Search PubMed⌕ Search

Biomedical subjects

M Schramm

Publications and source records attributed to M Schramm.

At least 91 records · Page 5Linked to original sources

Effect of potassium adaptation on the distribution of potassium, sodium and chloride across the apical membrane of renal tubular cells.

To assess the effect of K adaptation on the electrolyte concentrations of renal tubular cells and on the concentration gradients across the luminal membrane, electron microprobe analysis was employed on freeze-dried cryosections of the renal cortex and on freeze-dried samples of tubular fluid in control and high-K rats. The measurements were performed in individual cells of the proximal and superficial distal tubule and on samples of tubular fluid obtained by free flow micropuncture from proximal and early and late distal collection sites. The ingestion of a potassium-rich diet for at least 10 days together with an acute potassium load of 0.4 mmol/kg/h led to a small increase in potassium concentration of about 7 mmol/kg wet weight (w.w.) in all cell types analysed. In distal convoluted tubule, connecting tubule and principal cells sodium concentration was markedly decreased by 4, 4, and 6 mmol/kg w.w., respectively, while no significant changes in sodium concentration were found in proximal tubule and intercalated cells. No consistent changes in cell chloride could be observed under K adaptation. Analysis of the tubular fluid samples showed that the K concentration gradient across the apical cell membrane of all distal tubular cell types investigated was diminished in the high-K rats. The concentration gradient for sodium entry, however, was clearly enhanced in the distal convoluted tubule, connecting tubule and principal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Calcium-agonists.

In contrast to nifedipine-like calcium antagonists, calcium agonistic 1,4-dihydropyridines have vasoconstricting and positive inotropic properties. BAY K 8644 has become the prototype of this new class. Its enantiomers show opposite effects on the calcium channel: one acts as a calcium agonist with the pharmacological profile of the racemic compound, its antipode has calcium antagonistic effects at 10 times higher concentrations. Voltage clamp studies reveal calcium current increasing effects at 3 X 10(-8) mol/l BAY K 8644, while the current is reduced at 3 X 10(-6) mol/l. Analysis of the calcium current activation and deactivation kinetics shows that BAY K 8644 leaves the mean closed times of the calcium channel unchanged while it increases the mean open times. From these data a reaction model of drug action is derived, suggesting that BAY K 8644 binds only to the open state of the Ca-channel.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

High potency congeners of isoproterenol. Binding to beta-adrenergic receptors, activation of adenylate cyclase and stimulation of intracellular cyclic AMP synthesis.

The potency of a p-toluide derivative and a p-trifluoromethyl derivative of isoproterenol on the beta1 receptor of turkey erythrocytes and on the beta2 receptor of S49 lymphoma cells was measured in comparison with isoproterenol. Binding assays showed that the p-trifluoromethyl derivative possessed an affinity for the receptor, which was two hundred times higher than that of isoproterenol, in the case of turkey erythrocytes, and sixty times higher in the case of the S49 cells. By measuring the Kact of adenylate cyclase, the activity of the p-trifluoromethyl derivative was thirty to forty times higher than that of isoproterenol for the turkey erythrocyte membrane as well as for the S49 lysed cells. In stimulation of intracellular cyclic AMP accumulation, the Kact showed that the p-trifluoromethyl derivative was forty and twenty times more active than isoproterenol in turkey erythrocytes and in S49 cells, respectively. The p-toluide derivative gave similar results. The superior affinity of the above isoproterenol congeners for both beta 1 and beta 2 adrenergic receptors makes these compounds excellent candidates for use as labeled agonist ligands in studies of beta receptors. The possibility is discussed that the relatively large substituent on the amino group of the catecholamine congeners might perhaps bind to lipids associated with the receptor.

Adenylyl Cyclases↗

Modulation of calcium channel function by drugs.

Calcium channel blocking drugs, or "calcium antagonists", have been increasingly used in the last decade, both as valuable cardiovascular drugs, and as tools to investigate the pharmacology of the calcium channels which play a vital role in the excitation-activation coupling of many excitable cells. Three important developments, "patch clamping" to investigate single calcium channels, ligand binding studies to investigate the calcium antagonist "receptor sites", and the introduction of novel calcium channel activators, or "calcium agonists", have recently led to greater understanding of the mechanism of action of drugs on the calcium channel. We show here how the calcium channel modulators interact with the binding sites to increase or decrease calcium flux, and hence to modulate the activity of many excitable tissues. We predict that these new developments will soon result in the isolation of purified calcium channels, and investigation of their subtypes and drug sensitivities. This information could lead to the introduction of novel, more selective calcium antagonists for a variety of indications such as atherosclerosis or neurological disorders. Of particular interest is the potential of tissue-selective calcium agonistic drugs to combat cardiac failure or endocrinological disorders.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

The optical isomers of the 1,4-dihydropyridine BAY K 8644 show opposite effects on Ca channels.

