Receptors for secretagogues on pancreatic acinar cells.
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Animals↗
Biomedical subjects
J D Gardner
Publications and source records attributed to J D Gardner.
Derivatives of CCK-(26-32) as cholecystokinin receptor antagonists in guinea pig pancreatic acini.
In the present study we synthesized cholecystokinin-(26-32)-amide [CCK-(26-32)-NH2], N-acetyl-cholecystokinin-(26-32) [Ac-CCK-(26-32)], and N-acetyl-cholecystokinin-(26-32)-amide [Ac-CCK-(26-32)-NH2]. None of these peptides altered amylase secretion from dispersed acini prepared from guinea pig pancreas, but each peptide inhibited the stimulation of amylase secretion caused by the C-terminal octapeptide of cholecystokinin [CCK-(26-33)]. Half-maximal inhibition of CCK-(26-33)-stimulated amylase secretion occurred with 10 microM CCK-(26-32)-NH2, with 25 microM Ac-CCK-(26-32)-NH2, and with 100 microM Ac-CCK-(26-32). Ac-CCK-(26-32) caused a parallel rightward shift in the dose-response curve for CCK-(26-33)-stimulated amylase secretion. Ac-CCK-(26-32)-NH2 inhibited the stimulation of amylase secretion caused by CCK-(26-33), caerulein, or gastrin-(2-17) but did not alter the stimulation caused by carbachol, bombesin, physalaemin, A23187, vasoactive intestinal peptide, secretin, or 8-bromoadenosine 3',5'-cyclic monophosphate. There was a close correlation between the abilities of derivatives of CCK-(26-32) to inhibit binding of 125I-cholecystokinin (125I-CCK) to pancreatic acini and their abilities to inhibit the stimulation of amylase secretion caused by CCK-(26-33). Half-maximal inhibition of binding of 125I-CCK occurred with 5 microM CCK-(26-32)-NH2, with 7 microM Ac-CCK-(26-32)-NH2, and with 70 microM Ac-CCK-(26-32). These findings indicate that each of the three derivatives of CCK-(26-32) is a specific competitive antagonist of the interaction of cholecystokinin with its cell surface receptors on pancreatic acini.(ABSTRACT TRUNCATED AT 250 WORDS)
Amylases↗
Cholecystokinin receptor antagonists.
Since 1979 three classes of cholecystokinin receptor antagonists have been described: 1) derivatives of cyclic nucleotides, 2) derivatives of amino acids, and 3) C-terminal fragments or partial sequences of cholecystokinin. These various antagonists share a number of common features, such as their specific, reversible, and competitive actions, but they vary in the potency with which they inhibit the actions of cholecystokinin.
Amino Acids↗
Receptors for vasoactive intestinal peptide and secretin on rat pancreatic acini.
In dispersed acini from rat pancreas, binding of 125I-labeled vasoactive intestinal peptide and 125I-labeled secretin was relatively rapid, reversible, saturable, and temperature dependent. The rate of dissociation of bound 125I-labeled peptide was not a function of the concentration of free vasoactive intestinal peptide or secretin, indicating that the apparent affinities of these labeled peptides for their binding sites do not depend on the extent of receptor occupation. Four classes of receptors are required to account for the actions of vasoactive intestinal peptide and secretin on enzyme secretion, cellular cAMP, and binding of 125I-vasoactive intestinal peptide and 125I-secretin. One class has a high affinity for vasoactive intestinal peptide, and occupation of this class of receptors causes increased cellular cAMP and stimulation of amylase secretion. A second class has a low affinity for vasoactive intestinal peptide and for secretin, and occupation of these receptors does not cause changes in cAMP or amylase secretion. A third class of receptors has a high affinity for secretin, and occupation of these receptors causes increased cAMP and stimulation of amylase secretion. A fourth class of receptors has a low affinity for secretin, and occupation of these receptors causes stimulation of amylase secretion by a non-cAMP-mediated mechanism.
Amylases↗
Pepsinogen secretion from dispersed chief cells from guinea pig stomach.
