Actions of derivatives of cyclic nucleotides on dispersed acini from guinea pig pancreas. Discovery of a competitive antagonist of the action of cholecystokinin.

Peikin, Steven R.; Costenbader, Cynthia L.; Gardner, Jerry D.

doi:10.1016/s0021-9258(18)50598-6

Cited by 153 publications

(3 citation statements)

References 14 publications

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“…It is seen that caerulein evokes an inward current and that the inward current response is sustained for the entire period of stimulation. Cessation of stimulation with simultaneous addition of the specific C C K -Pz antagonist dbcG M P (Peikin et al 1979;) caused an immediate return to the resting situation. A series of short-lasting (100 ms) voltage jum ps of varying m agnitude were applied before and during the period of A detailed ionic analysis of the currents flowing during sustained stimulation has not yet been carried out, but since the reversal potential for the secretagogue-evoked currents is of nearly the same m agnitude during sustained stimulation as in the initial phase of stimulation (short pulse experiments) it is reasonable for the time being to assume th at the ionic events are essentially the same.…”

Section: Secretagogue-evoked Ionic Currents Across the Acinar Membranementioning

confidence: 98%

Ionic currents across pancreatic acinar cell membranes and their role in fluid secretion

Petersen

Maruyama

Graf

et al. 1981

Phil. Trans. R. Soc. Lond. B

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Fluid and enzyme secretion from a number of mammalian exocrine glands is controlled by the action of neurotransmitters and hormones on acinar cell membranes. Sustained stimulation evoking sustained fluid and enzyme secretion also evokes sustained membrane depolarization and increase in conductance. Mouse and rat pancreatic fluid and enzyme secretion, as well as membrane depolarization and conductance increase evoked by sustained stimulation with acetylcholine or cholecystokinin-gastrin peptides, are acutely dependent on extracellular calcium. However, the initial stimulant-evoked conductance increase and secretion appear to be triggered by calcium released from inside the cells. Direct measurement of membrane current during sustained stimulation in voltage-clamp experiments with resolution of the total current into its Na, Cl and K components has allowed calculations of stimulant-evoked Na and Cl uptake into the acinar cells. The NaCl uptake is quantitatively sufficient to account for the stimulant-evoked fluid secretion. The role of the stimulant-evoked transmembrane ionic current appears to be the supply of salt for the fluid secretion. Calcium derived from intracellular sources in the initial phase of secretion, and from the extracellular fluid in the sustained phase, couples fluid and enzyme secretion to hormone-receptor interaction.

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Section: Secretagogue-evoked Ionic Currents Across the Acinar Membranementioning

confidence: 98%

Ionic currents across pancreatic acinar cell membranes and their role in fluid secretion

Petersen

Maruyama

Graf

et al. 1981

Phil. Trans. R. Soc. Lond. B

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“…In another series of experiments, the effect of CCK was investigated in the presence of the CCK antagonist dibutyryl cyclic GMP (Peikin et al, 1979;Philpott and Petersen, 1979;Jensen et al, 1980). In these cases, CCK always failed to activate the unitary inward currents, but after excision of the patch and exposure of the inner aspect of the membrane to the high Ca2+ concentration of the bath (in most cases 1 mM), single-channel currents of the usual type were invariably observed (Maruyama and Petersen, 1982b).…”

Section: Indirect Activation Of Unitary Inward Currents By Cholecystokinin and Acetylcholine In The Cell-attached Recording Configurationmentioning