The optical isomers of the 1,4-dihydropyridine BAY K 8644 were studied in isolated rabbit aorta and heart preparations. The (-)-enantiomer has the known vasoconstricting and positive inotropic properties of the Ca agonistic compound. In contrast, its antipode shows at about 10-50 times higher concentrations the vasodilating and negative inotropic effects of Ca antagonistic drugs. It is concluded that neither simple chemical nor physical actions can be responsible for the opposite effects of Ca antagonistic and Ca agonistic dihydropyridines.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Lipid requirements for reconstitution of the delipidated beta-adrenergic receptor and the regulatory protein.

The role of lipids in the interaction of the beta-adrenergic receptor (R) with the regulatory protein (Gs) was investigated. Solubilized preparations of R and of Gs from turkey erythrocytes were delipidated by gel filtration. They were subsequently combined and reconstituted by the addition of various lipids. When reconstitution was carried out in the presence of soybean lipids, Gs could be fully activated via R by addition of hormone plus GTP gamma S. In contrast, purified phospholipids or a phospholipid fraction from soybean failed to produce an active system. Fractionation of soybean lipids revealed that acetone-soluble neutral lipids are essential for the reconstitution of a hormone responsive system. The acetone fraction could be replaced by specific neutral lipids such as alpha-tocopherol or cholesteryl arachidonate while a mixture of phosphatidylethanolamine, -choline and -serine satisfied the phospholipid requirement of the system.

Animals↗

[Determination of 5-methoxypsoralen in suntan cosmetics].

A method for the determination of 5-methoxypsoralene in suntan-cosmetics is described. After liquid chromatographic clean-up, the final extract is screened by twodimensional thin layer chromatography. For positive extracts 5-methoxypsoralene is analysed quantitatively by capillary gas chromatography, using 5-alpha-cholestane as an internal standard and flame ionization detection (FID). The results were confirmed by gas chromatography-mass spectrometry (GC-MS). The recoveries for suntan-cosmetics of emulsion type were 70% and for tanning oils 90%. Detection limits of the method were 0,1 to 0,5 mg/kg, depending on the sample type. By application of this method 5-methoxypsoralene was detected in 6 of the 21 cosmetic products at levels up to 28 mg/kg.

5-Methoxypsoralen↗

Cardiovascular effects of the calcium-agonistic dihydropyridine BAY K 8644 in conscious dogs.

The hemodynamic effects of the dihydropyridine-derivative BAY K 8644 (methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoro-methylphenyl)-pyridine-5-carboxylate), a chemical analogue of Nifedipine, were evaluated in 9 conscious, chronically instrumented dogs. Compared to Nifedipine, BAY K 8644 displays an opposite pharmacological profile. Dose-dependent hemodynamic effects are observed at doses of 4 micrograms/kg i.v. and above. With 32 micrograms/kg i.v. BAY K 8644 increases total peripheral vascular resistance by 100%. It causes a rise of both, systolic and diastolic, blood pressure up to 196/138 mm Hg at spontaneous sinus rhythm and up to 216/162 mm Hg when keeping heart rate constant at 150 beats/minute. Spontaneous heart rate reflexly drops to 52 beats/minute. Cardiac contractility as indicated by LV(dP/dt)max markedly increases from 2800 to 5600 mm Hg/s at spontaneous sinus rhythm and from 2900 to 6100 mm Hg/s while pacing at 150 beats/minute. These effects are apparently neither affected by alpha-adrenergic blockade with Phenoxybenzamine (5 mg/kg i.v.) nor by beta-blockade with Propranolol (0.5 mg/kg i.v.) but can be reserved by equivalent doses of Nifedipine. In conclusion, the Calcium-agonistic dihydropyridine BAY K 8644 due to its novel mechanism of action could be the precursor of a new class of positive inotropic or antihypotensive drugs.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Calcium channel modulators and calcium channels.

In recent years calcium has become recognized as an important 'second messenger', in that an increase in free intracellular calcium ion concentration is involved in many aspects of cellular activation. In excitable cells such as smooth muscle or cardiac tissue an influx of extracellular calcium ions through voltage sensitive calcium channels plays a major role in increasing the cytoplasmic free calcium concentration. It is now known that the activity of these calcium channels may be inhibited or stimulated by a range of ions, toxins and drugs. This article outlines the biochemistry and pharmacology of these 'calcium modulators', and discusses their present and future role as both biological tools, and as potent and selective drugs.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Calcium agonism, a new mechanism for positive inotropy. Hemodynamic effects and mode of action of BAY K 8644.

BAY K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyl -phenyl)-pyridine-5-carboxylate] is a nifedipine-like 1,4-dihydropyridine (DHP). In contrast to the well-known calcium antagonistic DHPs, it has vasoconstricting and positive inotropic properties. In the pentobarbital-anesthetized dog, it increases blood pressure, peripheral resistance, and left ventricular (dP/dt)max dose-dependently from 3 to 100 micrograms/kg i.v. If the vagus is blocked, heart rate is unchanged. In the isolated isovolumic perfused guinea pig heart, BAY K 8644 has positive inotropic and coronary constricting actions from 10(-9) mole/liter. At 10 times higher concentrations, this compound also increases the heart rate up to 20%. BAY K 8644 has no effect on rabbit aortic strip at physiological K+ concentrations, but potentiates the K+ -induced contraction of the strip. In the partially depolarized aortic strip (18 mM K+), BAY K 8644 induces concentration-dependent contractions, which are competitively inhibited by the calcium-antagonistic DHP nifedipine. Chemically different calcium antagonists such as verapamil or diltiazem inhibit the BAY-K-8644-induced contractions noncompetitively. These results indicate that a specific DHP receptor exists, which binds nifedipine and BAY K 8644. In contrast to the calcium-antagonistic DHPs like nifedipine, BAY K 8644 increases the calcium influx into the cell.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Message transmission: receptor controlled adenylate cyclase system.

