce the positive inotropic action of digoxin measured by systolic time intervals and PTQ index.
Photoaffinity labeling of membrane-bound nicotinic acetylcholine receptor from Torpedo marmorata electric tissue with the ion-channel blocker [3H]TPMP+ reveals various functional states of the receptor protein if labeling is performed with ms time resolution. In the resting and in the activated state most of the label is incorporated into the alpha-polypeptide chains of the receptor complex. When equilibrated with agonists and antagonists, predominantly the delta-polypeptide chain (and to a lesser extent the beta-chain) reacts with the photolabel. Reactivity of the delta-chain increases after exposure to cholinergic effectors with a half-life slower than the kinetics of receptor activation or rapid desensitization. Agonists and antagonists stimulate photolabelling of the delta-chain with different kinetics. For acetylcholine, carbamoylcholine and suberyldicholine the half-life of the reactivity increases is 400 - 500 ms; for the antagonists hexamethonium, d-tubocurarine and flaxedil it is about 10 s. The latter slow kinetics are also observed when the receptor is preequilibrated with agonists or antagonists prior to mixing with [3H]TPMP+ and starting the photoreaction. We conclude that time-resolved photoaffinity labeling can convalently mark protein structures involved in receptor functions. Of special interest is the observation that antagonists also induce a conformational change in the receptor protein.
The experiments were carried out in order to clarify the mechanisms of attenuation of hypertension development by means of diets enriched with polyunsaturated fatty acids (PUFA) in spontaneously hypertensive rats (SHR). Female SHR were fed a linoleic acid rich (LAr) diet (13.3 cal % LA, sunflower oil), a linolenic acid rich (LNAr) diet (18.8 cal % LNA, 3.9 cal % LA; linseed oil) and a PUFA deficient diet (0.5 cal % LA, hydrogenated palm kernel fat), respectively, during the last week of pregnancy and during the suckling period. Corresponding diets were given to the male offspring up to an age of 16 weeks. Our results demonstrate that the attenuation of hypertension development in LAr and LNAr fed male SHR was paralleled by an increased in-vitro uptake of 14C-norepinephrine into cardiac and aortic tissues as well as an increased degradation rate of 14C-norepinephrine in cardiac tissue. Ex vivo prostaglandin (PG) formation was reduced after LNAr diet in the aorta (PGF2 alpha, PGI2-like material) and in the kidney medulla (PGE, PGF2 alpha). It is concluded that an increased catecholamine inactivation may play a role in the attenuation of hypertension development in LAr and LNAr diet fed SHR.
Photoaffinity labeling of the nicotinic acetylcholine receptor from Torpedo marmorata electric tissue was performed in the presence of cholinergic effectors in the millisecond to second time range by a combination of a stopped-flow apparatus and a high-energy pulse laser. The label applied was [3H]triphenylmethylphosphonium, a lipophilic cation previously shown to be a specific blocker of the acetylcholine receptor ion channel. With the receptor in the resting state most of the label was incorporated into the alpha polypeptide chains. In the presence of agonists and antagonists increasing incorporation into the delta- and (less pronounced) the beta-chain was observed. The time course of this increase had a half-life of about 0.4 s, being slower than receptor activation and channel opening. in the resting, active, and even rapidly desensitized state, the alpha polypeptide chains appear to be the primary targets of the photoaffinity reaction. The action spectrum of the photolabeling has a sharp maximum at lambda = 270 nm and a small-side maximum at lambda = 290 nm. It does not resemble the absorption spectrum of the label and may hint at amino acid side chains as the moieties activated by UV light causing the photolabeling. The effector specificity of the observed slow increase of label incorporation into the delta polypeptide chain was investigated. It does not prove that slow desensitization is the underlying event. The agonists acetylcholine and carbamoylcholine as well as treatment of receptor-rich membranes with phospholipase A2 (but not phospholipase D) triggered labeling of delta, but antagonists such as D-tubocurarine and most conspicuously flaxedil had a similar effect.