confidence: 99%

Bursts of Openings in Transmitter-Activated Ion Channels

Colquhoun¹,

Sakmann²

1983

Single-Channel Recording

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Single-channel recording has become a widely used tool for the study of ion permeation mechanisms in biological membranes. Whereas the technique might have been considered an "art" after its introduction in 1976, it developed into a relatively simple method after it became possible to obtain high-resistance (several gigaohm) membrane-pipette seals. In the summer of 1982, a course on the technique was held at the Ettore Majorana Center for Scientific Culture in Erice, Sicily. It brought together people from most of the laboratories involved in patch clamping at that time. During the course, it became apparent that the technique had reached a state of maturity. Repeatedly, the opinion was expressed that a detailed description of all the aspects of the technique including representative examples of results should be available. We therefore asked the course instructors, as well as several other colleagues, to provide chapters on selected topics in order to produce this volume.The different variants of patch clamping were described quite extensively in an article by Hamill, Marty, Neher, Sakmann, and Sigworth (Pflugers Archiv 391:85) in 1981. Rather than repeating this survey in an introductory chapter, we chose to reprint that article in the Appendix of this volume (by permission of Springer-Verlag). The methods section will, therefore, go straight into detailed aspects of the technology. The second section on Concepts and Analysis is intended to provide an understanding of the statistical methods suitable for the interpretation and analysis of experimental results. The third section gives representative examples of patchclamp results from many of the fields to which the technique has so far been applied. We hope that this volume will prove useful to anyone who wishes to do singlechannel recording or to understand the results of such experiments.We would like to thank the Ettore Majorana Center for Scientific Culture as well as the European Molecular Biology Organization for providing and funding a pleasant nucleus for this volume. We also express our thanks to Ms.

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“…Compound 11 (6 g, 12.8 mmol) dissolved in 30 mL of a TFA-CH2C12 (1/1) mixture was stirred at 0 °C for 1 h and at room temperature for 1 h, yielding after evaporation, precipitation, rinsing with dry ether, and filtration, a white solid: 5.45 g (88%); Rf 0.56 (D). Z-Orn(Boc)-Asp(OBzl)-Phe-NH2 (13). To a solution of Z-Orn(Boc)-OH (1.5 g, 2.86 mmol) in 5 mL of dry DMF were added HOSu (330 mg, 2.87 mmol) and DCC (590 mg, 2.87 mmol).…”

Section: Methodsmentioning

confidence: 99%

Boc-Trp-Orn(Z)-Asp-NH2 and derivatives: a new family of CCK antagonists

González‐Muñiz

Bergeron²,

Marseigne³

et al. 1990

J. Med. Chem.

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The respective roles of the benzyloxycarbonyl group (Z) and of the N-terminal tripeptide moiety in the antagonist properties of the cholecystokinin CCK8 analogue Boc-[Nle28,Orn(Z)31]CCK27-33 (Marseigne et al. J. Med. Chem. 1988, 31, 966.) were studied with the following derivatives: Boc-[Nle28,Orn(X)31]CCK27-33, Boc[Nle28,Orn(X)31]CCK27-32, Boc-[Orn(X)31]CCK30-33, and Boc-[Orn(X)31]CCK30-32 (X = Z, Boc, H). These derivatives, the synthesis of eight of which is reported here, were tested for their abilities to inhibit the binding of [3H]pCCK8 to guinea pig pancreatic and brain membranes and for their potencies in stimulating amylase release from guinea pig pancreatic acini. None of the Z derivatives produced amylase secretion, but they competitively antagonized the stimulation induced by CCK8. The deletion of the N-terminal tripeptide and/or Phe-NH2(33) residue did not play a key role in the recognition of peripheral receptors and in the activity of these peptides, whereas replacement of the Z group by a Boc group slightly decreased the affinities of the compounds for both pancreatic and brain binding sites and their potencies as peripheral antagonists. Moreover, the tetrapeptide Boc-Trp-Orn(Boc)-Asp-Phe-NH2 behaved as a partial agonist and analogues in which the Z or Boc groups on the ornithine residue were removed were full agonists. Interestingly, the short peptide derivative Boc-Trp-Orn(Z)-Asp-NH2 displayed the same affinity (KI = 2.0 +/- 0.2 x 10(-7] and the same antagonist activity (pA2 = 6.63) as its parent compound Boc-[Nle28,Orn(Z)31]CCK27-33. This tripeptide could be an interesting tool for studying the structural relationships between peptide and non-peptide CCK antagonists.

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Actions of derivatives of cyclic nucleotides on dispersed acini from guinea pig pancreas. Discovery of a competitive antagonist of the action of cholecystokinin.

Cited by 153 publications

References 14 publications

Ionic currents across pancreatic acinar cell membranes and their role in fluid secretion

Ionic currents across pancreatic acinar cell membranes and their role in fluid secretion

Bursts of Openings in Transmitter-Activated Ion Channels

Boc-Trp-Orn(Z)-Asp-NH2 and derivatives: a new family of CCK antagonists

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