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J R Grider

Publications and source records attributed to J R Grider.

81 records · Page 5Linked to original sources
PubMed1987

Suppression of inhibitory neural input to colonic circular muscle by opioid peptides.

The aim of this study was to identify the neurotransmitter responsible for the dominant inhibitory neural input that normally masks myogenic phasic activity in the intestine. Opioid agonists, including opioid derivatives of proenkephalin and prodynorphin, caused direct tonic and indirect phasic contractions of strips from the circular muscle layer of rat colon. Both contractile responses appeared to be mediated by preferential interaction with delta opioid receptors. Elimination of most, if not all, neural input with tetrodotoxin (TTX) induced concentration-dependent phasic contractions. Neutralization of background vasoactive intestinal peptide (VIP) with VIP antiserum induced phasic contractions in previously quiescent muscle strips. The effect of VIP antiserum was concentration-dependent in the range of 1:960 to 1:60. A threshold concentration of VIP antiserum (1:960) increased the sensitivity of the phasic responses to [Met]enkephalin (100-fold) and TTX (20-fold) whereas exogenous VIP had the opposite effect. [Met]enkephalin and TTX inhibited basal VIP release by 43 +/- 8% (P less than .001) and 65 +/- 13% (P less than .01), respectively. It was concluded that VIP was the neurotransmitter responsible for the dominant inhibitory neural input to intestinal circular muscle and that opioid peptides induce phasic contractions by suppressing VIP release.

Animals↗
PubMed1986

Colonic peristaltic reflex: identification of vasoactive intestinal peptide as mediator of descending relaxation.

Isolated segments of rat and guinea pig midcolon were used to examine the neurotransmitters responsible for ascending contraction and descending relaxation components of the peristaltic reflex. Graded radial stretch of the extreme orad end caused only descending relaxation accompanied by significant release of vasoactive intestinal peptide (VIP) in rat (82%, P less than 0.005) and guinea pig (47%, P less than 0.05). Radial stretch of the caudad end caused only ascending contraction without VIP release. VIP antiserum (1:480 to 1:60) inhibited descending relaxation in a concentration-dependent manner at all grades of stretch (40 +/- 12% to 74 +/- 15%) but augmented ascending contraction (25 +/- 7% to 108 +/- 21%). Axonal blockade with tetrodotoxin and ganglionic blockade with hexamethonium abolished both components, indicating the participation of cholinergic neurons. Atropine and the tachykinin antagonist [D-Pro2,D-Trp7,9]substance P inhibited ascending contraction but not descending relaxation; their combination abolished ascending contraction at all grades of stretch. We conclude that cholinergic neurons coupled to VIP motor neurons regulate descending relaxation and that cholinergic neurons coupled to tachykinin and cholinergic motor neurons regulate ascending contraction.

Animals↗
PubMed1985

Selective inhibition of pentagastrin- and cholecystokinin-stimulated exocrine secretion by proglumide.

The effectiveness and selectivity of proglumide, a putative cholecystokinin/gastrin receptor antagonist in vitro, were examined on gastric acid and pancreatic secretion in vivo. Gastric secretion was measured in conscious dogs in the basal state and during infusion of pentagastrin, histamine, or bethanechol, alone or in combination with proglumide (300 mg/kg . h). Pancreatic secretion was measured in anesthetized rats in response to cholecystokinin-octapeptide or secretin, alone or in combination with proglumide (100 mg/kg). Proglumide inhibited pentagastrin-stimulated secretion but had no effect on basal, histamine-stimulated, or bethanechol-stimulated gastric acid secretion. Inhibition of pentagastrin-stimulated secretion was of the competitive type. An apparent inhibitory constant was calculated to be 300 mg/kg . h; this dose is capable of eliciting plasma concentrations of approximately 1 mM. This estimate corresponds closely to that derived from measurements in isolated canine parietal cells. Proglumide also inhibited cholecystokinin-stimulated but not secretin-stimulated pancreatic secretion. The lack of effect of proglumide on basal, histamine-stimulated, or bethanechol-stimulated gastric acid secretion implies that background gastrin has no direct or synergistic influence on stimulation by other secretagogues. The selective effect of gastrin receptor antagonists contrasts with the effectiveness of muscarinic and histamine H2-receptor antagonists against secretion induced by all types of stimulants. Accordingly, the antisecretory potential of gastrin receptor antagonists is confined to digestive secretion when the effect of gastrin is optimal. Their potential as antitrophic agents in duodenal ulcer disease, however, has not been explored yet.

Animals↗
PubMed1985

Vasoactive intestinal peptide as a neural mediator of gastric relaxation.

Two main candidates, adenosine 5'-triphosphate (ATP) and vasoactive intestinal peptide (VIP), have been proposed as inhibitory transmitters at neuromuscular junctions in the gut. We have used a photoaffinity analogue of ATP, 3'-O-(4-benzoyl)benzoyl ATP or BzATP, that binds covalently to ATP receptors and inactivates them in the presence of light and a specific high-affinity VIP antiserum in order to examine the contributions of ATP and VIP to neurally induced relaxation in circular smooth muscle of the gastric fundus of the guinea pig. VIP and ATP caused dose-dependent relaxation; the effect of ATP was equal to that of its stable isostere, alpha, beta-methylene ATP, and was resistant to degradation by adenosine deaminase, indicating interaction of ATP with purinergic P2-receptors. Relaxation induced by VIP was selectively inhibited by VIP antiserum (final dilution 1:120), while that induced by ATP was selectively inhibited by photoactivated BzATP. Relaxation induced by electrical field (i.e., neural) stimulation was inhibited by VIP antiserum only; photoactivated BzATP had no effect. Inhibition of neurally induced relaxation ranged from 86% (P less than 0.01) at the lowest frequencies to 34% (P less than 0.01) at the highest frequencies. Maximal field stimulation caused an 11-fold increase in VIP release from intramural neurons. The results strongly favor VIP as the neural mediator of gastric relaxation.

