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Biomedical subjects

H W Kosterlitz

Publications and source records attributed to H W Kosterlitz.

At least 91 records · Page 5Linked to original sources
PubMed1978

Factors influencing the release of acetylcholine from the myenteric plexus of the ileum of the guinea-pig and rabbit.

1 The effects of electrical stimulation, changes in external ion concentrations and various drugs on acetylcholine release from the myenteric plexus were measured by bioassay in the presence of physostigmine and by recording the responses of the longitudinal muscle. In preparations from the guinea-pig, the acetylcholine output per pulse increased with decreasing frequency of stimulation and reached its maximum at a frequency of 0.017 Hz (1/min) and thus ensured that the output per unit of time was constant at frequencies below 0.5 Hz. Spontaneous release was suppressed during stimulation at 0.017 Hz. 2 In the rabbit, the fractional acetylcholine release was lower than in the guinea-pig. The output per pulse increased with decreasing frequency of stimulation but at a lesser rate, with the effect that the output per unit decreased between 0.5 and 0.017 Hz. 3 In the guinea-pig, reduction of the Ca2+ concentration, addition to the bath fluid of Mn2+, ganglion-blocking drugs, morphine and catecholamines reduced output more at low than at high frequencies of stimulation. In the rabbit, acetylcholine output was less sensitive to changes in Ca2+ concentration and insensitive to Mn2+ and morphine. 4 In the guinea-pig, morphine and catecholamines depressed both the contractile response and acetylcholine output whereas Mn2+ in concentrations up to 125 muM, bretylium and ganglion-blocking drugs depressed only acetylcholine output. 5 In preparations from the guinea-pig, drugs blocking noradrenergic neurons or alpha-adrenoceptors, e.g. bretylium, phenoxybenzamine, thymoxamine and phentolamine, increased acetylcholine output during stimulation at high (1.5 to 10 Hz) but not at low frequencies. 6 The implications of these findings for the release of acetylcholine from different pools in the heterogeneous myenteric plexus are considered. The possible errors, introduced by the effects of physostigmine, on the size of the acetylcholine pools and on the transmission of impulses within the myenteric plexus are discussed.

Acetylcholine↗
PubMed1978

Comparison of the receptor binding characteristics of opiate agonists interacting with mu- or kappa-receptors.

1 The receptor binding characteristics of various morphine-like and ketazocine-like opiate agonists were measured by inhibition of [3H]-naloxone binding in homogenates of brain and of ileal myenteric plexus-longitudinal muscle of the guinea-pig. No differences were found for the two tissues. 2 The depressant effect of Na+ on the inhibition of [3H]-naloxone binding by opiate agonists varies widely, giving sodium shifts between 5 and 140. The relationship between Na+ concentration and inhibition of binding is non-linear, the magnitude of the sodium shift varying directly with the slope of the regression of log IC50 on log [NaCl]. 3 The sodium shift of ketazocine-like agonists is lower than that of morphine-like agonists but higher than that of opiates with dual agonist and antagonist action. A working hypothesis is proposed which suggests that the kappa-receptors for the ketazocine-like drugs are less susceptible to the Na+ effect than the mu-receptors for the morphine-like drugs. 4 For most of the morphine-like but not the ketazocine-like agonists, a good correlation has been found for the pharmacological activity in the myenteric plexus-longitudinal muscle preparation and the inhibition of binding of [3H]-naloxone at 12 mM Na+. An exception is fentanyl which has a much greater pharmacological potency than may be expected from its potency in inhibiting [3H]-naloxone binding.

Animals↗
PubMed1977

Endogenous opioid peptides: multiple agonists and receptors.

Opioid peptides were assayed by inhibition of 3H-naloxone and 3H-leu-enkephalin binding in brain homogenates and by depression of contractions of the guinea pig ileum and mouse vas deferens. We conclude that the opioid peptidergic system has agonists of different characteristics which interact with more than one type of receptor.

Animals↗
PubMed1977

In vitro pharmacology of the opioid peptides, enkephalins and endorphins.

In the guinea-pig ileum methionine-enkephalin, normorphine and morphine are equipotent in depressing electrically evoked contractions; leucine-enkephalin has about 25% of the activity. The mouse vas deferens is more sensitive to the enkephalins which are 30 to 60 times more potent than morphine. Fragments of beta-lipotropin61-91 (beta-endorphin) having sequences up to LPH76 are more potent in the mouse vas deferens than in the guinea-pig ileum but beta-endorphin is about equipotent in the two preparations. None of the peptides has antagonist activity. Methionine-enkephalin and normorphine are equipotent in inhibiting [3H]-naloxone binding by homogenate of guinea-pig brain in the absence of Na+ while leucine-enkephalin has only 25% of this activity. In the guinea-pig ileum, naloxone antagonises normorhine and the enkephalins equally well whereas in the mouse vas deferens about ten times more naloxone is required for the enkophalins that for normorphine. Methionine-enkephalin depresses output of acetylcholine in the guinea-pig ileum and of noradrenaline in the mouse vas deferens.

