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Biomedical subjects

F Lembeck

Publications and source records attributed to F Lembeck.

At least 19 recordsLinked to original sources
PubMed1992

CP-96,345, a non-peptide antagonist of substance P: I. Effects on the actions mediated by substance P and related tachykinins on the guinea-pig ileum and rabbit jejunum.

The effects of a non-peptide antagonist of substance P, CP-96,345, were investigated, in vitro, on the guinea-pig ileum and the rabbit jejunum. Contractions of the guinea-pig ileum, induced by substance P and neurokinin A, were specifically inhibited by the racemate (+/-)CP-96,345 (pIC50 7.8 and 7.3, respectively). The inhibition by (+/-)CP-96,345 of contractions evoked by neurokinin B and by bradykinin (pIC50 6.1 and 4.9, respectively) was attributed to unspecific effects of the antagonist. The inhibition of substance P-induced contractions of the rabbit jejunum required a 10 times higher concentration of (+/-)CP-96,345 (pIC50 = 6.8) than was required with the guinea-pig ileum. The plateau phase of contraction of the guinea-pig ileum induced by high concentrations of substance P, neurokinin A or neurokinin B, which is known to be mediated through tachykinin receptors on intrinsic cholinergic neurones, was inhibited by 200 nM (+/-)CP-96,345 but not by the inactive enantiomer, CP-96,344. This indicates a specific inhibition of these neuronal tachykinin receptors by (+/-)CP-96,345. Contractions known to be mediated by the release of substance P, such as those evoked by capsaicin and by mesenteric nerve or field stimulation, were partially inhibited by (+/-)CP-96,345 at concentrations of 200 to 600 nM. Unspecific inhibitory effects of CP-96,345, in concentrations of 1 microM or higher, were observed on histamine-induced contractions, and on the cholinergic twitch response to electrical stimulation, of the guinea-pig ileum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

CP-96,345, a non-peptide antagonist of substance P: II. Actions on substance P-induced hypotension and bronchoconstriction, and on depressor reflexes in mammals.

In order to extend the in vivo pharmacological profile of CP-96,345 ((2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)- methyl)-1-azabicyclo[2.2.2]octan-3-amine dihydrochloride), a non-peptide antagonist of substance P, the compound was tested against substance P-induced effects on blood pressure in rabbits and on respiration pressure in guinea-pigs. In addition, CP-96,345, and its inactive (2R,3R)-enantiomer, CP-96,344, were also tested in 2 models involving presumably substance P-mediated reflexes in the rat. The fall in blood pressure evoked by i.v. injections of substance P in the rabbit was inhibited by 0.3 mumol kg-1 CP-96,345 i.v. for at least 30 min, and almost abolished, for at least 2 h, by 3 mumol kg-1. In guinea-pigs, the bronchoconstriction induced by i.v. injections of substance P, but not that in response to histamine or bradykinin, was inhibited by CP-96,345 (0.6 and 6.0 mumol kg-1, i.v.) in a dose-dependent manner and this inhibition lasted for 40 min and 70 min, respectively. CP-96,345 (3-20 mumol kg-1, i.v.) reduced depressor reflexes in response to stimulation of peripheral capsaicin-sensitive neurones in the rat. However, the inhibition was not dose-dependent and was also seen with the inactive enantiomer, CP-96,344. This effect can hardly be attributed to receptor-specific effects of CP-96,345 and may be related to unspecific actions such as those involved in the cardiac depression exhibited by both enantiomers. The present results show that CP-96,345 is a potent antagonist of substance P in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

CP-96,345, a non-peptide antagonist of substance P. III. Cardiovascular effects in mammals unrelated to actions on substance P receptors.

The cardiovascular effects of CP-96,345, a non-peptide antagonist of substance P, were analyzed in vivo and in vitro. In the anaesthetized rat, the i.v. injection of 3 mumol kg-1 of CP-96,345 induced a fall in mean arterial blood pressure and a reduction in heart rate. Similar effects were obtained with the enantiomer CP-96,344 (2R,3R)-cis-isomer of CP-96,345) which does not interact with substance P receptors. Both enantiomers, at a concentration of 10 microM, decreased the beating frequency of the isolated atria and of the isolated perfused heart of the guinea-pig to a similar extent, and caused transient coronary dilatation. CP-96,345 (10 microM) decreased the spontaneous sinus rate, prolonged the atrioventricular-nodal conduction interval and the His-bundle conduction interval of the perfused guinea-pig heart. The intraventricular spread of conduction was markedly inhibited. During programmed stimulation 10 min after the beginning of the drug application, the effective refractory periods evaluated by stimulation with premature beats, as well as rate dependent effective refractory periods, of the atrioventricular node, of the atrial and of the ventricular myocardium, were prolonged. Sinus node recovery time was also prolonged. It was concluded that these cardiac effects of CP-96,345 were not caused by an action of the compound on substance P receptors.