Adenosine Triphosphate↗
PubMed1985

Receptors for mammalian tachykinins on isolated intestinal smooth muscle cells.

The existence of receptors for three mammalian tachykinins, substance P (SP), substance K (SK), and neuromedin K (NK), was examined in smooth muscle cells, isolated separately from the longitudinal and circular muscle layers of guinea pig ileum. Tachykinin receptors capable of mediating contraction were present in muscle cells from both layers. The receptors were selectively blocked by the tachykinin antagonist [D-Pro2, D-Trp7,9]substance P but not by muscarinic, gastrin/cholecystokinin, or opiate antagonists (0.3 nM atropine, 1 mM proglumide, and 0.3 nM naloxone, respectively). The rank order of potency of tachykinins in causing contraction, NK greater than SP greater than SK, was similar in both muscle cell types. The results obtained in isolated muscle cells were closely paralleled by results obtained in intact muscle strips; the main difference was the greater sensitivity of isolated cells to tachykinin agonists (250-fold) and antagonist (210-fold). The inhibitory dissociation constant (Ki) of [D-Pro2, D-Trp7,9]substance P estimated from the displacement of dose-response curves (muscle cells) or from Schild plots (muscle strips) differed minimally or not at all, when either SP or SK was used as agonist, consistent with interaction of the two peptides with the same receptor subtype. The notion of a single receptor subtype in ileal muscle cells of the guinea pig was further supported by the occurrence of complete cross-desensitization between SP and SK in muscle strips.

Animals↗
PubMed1985

Vasoactive intestinal peptide. Relaxant neurotransmitter in tenia coli of the guinea pig.

Two main candidates have been proposed for the role of relaxant neurotransmitter in the intestine: (a) the purine nucleotide, 5'-adenosine triphosphate (ATP) and (b) the neuropeptide, vasoactive intestinal peptide (VIP). The candidacy of VIP is favored by its precise location in nerve fibers that innervate circular smooth muscle and tenia coli. We have used a photoaffinity analog of ATP, 3'-O-(4-Benzoyl)benzoyl ATP, that binds irreversibly to ATP receptors and inactivates them in the presence of light, and a specific VIP antiserum to examine the claims of VIP and ATP as relaxant neurotransmitters in tenia coli of the guinea pig. Both VIP and ATP caused dose-dependent, tetrodotoxin-insensitive relaxation of tenia coli. The effect of ATP was equipotent to that of its stable isostere alpha, beta-methylene ATP and resistant to degradation by adenosine deaminase, indicating interaction of ATP with purinergic-P2 receptors. Photoactivated 3'-O-(4-Benzoyl) benzoyl adenosine triphosphate selectively inhibited relaxation induced by ATP but had no effect on relaxation induced by VIP or by field (i.e., neural) stimulation. Vasoactive intestinal peptide antiserum (final dilution 1:60), on the other hand, inhibited relaxation caused by VIP and by field stimulation but had no effect on relaxation caused by ATP. Neither normal rabbit serum nor preneutralized VIP antiserum had any effect on relaxation induced by ATP, VIP, or field stimulation. Inhibition of neurally induced relaxation by VIP antiserum ranged from 52% +/- 7% (p less than 0.01) at the lowest frequency of stimulation to 15% +/- 4% (p less than 0.01) at the highest frequency, consistent with competitive interaction between antiserum and neurally released VIP. Near-maximal field stimulation at 1 Hz caused an eightfold (800% +/- 49%, p less than 0.01) increase in VIP release into the bathing medium. The results favor VIP (and probably peptide histidine isoleucine, a relaxant homologue known to be cosynthesized with VIP) as the main neural mediator of relaxation in tenia coli.

Adenosine Triphosphate↗
PubMed1976

Amylase isoenzyme clearances in normal subjects and in patients with acute pancreatitis.

Renal clearances of amylase isoenzymes, expressed as percentages of creatinine clearances, were determined in 20 normal subjects and in 8 patients with acute pancreatitis. The isoenzyme assay employed thin layer isoelectric focusing, starch iodine staining, and densitometry. Normal clearance of pancreatic-like amylase (mean +/- SE: 3.00 +/- 0.40%) was greater than the clearance of salivary-like amylase (0.51 +/- 0.06%) in ea ch individual (P less than 0.001). However, the amount of pancreatic amylase in the serum was not the major determinant of amylase clearance. Normal clearance of pancreatic-like amylase was significantly (P less than 0.001) less than the clearance of total serum amylase in acute pancreatitis (6.49 +/- 1.07%). In pancreatitis the clearance of pancreatic-like amylase (7.29 +/- 1.19%) and the clearance of salivary-like amylase (4.55 +/- 1.02%) were both elevated compared to normal (P less than 0.001). These findings indicate that the increased clearance of amylase in pancreatitis results from a change in renal function rather than a change in serum amylase. Renal changes not reflected by increased serum creatinine or more than mild proteinuria may be manifestations of the systemic toxicity of acute pancreatitis.

Acute Disease↗