In the present study we examined the actions of various secretagogues on pepsinogen secretion from freshly dispersed chief cells prepared from guinea pig stomach. Chief cells were obtained by preparing dispersed gastric glands, subjecting the glands to mechanical disruption in the presence of EGTA, and fractionating the resulting mucosal cells on a Percoll density gradient. Chief cells constituted 90% of the final cell suspension and cell viability was 99%. In these cells, pepsinogen secretion was stimulated by agents whose actions are probably mediated by calcium: carbachol, cholecystokinin, and A23187. Pepsinogen secretion was also stimulated by agents whose actions are probably mediated by cAMP: secretin, vasoactive intestinal peptide, and 8-bromo-cAMP. Reducing the incubation temperature from 37 degrees to 4 degrees C or adding carbonyl cyanide m-chlorophenylhydrazone abolished secretagogue-induced pepsinogen secretion. These results indicate that freshly dispersed chief cells from guinea pig stomach are responsive to secretagogues and provide a suitable model for investigating cellular mechanisms of secretagogue-induced pepsinogen secretion.
8-Bromo Cyclic Adenosine Monophosphate↗
Discovery of a cholecystokinin analogue with partial agonist activity.
In dispersed acini from guinea pig pancreas, cholecystokinin-(27-32)-amide [CCK-(27-32)-NH2] did not stimulate amylase secretion and inhibited the stimulation caused by CCK-(26-33). In dispersed acini from mouse or rat pancreas, CCK-(27-32)-NH2 stimulated amylase secretion. The stimulation of amylase secretion caused by a maximally effective concentration of CCK-(27-32)-NH2 was less than that caused by a maximally effective concentration of cholecystokinin-(26-33), and in contrast to the action of cholecystokinin-(26-33) supramaximal concentrations of CCK-(27-32)-NH2 did not cause submaximal stimulation of amylase secretion. Dibutyryl cGMP and proglumide each inhibited the stimulation of amylase secretion caused by CCK-(27-32)-NH2. CCK-(27-32)-NH2 inhibited binding of 125I-labeled CCK to mouse and rat pancreatic acini. These results indicate that, in mouse and rat pancreatic acini, CCK-(27-32)-NH2 is a partial agonist and that this partial agonist activity is produced by occupation of the CCK receptor by CCK-(27-32)-NH2.
Amylases↗
Localization of islet cell tumors by dynamic CT: comparison with plain CT, arteriography, sonography, and venous sampling.
Ten patients with suspected islet cell tumors (seven with possible gastrinomas, three with insulinomas) underwent diagnostic evaluation with dynamic CT scanning, routine CT scanning, angiography, and sonography. Venous sampling was also performed in selected instances. Nine sites of gastrinoma and three insulinomas were confirmed surgically in eight patients. Two patients had negative surgical explorations. Routine CT demonstrated five of the nine gastrinomas and one of two insulinomas. Angiography was positive in six of nine gastrinomas and all three insulinomas. Sonography showed only two of the nine gastrinomas and two of the three insulinomas. Dynamic CT scanning demonstrated three additional lesions (two gastrinomas, one insulinoma) not visible on routine CT scanning. Although most of these lesions were visible arteriographically, dynamic CT scans at the appropriate level localized the pathology in the transverse plane and greatly aided in surgical resection of these lesions. Dynamic CT scanning is a useful adjunct to routine angiographic and CT workup of patients with islet cell tumors.
Adenoma, Islet Cell↗
Comparison of ranitidine and cimetidine in the treatment of gastric hypersecretion.
The H2-histamine receptor antagonists, cimetidine and ranitidine, were compared for their abilities to control acid secretion on a short- and long-term basis in 13 patients with gastric hypersecretory disorders. The rate of onset of action did not differ between the two drugs. The actions of both drugs were increased by an anticholinergic agent, and there was a close correlation between the daily maintenance dose of each drug needed to control acid secretion. However, ranitidine was threefold more potent than cimetidine and no male patient developed breast changes or impotence while taking ranitidine. Treatment with high doses of ranitidine for 6 to 25 months was not associated with hepatic or hematologic toxicity or alterations of serum gastrin levels, but was associated with a significantly lower serum creatinine level than that seen with cimetidine therapy. These studies show that ranitidine can adequately inhibit acid secretion in patients with gastric hypersecretory disorders, is safe at high doses, does not cause the antiandrogen side effects frequently seen with high doses of cimetidine, and is threefold more potent than cimetidine. Patients who are relatively resistant to cimetidine will have proportional resistance to ranitidine.
Adult↗
Takayasu's arteritis: reversal of pulse deficit after early treatment with corticosteroids.
Takayasu's arteritis is a rare disease characterized by inflammation and stenosis of large arteries. The aortic arch and its branches are most often affected. Initial symptoms are nonspecific and the diagnosis may be delayed until signs of vascular insufficiency appear. Results of medical treatment have been conflicting. We report a case of a young woman with a short history of pulse deficits, high erythrocyte sedimentation rate, narrowing of the subclavian arteries on arteriography, and a complete return of pulses after high dose corticosteroids. Takayasu's arteritis is a treatable disease in its early phase, but treatment response may be disappointing after irreversible vascular lesions develop.