The adenylate cyclase system is composed of an activating hormone or neurotransmitter (H), its receptor (R), the guanosine triphosphate (GTP) binding protein (Gs), and the catalytic unit (C). The activation of the receptor R involves a transient change in conformation, from a loose binding of the neurotransmitter H to an extremely tight interaction, termed locking. The system is regulated in the activation steps and also by three deactivation processes. A guanosine triphosphatase activity is built into the Gs protein so that the active GsGTP has only a limited lifetime during which it is able to activate C. In addition, the continued occupation of R by H causes desensitization of R. Finally, there are inhibitory receptors, such as alpha-adrenergic and opiate receptors, which inhibit the adenylate cyclase by way of a specific GTP binding protein (Gi). Yet to be determined are the conformational transformations of pure R on binding of an agonist or a partial agonist; the genes that code for the many different receptors that activate the adenylate cyclase, and the possibility that the G components interact with systems in the cell other than the adenylate cyclase.

Adenylyl Cyclases↗

Aztreonam compared with gentamicin for treatment of serious urinary tract infections.

52 patients with serious urinary tract infections were randomised to receive either aztreonam (35) or gentamicin (17). In the aztreonam group 23 patients had unqualified cures, 6 cures with relapse, and 6 cures with reinfection; the comparable numbers in the gentamicin group were 9, 1, and 4. There were no failures with aztreonam and 3 with gentamicin. The most important determinant of outcome was the presence or absence of urological abnormalities. 11 further patients, with renal failure or gentamicin-resistant isolates, treated with aztreonam were all cured. Toxic effects were limited to symptomless liver-function-test abnormalities with aztreonam , whereas deterioration in renal function occurred in 4 gentamicin-treated subjects. Urinary colonisation with group D streptococci occurred in 14 of 46 aztreonam -treated patients (1 required treatment) compared with only 1 of 17 gentamicin-treated patients. 97% of 309 consecutive gram-negative urinary isolates tested, including 50 Pseudomonas aeruginosa, were susceptible in vitro to aztreonam and 91% to gentamicin. Aztreonam may prove an effective and safe alternative to the aminoglycosides.

Adolescent↗

The beta-adrenergic receptor survives solubilization in deoxycholate while forming a stable association with the agonist.

Agonist, but not antagonist, protects the beta-adrenergic receptor from inactivation during solubilization in deoxycholate. Protection is apparently due to locking of the agonist in the receptor, a high affinity interaction induced or stabilized by this detergent. The guanyl nucleotide-binding protein which normally interacts with the receptor to induce high affinity binding of the hormone is apparently not required in this agonist-specific locking process. It is therefore possible that deoxycholate mimics the effect of the guanyl nucleotide-binding protein on the conformation of the hormone-occupied receptor. The experiments further show that the receptor in deoxycholate is quite stable for days, provided that it is occupied by the agonist. Removal of deoxycholate brings about the release of the locked agonist and the return of the receptor to the dynamic functional state.

Adenylyl Cyclases↗

Delipidation of a beta-adrenergic receptor preparation and reconstitution by specific lipids.

The role of lipids in the function of membrane receptors for hormones and neurotransmitters is still obscure. To gain information on this subject, a delipidated receptor preparation was developed. The beta-adrenergic receptor from turkey erythrocyte membranes was solubilized in deoxycholate and was freed extensively of phospholipids and of cholesterol by gel filtration. The delipidated preparation, after removal of the detergent, showed little, if any, ligand binding to the receptor as measured with the beta-adrenergic antagonist [125I] iodocyanopindolol. Readdition of soybean lipids restored specific radioligand binding. The lipid reconstituted receptor demonstrated agonist and antagonist binding affinities which were not very different from those of the native receptor. The receptor also retained its ability to function, as demonstrated by transfer to a foreign adenylate cyclase system. The delipidated receptor preparation lent itself conveniently to study the requirement for specific lipids in restoration of agonist and antagonist binding. Phosphatidylethanolamine restored maximal binding. Acidic phospholipids and sphingomyelin were inefficient in reconstitution of the receptor. The effect of cholesterol addition was also investigated. Binding was dramatically increased when a cholesterol ester was added in mixture with the acidic phospholipids, cardiolipin or phosphatidylinositol. Further studies unexpectedly revealed that reconstitution of the delipidated receptor is not exclusively dependent on the addition of a phospholipid; a mixture of 1-monooleylglycerol with cholesteryl hemisuccinate restored binding as efficiently as phosphatidylethanolamine. The presently described preparation should be useful in elucidating the part played by lipids in the action of the receptor in the adenylate cyclase system.

Adenylyl Cyclases↗