Anesthesia↗
PubMed1992

The non-peptide tachykinin antagonist, CP-96,345, is a potent inhibitor of neurogenic inflammation.

1. Release of the tachykinin, substance P, from the peripheral terminals of polymodal afferent C-fibres is thought to be largely responsible for the vasodilatation and plasma protein extravasation described as neurogenic inflammation. The effects of CP-96,345, a non-peptide antagonist at the substance P (NK1) receptor, on these vascular reactions were investigated in the rat. 2. Intravenously (i.v.) injected CP-96,345 (0.4-3.0 mumol kg-1) prevented the drop in blood pressure, a measure of the peripheral vasodilatation, evoked by substance P and neurokinin A in a dose- and time-dependent manner, but did not affect that elicited by the non-tachykinin peptides calcitonin gene-related peptide and vasoactive intestinal polypeptide. 3. Plasma protein extravasation evoked by i.a. infusion of substance P, antidromic stimulation of the saphenous or the vagus nerve, and stimulation of cutaneous afferent nerves with mustard oil, were each significantly inhibited by CP-96,345 (3.0-9.0 mumol kg-1, i.v.). Furthermore, CP-96,345 was orally active in blocking mustard oil-induced plasma extravasation with an ED50 of 10 mumol kg-1. 4. The inhibition of substance P-induced vasodilatation and of neurogenic plasma extravasation by CP-96,345 was stereospecific as the inactive isomer CP-96,344 (2R, 3R enantiomer of CP-96,345) had no effect. 5. Thus CP-96,345 is a specific, highly potent, long-acting and orally active inhibitor of tachykinin-mediated neurogenic inflammation.

Animals↗
PubMed1992

Effects of the bradykinin antagonist, HOE 140, in experimental acute pancreatitis.

1. The novel bradykinin antagonist, HOE 140, completely blocked the fall in rabbit blood pressure caused, not only by i.v. bradykinin, but also by i.v. kallikrein. This shows that both the effects of exogenously administered bradykinin and those of endogenously released kinins are antagonized by HOE 140. 2. Acute pancreatitis was induced in rats by i.v. infusion of the cholecystokinin analogue, caerulein. This treatment resulted in massive oedema of the pancreas, increased activities of amylase and lipase in serum and a characteristic, biphasic fall in blood pressure. 3. HOE 140 prevented the caerulein-induced pancreatic oedema and the second phase of hypotension whereas NPC 349, a widely used, but short-acting, bradykinin antagonist did not show a significant inhibition. HOE 140, in contrast to its inhibitory effects on caerulein-induced pancreatic oedema and hypotension, significantly augmented the increases in amylase and lipase activities in serum. 4. It is concluded that in this model of acute pancreatitis, the release of kinins induces pancreatic oedema and hypotension. Prevention by HOE 140 of the kinin-induced oedema allows the pancreatic enzymes to leave the tissue without hindrance and thus will diminish subsequent pathological events. It is suggested that the results obtained with the highly potent and long-acting bradykinin antagonist, HOE 140, provide a pharmacological basis for a clinical trial in acute pancreatitis.

Acute Disease↗
PubMed1992

Lack of significant unspecific effects of HOE 140 and other novel bradykinin antagonists in vitro and in vivo.

The novel, potent and long-acting bradykinin (BK) antagonists, HOE 140, compound II and compound III, slightly decreased blood pressure, but did not affect heart rate and respiration of rats. The antagonists did not cause bronchoconstriction in guinea-pigs. Neither HOE 140 nor BK released histamine from isolated perfused hindlegs of rats. The lack of significant unspecific side effects of the novel antagonists of effective doses will further increase the usefulness of these compounds for experimental and therapeutic purposes.