Adult↗
Secretagogue-induced membrane alterations in dispersed acini from rat pancreas.
Dispersed acini from rat pancreas were used to examine the effects of various pancreatic secretagogues on the fine structure of the acinar cell plasma membrane. With the C-terminal octapeptide of cholecystokinin, the C-terminal tetrapeptide of cholecystokinin, carbamylcholine, bombesin, A23187, vasoactive intestinal peptide or 8-bromo cyclic adenosine monophosphate, concentrations of the secretagogues that caused maximal stimulation of enzyme secretion did not produce alterations of the acinar cell plasma membrane. Supramaximal concentrations of the C-terminal octapeptide of cholecystokinin, the C-terminal tetrapeptide of cholecystokinin or carbamylcholine induced the formation of cytoplasmic protrusions at the basolateral plasma membrane of the pancreatic acinar cell, whereas supramaximal concentration of bombesin, A23187, vasoactive intestinal peptide or 8-bromo cyclic AMP did not alter the morphology of the acinar cell. Effects of the C-terminal octapeptide of cholecystokinin could be detected as early as after two minutes of incubation and these effects progressed for up to 30 minutes of incubation.
8-Bromo Cyclic Adenosine Monophosphate↗
The cellular basis of action of gastrointestinal peptides.
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Animals↗
Structure-function studies of N-acyl derivatives of tryptophan that function as specific cholecystokinin receptor antagonists.
Benzotript, N-p-chlorobenzoyl-L-tryptophan, is a specific cholecystokinin receptor antagonist. In the present study we used dispersed pancreatic acini to examine tryptophan as well as several different N-acyl derivatives of tryptophan for their abilities to function as cholecystokinin receptor antagonists. L-Tryptophan, D-tryptophan as well as each acyl derivative tested inhibited cholecystokinin-stimulated amylase secretion and outflux of 45Ca and there was a good correlation between the ability of a particular agent to inhibit the action of cholecystokinin on acinar function and its ability to inhibit binding of 125I-labeled cholecystokinin to pancreatic acini. Results with butyloxycarbonyl-L-tryptophan indicated that the inhibition of the action of cholecystokinin caused by L-tryptophan and various acyl derivatives is specific, competitive and fully reversible. In functioning as a cholecystokinin receptor antagonist the relative potencies of the agents tested were: carbobenzoxy-L-tryptophan greater than benzotript greater than benzoyl-L-tryptophan = butyloxycarbonyl-L-tryptophan greater than acetyl-L-tryptophan greater than L-tryptophan. In inhibiting the actions of cholecystokinin, native as well as N-acyl derivatives of D-tryptophan were equipotent with the corresponding compound containing L-tryptophan. Although L-tryptophan inhibited the actions of cholecystokinin, L-phenylalanine, L-methionine or L-aspartic acid, even when tested at concentrations as high as 3 mM, did not alter the action of cholecystokinin on pancreatic acini. The antagonism of the actions of cholecystokinin was not restricted to N-acyl derivatives of L-tryptophan because butyloxycarbonyl-L-methionine and butyloxycarbonyl-L-phenylalanine but not butyloxycarbonyl-L-aspartic acid also antagonized the actions of cholecystokinin. These results demonstrate that both the nature of the N-acyl group and the amino acid residue are important determinants of the affinity of the antagonist for the cholecystokinin receptor. For derivatives of L-tryptophan, the more hydrophobic the N-acyl moiety, the greater the affinity of the derivative for the cholecystokinin receptor.
Animals↗
Cholecystokinin-27-32-amide. A member of a new class of cholecystokinin receptor antagonists.
In dispersed acini from guinea pig pancreas, cholecystokinin-27-32-amide (CCK-27-32-NH2) did not alter amylase secretion but was able to antagonize the stimulation caused by cholecystokinin-related agonists. CCK-27-32-NH2 caused a parallel rightward shift in the dose-response curve for the stimulation of amylase secretion caused by cholecystokinin and inhibited binding of 125I-labeled cholecystokinin to pancreatic acini. These results indicate that CCK-27-32-NH2 is a fully competitive cholecystokinin receptor antagonist. CCK-27-32-NH2 did not alter the rate of dissociation of bound 125I-cholecystokinin from pancreatic acini but was able to reverse the residual stimulation of enzyme secretion caused by first incubating pancreatic acini with a relatively high concentration of cholecystokinin. Compared to other cholecystokinin receptor antagonists, CCK-27-32-NH2 is the most potent antagonist described to date, i.e. 30 times more potent than N2,O2-dibutyryl guanosine 3':5'-monophosphate. These results also indicate that the COOH-terminal phenylalanine residue of cholecystokinin is essential for intrinsic cholecystokinin-like activity but is not essential for binding of the peptide to cholecystokinin receptors in pancreatic acini.