Animals↗
PubMed1977

Opiate receptors and endogenous opioid peptides in tolerance and dependence.

The impact of the discovery of the endogenous opioid peptides, the enkephalins and endorphins, on our concepts of the mechanisms of tolerance to, and dependence on, opiates is discussed. After a brief survey of the chemistry of the opioid peptides, the possibility of an interaction between opiates and the peptides is considered and a hypothesis formulated. Experimental proof is presented as far as it has become available. The possible mechanisms involved in the development of tolerance and dependence for alcohol, barbiturates and opiates are compared briefly.

Adenylyl Cyclases↗
PubMed1977

Opioid peptides.

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Analgesia↗
PubMed1977

The distribution of methionine-enkephalin and leucine-enkephalin in the brain and peripheral tissues.

1 A method is described for the rapid extraction of opioid peptides from the brain and other tissues. The method is based on acid extraction of tissues followed by adsorption of the extract onto Amberlite XAD-2 resin. Elution with methanol separates the enkephalins and alpha-endorphin from beta-endorphin.2 Over 90% of the opioid peptide activity isolated from brain and gut of several species by our method was due to methionine- and leucine-enkephalin. In contrast, the major opioid peptide activity recovered from the pituitary was due to peptides of much greater mol. wt. than the enkephalins.3 An opioid peptide with properties unlike those of the known endorphins or enkephalins was present in brain extracts. This peptide, termed epsilon-endorphin, has an apparent mol. wt. of 700 to 1200; it constituted between 5 to 10% of the total opioid activity in our extracts.4 A differential assay of methionine- and leucine-enkephalin was made either by destroying methionine-enkephalin activity with cyanogen bromide or by separating the peptides by thin layer chromatography.5 The ratio of methionine-enkephalin to leucine-enkephalin varied greatly in different brain regions. The highest proportions of leucine-enkephalin were found in the cerebral cortex and hippocampus.6 Formaldehyde perfusion and fixation of the brain in vivo had no significant effect on the brain content of enkephalin, indicating that proteolytic breakdown is not a major problem in the extraction of these peptides.7 It is suggested that the enkephalins may have a neurotransmitter role in both brain and peripheral tissues and that methionine- and leucine-enkephalin may subserve separate neuronal functions.

Animals↗
PubMed1977

Peptides with morphine-like action in the brain.

The reasons which led to the search in the brain for substances with morphine-like actions actions are discussed. Two pentapeptides, methionineenkephalin and leucine-enkephalin, were isolated. The amino acid sequence of methionine-enkephalin occurs also in the pituitary prohormone beta-lipotropin, of which longer fragments (endorphins) of up to 31 amino acids exhibit strong morphine-like action. The physiological significance of these short and long opioid peptides is discussed, particularly with regard to their possible roles as neurotransmitter or neuromodulator. With regard to the mechanisms involved in the development of tolerance to and dependence on opiates, the importance of interaction between the endogenous opioid peptides and the exogenous opiate alkaloids is stressed. The possible therapeutic implications are discussed briefly.

Amino Acid Sequence↗
PubMed1976

Effects of physostigmine and electrical stimulation on the acetylcholine content of the guinea-pig ileum.

Incubation with physostigmine (7.7 muM) caused an approximately 2 fold increase in the acetylcholine content of the myenteric plexus--longitudinal muscle preparation of the guinea-pig ileum. This effect was due mainly to an increase in 'free' acetylcholine, which was directly assayable in either the homogenate after removal of cell debris or the supernatant fraction (100,000 g for 60 min) after subcellular fractionation. Acetylcholine output during stimulation at 0.017, 0.1 or 1 Hz was maintained for 60 min at a rate 2--4 times greater than the non-stimulated output; there was no change in content. At 10 HZ, output was high at the start of stimulation and then decreased continuously; there was a proportionate loss of mainly 'free' acetylcholine from the tissue. Mn2+, hexamethonium, morphine and noradrenaline, which depressed acetylcholine output during stimulation at 0.1 HZ, had no effect on the acetylcholine content nor did they affect the increase in acetylcholine content during incubation with physostigmine.

Acetylcholine↗