Animals↗
PubMed1992

[Pain and stress: biological protection].

The biological methods of animal organism protection, the role of stress and the nociceptive signals, the hierarchy of defence mechanism--from the autonomic reflexes, neuroendocrine regulations, emotional reactions and expressions up to peculiar to the human being intellectual safeguard have been considered. The latest data on the role of tachykinins in transmission have been examined. The discovery of mediator function of "substance P" (SP), other related peptides, which coexists and realizes from the primary afferents and other terminals of SP-containing, capsaicin-sensitive neurons--opened a new chapter in the neurobiology and medicine. The necessity to support the medico-biological (fundamental) experiments by the modern society is grounded.

Adrenal Glands↗
PubMed1979

Nociceptive threshold after neonatal capsaicin treatment.

The nociceptive threshold as determined by the reaction time in the hot-plate and tail-flick tests was measured 3 to 4 months after pretreatment of young rats with capsaicin (50 mg kg-1 s.c.). The reaction time in the tail-flick test was prolonged in rats pretreated with capsaicin on the 2nd day of life. Capsaicin pretreatment up to the 10th day of life also resulted in a prolonged reaction time in the hot-plate test whereas capsaicin pretreatment after the 10th day of life was without effect. The elevation of the nociceptive threshold after neonatal capsaicin pretreatment most likely follows from degeneration of afferent nerve fibres activated by noxious stimuli.

Animals↗
PubMed1979

Longitudinal contraction of isolated guinea-pig ileum induced by rapid cooling.

1. Rapid change of bath temperature from 37 degrees C to 27 degrees C and vice versa caused longitudinal contraction of the isolated guinea-pig ileum. 2. Tetrodotoxin, tropicamide, noradrenaline, isoprenaline, morphine, and the met-enkephalin analogue FK 33-824 depressed the responses or accelerated the fade of the contraction induced by rapid cooling when added after the response had reached its maximum. 3. Hexamethonium had no influence on the responses. 4. Physostigmine potentiated all responses and reversed the fade of contraction induced by rapid cooling when added after this contraction had reached its maximum. 5. The effects of rapid cooling or warming were not altered in preparations made tachyphylactic to substance P; the response to rapid warming, but not cooling, was partially inhibited under tachyphylaxis to 5-hydroxytryptamine. 6. Antazoline, phentolamine, naloxone, and indomethacin did not block the responses. 7. Capsaicin firt potentiated and subsequently depressed the responses to both rapid cooling and warming. 8. The results indicate that rapid change of bath temperature induces longitudinal contraction by excitation of postganglionic cholinergic fibres.

Animals↗
PubMed1979

Inhibition of PGE1 induced intestinal secretion by the synthetic enkephalin analogue FK 33-824.

1. The effects of the enkephalin analogue, FK 33-824 were compared with those of morphine and naloxone on the prostaglandin E1-induced increase in intestinal fluid volume and unanaesthetized and pithed rats. 2. FK 33-824 inhibits the prostaglandin E1-induced increase in intestinal fluid volume both in unanaesthetized and pithed rats. 3. Naloxone abolished the inhibitory effect of FK 33-824 in both experimental models. 4. It can be concluded from the experiments in pithed rats that the inhibitory effect of FK 33-824, like that of morphine, on prostaglandin E1-induced secretion is caused by a peripheral action. 5. It is assumed that endogenous enkephalins protect against prostaglandin-mediated loss of fluid into the gut lumen. This protective effect can be mimicked by an enkephalin analogue and blocked by naloxone.

Animals↗
PubMed1979

Indirect evidence for presynaptic location of opiate receptors on chemosensitive primary sensory neurones.

1. Rats were pretreated with 50 mg/kg s.c. capsaicin or solvent on the second day of life; 5 months later 3H-diprenorphine binding to homogenates of the whole spinal cord or of the upper dorsal horn of the spinal cord was investigated. 2. Capsaicin pretreatment resulted in a 17% decrease of opiate binding sites in the whole spinal cord and a 37% decrease in the upper dorsal horn with no change in their affinity. 3. Since neonatal capsaicin pretreatment causes degeneration of chemosensitive primary sensory neurones it is concluded that some opiate receptors are located presynaptically on the central terminals of these neurones.

Animals↗
PubMed1979

Substance P: model studies of its binding to phospholipids.