Animals↗
The actions of tetraethylammonium on dispersed acini from guinea pig pancreas.
In dispersed acini from guinea pig pancreas, replacing extracellular sodium by tetraethylammonium (1) abolished carbamylcholine-stimulated amylase secretion but did not alter the increase in amylase secretion caused by the C-terminal octapeptide of cholecystokinin, bombesin, ionophore A23187, vasoactive intestinal peptide or 8-bromoadenosine 3':5' monophosphate, (2) caused a parallel rightward shift in the dose-response curve for carbamylcholine-stimulated amylase secretion and (3) inhibited binding of N-[3H]methyl scopolamine to muscarinic cholinergic receptors. Detectable inhibition of carbamylcholine-stimulated amylase secretion and binding of N-[3H]methyl scopolamine occurred with 300 microM tetraethylammonium, and half-maximal inhibition of these functions occurred with 1-2 mM tetraethylammonium. Replacing extracellular sodium by Tris did not alter the stimulation of enzyme secretion caused by any secretagogue tested. These results indicate that the tetraethylammonium is a muscarinic cholinergic receptor antagonist and that enzyme secretion from pancreatic acini does not depend on extracellular sodium.
Amylases↗
COOH-terminal fragments of cholecystokinin. A new class of cholecystokinin receptor antagonists.
COOH-terminal fragments of cholecystokinin varying in length from 1 to 3 amino acids and their NH2-terminal butyloxycarbonyl derivatives were investigated for their ability to interact with the cholecystokinin receptor on dispersed acini from guinea pig pancreas. No fragment stimulated amylase secretion when present alone, but each of the butyloxycarbonyl derivatives and the COOH-terminal tripeptide amide inhibited the stimulation of enzyme secretion by cholecystokinin. In each case the inhibition was surmounted by increasing the concentration of cholecystokinin. Each fragment also inhibited binding of 125I-labeled cholecystokinin, with significant inhibition occurring with 30 microM butyloxycarbonyl tripeptide amide, 0.3 mM butyloxycarbonyl dipeptide amide, 10 mM butyloxycarbonyl phenylalanine amide and 3 mM tripeptide amide of cholecystokinin. In each case, there was a close correlation between the ability of the fragment to inhibit binding of 125I-labeled cholecystokinin and its ability to inhibit cholecystokinin-stimulated amylase release, cholecystokinin-stimulated 45Ca outflux and cholecystokinin-stimulated residual stimulation of amylase secretion. The inhibition of amylase secretion caused by the butyloxycarbonyl tripeptide of cholecystokinin was reversible and specific for those peptides which interact with the cholecystokinin receptor (i.e., cholecystokinin, caerulein, gastrin); it did not inhibit the actions of bombesin, carbachol, physalaemin, vasoactive intestinal peptide, secretin, PHI, ionophore A23187 or 8-bromo cyclic AMP. These results demonstrate that COOH-terminal fragments of cholecystokinin comprise a new class of cholecystokinin receptor antagonists.
Amino Acid Sequence↗
Cimetidine-induced impotence and breast changes in patients with gastric hypersecretory states.
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Adult↗
Gastrointestinal peptides: the basis of action at the cellular level.
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Amino Acid Sequence↗
Diagnosis and management of the Zollinger-Ellison syndrome.
In the last 10 years, the basis for the diagnosis and treatment of gastric hypersecretion in Zollinger-Ellison syndrome has changed dramatically. The diagnostic criteria have changed because gastrin hypersecretion by a non-beta islet tumor is now known to be responsible for gastric hypersecretion, and gastrin radioimmunoassays are now widely available. The treatment of the gastric hypersecretion in Zollinger-Ellison syndrome has changed since development of histamine H2-receptor antagonists and the demonstration that gastric acid secretion can be controlled medically in most patients, obviating routine total gastrectomy. In this paper, we review currently available and newer antisecretory drugs, the results of long-term medical treatment, potential problem areas, and our current approach to controlling gastric hypersecretion in patients with Zollinger-Ellison syndrome.
Gastric Acid↗