Photoaffinity labeling of acetylcholine receptors can be performed with a time resolution allowing to discriminate reaction sites within the receptor protein in its different functional states. This is achieved by a combination of a stopped-flow apparatus with a high energy pulse laser. The photoaffinity label used is the lipophilic cation [3H]TPMP+ which has been shown to be a non-competitive antagonist and a specific ion channel blocker. AChR in its resting (channel closed) and active (channel open) state incorporates the label mainly into the alpha-polypeptide chain of the receptor. Only several hundred milliseconds after mixing AChR with agonist labeling of delta-chains becomes significant.
Purified bovine rod outer segment disk membranes were attached to a lecithin bilayer membrane. After photoexcitation with a 500-nm flash delivered by a dye laser, a negative photovoltage was observed on the bilayer under normal ionic strengths (100 mM KCl), which had a rise phase of 1-3 ms at 20 degrees C. The photoresponse was obviously due to bleaching of rhodopsin as it decreased for successive flashes of light. It originated most probably during the metarhodopsin-I metarhodopsin-II (meta-I-II) transition of rhodopsin because it was pH dependent at 2 degrees C but not at 20 degrees C. At 10 mM KCl, i.e., under hypotonic conditions, a positive photovoltage with slower kinetics than at high salt was observed. As the disk membranes were merely attached to the bilayer membrane, the photovoltage was apparently due to a light-induced transmembrane potential change in the disk membranes. Possible electrogenic mechanisms underlying the photosignal will be discussed.
Clinical-pharmacological investigations on interactions between cyclo-oxygenase inhibitors and beta-adrenoceptor blocking agents continuing, indometacin and acetylsalicylic acid (ASA) were added to a monotherapy of talinolol in two groups of hypertensive outpatients. Both added drugs reduced slightly the blood pressure lowering effect of talinolol, but did not alter its negative chronotropic effect. Indometacin abolished a talinolol-induced increase in serum triglycerides and caused a small decrease in serum cholesterol. ASA diminished slightly blood glucose. Probably the observed interactions and side effects are not important practically.
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The influence of dipyridamole, given by a bolus injection (30 mg i. v.) on the synthesis of prostacyclin-like substances (PGI2-LS) in human shank varicose veins was investigated. The pretreatment with dipyridamole enhances the second step in PGI2 biosynthesis (transformation of endoperoxide to PGI2) in these preparations.
The effect of the cycloocygenase inhibitor indometacin (Indo) on the synthesis of prostacyclin-like substances (PGI2-LS) in human veins has been studied after in vivo and in vitro application of the drug. PGI2-LS were bioassayed by ADP-induced platelet aggregation during twenty minutes incubation time. We used human veins of varicose patients, which were removed during stripping operations. Indo was applied by rectal application in vivo or added to the incubation fluid. The synthesis of PGI2-LS was inhibited by Indo in both experiments in a time dependent manner.
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Using a volume-controlled infusion pump, a mean serum plateau level of digoxin of 4-5 ng/ml was rapidly achieved and maintained in 6 healthy volunteers. The infusion scheme was calculated on the basis of data published on the pharmacokinetics and pharmacodynamics of digoxin following bolus intravenous injection. The magnitude of the response (change in electromechanical systole) at the end of the plateau phase was comparable to that observed with the concentration in the therapeutic range at steady state.
1 The relationship between the blood pressure fall, induced by antihypertensive drugs or bleeding, and the formation of prostacyclin (PGI2)-like activity in the thoracic aorta of spontaneously hypertensive rats has been investigated. Inhibition of ADP-induced platelet aggregation was used to assess PGI2-like activity. 2 The decreases in blood pressure produced by clonidine, dihydralazine and prazosin were associated with increases of PGI2-like activity of 50-80%. The increase in PGI2-like activity correlated well with the blood pressure decrease, independently of the mechanism of the fall in blood pressure.