1. The partition of substance P (SP) between buffer solutions (pH 1.6--7.8) and an organic, phospholipid (phosphatidyl serine, phosphatidyl ethanolamine, phosphatidyl inositol and phosphatidyl choline) containing phase (chloroform:methanol 2:1) was studied. 2. The binding of SP to phosphatidyl serine, phosphatidyl ethanolamine and phosphatidyl inositol was lowest at pH 2 and increased with pH. The binding to phosphatidyl choline was much smaller and less dependent on pH. 3. In contrast to the basic peptide SP (pI 10.5), physalaemin (pI 7.0) did not show any binding to phospholipids at any investigated pH value which underlines the importance of a basic group in the peptide for its binding. 4. The high affinity (KD = 0.1 microM) and capacity of 44 pmol SP/microgram phosphatidyl serine and 48 pmol SP/microgram phosphatidyl ethanolamine at pH 7.2 under conditions of saturation contrasted with the very low binding of SP to phosphatidyl inositol or phosphatidyl choline. Ionic bindings between the basic peptide and phosphatidyl serine or phosphatidyl ethanolamine are regarded to be predominant, although other binding forces cannot be excluded. 5. There was a concentration-dependent reduction in the binding of SP to phosphatidyl serine or phosphatidyl ethanolamine by Na+ and Ca2+, whereas K+ showed hardly any effect at physiological concentrations. 6. The model studies served to consider the possibilities of the binding of a basic peptide to lipid storage or receptor sites.

Animals↗
PubMed1979

Substance P in the vagus nerve. Immunochemical and immunohistochemical evidence for axoplasmic transport.

1. The presence of immunoreactive substance P (I-SP) in the vagus nerve of 5 species was demonstrated by radioimmunoassay. Different amounts of SP per unit weight were found: Guinea pig greater than cat greater than rabbit, rat and cattle. 2. Infranodose ligations of the vagus nerve of cats and rabbits caused an accumulation of I-SP proximal but not distal to the ligation. The results obtained by radioimmunoassay and immunohistochemistry indicate a somatofugal axoplasmic transport of SP. 3. Double ligation experiments revealed that about 37% of I-SP of the cat vagus nerve are mobile. The transport rate of this mobile I-SP was found to be 170 mm per day. 4. Locally applied colchicine resulted in a similar accumulation of I-SP as after ligations. This is evidence favouring the involvement of microtubuli in the axoplasmic transport of SP. 5. Immunohistochemical data show that SP-fibers account for about 10% of the axons in the cat vagus nerve. Most of these SP-fibers seem to be unmyelinated. 6. Supranodose extracranial ligations of the cat vagus nerve led to an accumulation of I-SP on both sides of the ligature. Part of the SP-fibers are, therefore, afferent and their cell bodies are located in the nodose ganglion. The presence of efferent SP-fibers cannot be excluded.

Animals↗
PubMed1979

Substance P: characteristics of binding to synaptic vesicles of rat brain.

1. The binding of substance P (SP) to synaptic vesicles from rat brain was studied by use of the 125I-Tyr8-analogue of SP. 2. The pH dependence of the binding of both peptides to the lipid extractable fraction of synaptic vesicles was shown to be comparable. 3. The binding of 125I-Tyr8-SP shows a rate constant of association (k1 = 6.6 x 10(6) M-1 S-1), a rate constant of dissociation (k-1 = 6.4 x 10(-4) S-1) and gives a KD of 1 x 10(-10) M. Kd derived from equilibrium studies was 3.2 x 10(-10) M. 4. The binding of 125I-Tyr8-SP to lipids of synaptic vesicles was shown to be reversible, saturable and highly specific. 5. The kinetic data suggest one population of binding sites with a maximal number of 0.8 pmol per mg protein of the synaptic vesicle preparation. 6. Unlabeled SP and the (2--11)-, (3--11)- and (4--11)-analogues of SP inhibit the binding of 125I-Tyr8-SP in a decreasing order in a competitive way when added in excess. Tyr8-SP and eledoisin did not interfere with the binding of 125I-Tyr8-SP whereas uperolein and neurotensin caused a partial inhibition. Physalaemin and D-Ala2-D-Met5-enkephalin enhance the binding of 125I-Tyr8-SP in a cooperative way.

Animals↗