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PubMed1986

Effect of acute experimental colitis on rabbit colonic smooth muscle.

The membrane potential and contractile activity of colonic circular smooth muscle from New Zealand White rabbits were studied after the production of acute experimental colitis. Colitis was induced in the distal colon by rectal infusion of formaldehyde solution, followed by an intravenous bolus of soluble immune complexes. Despite active mucosal inflammation, there are only occasional inflammatory cells in the muscularis. Electrophysiological studies on tissue from control rabbits and rabbits with colitis were performed using double sucrose gap and intracellular microelectrode techniques. The resting membrane potential was lower (-44 +/- 3 mV) in muscle from rabbits with colitis compared with control animals (-54 +/- 2 mV) (P less than 0.02). Amplitude of the electrotonic potential after a hyperpolarizing current pulse was decreased (P less than 0.05) and the time constant was shortened (P less than 0.01) in muscle from animals with colitis compared with normal animals. Amplitude (13.1 +/- 2.3 mV) and maximum rate of rise (0.24 +/- 0.06 V/s) of the spike potential, initiated by a depolarizing current pulse, were decreased in muscle from animals with colitis compared with muscle from healthy animals (P less than 0.001). Isometric tension generation after electrical and chemical depolarization of the membrane or bethanechol administration was decreased (P less than 0.001) in muscle from colitic animals. These studies suggest 1) membrane resistance and membrane potential are decreased in muscle strips from animals with colitis; and 2) there is a disturbance in the electrical and mechanical response of these tissues after stimulation.

Action Potentials↗
PubMed1987

Reflex gastric relaxation in response to distention of the duodenum.

Using a newly developed gastric barostat, we studied the effect of duodenal distention on gastric tone in a chronic canine model. In the conscious, fasted dogs, duodenal distention for 15 s consistently induced a marked gastric relaxation (delta intragastric volume = 226 +/- 23 ml). This response could be induced repeatedly without evidence of fatigue. Neither bethanechol nor combined phentolamine and propranolol infused intravenously had any significant effect on gastric relaxation in response to duodenal distention. To investigate the pathway of this duodenogastric mechanism, in four dogs we isolated the vagal nerves at the supradiaphragmatic level within an implanted cooling jacket. During intravenous infusion of bethanechol (used as a cholinergic background to maintain base-line gastric tone), supradiaphragmatic vagal blockade by cooling abolished the gastric relaxatory response to duodenal distention (delta intragastric volume = 11 +/- 5 ml during vagal blockade vs. 194 +/- 36 after vagal rewarming; P less than 0.05). This effect of acute and reversible vagal blockade by cooling was also mimicked by bilateral surgical vagotomy. We conclude that a nonadrenergic, noncholinergic mechanism participates in gastric relaxation induced by duodenal distention. This mechanism is mediated by the vagus nerve.

Animals↗
PubMed1987

Effects of bethanechol and the octapeptide of cholecystokinin on colonic smooth muscle in the cat.

The aim of this study is to compare the action of the cholinergic agonist, bethanechol, with the action of the octapeptide of cholecystokinin (CCK-OP) on feline circular colonic smooth muscle membrane potential and isometric tension, using the double sucrose gap. Depolarization of the membrane greater than 10 mV by K+ or bethanechol increased tension and spontaneous spike activity. CCK-OP (10(-9) M) depolarized the membrane (6.1 +/- 1.3 mV) without an increase in tension or spike activity. Depolarization of the membrane by increasing [K+]o was associated with a decrease in the membrane resistance. The slow-wave duration (2.3 +/- 0.2 s) was unchanged by administration of K+ or bethanechol but was prolonged after increasing concentrations of CCK-OP. The maximum effect occurred at a 10(-10) M concentration of CCK-OP (4.5 +/- 0.4 s, P less than 0.01). At higher concentrations of CCK-OP (greater than 10(-10) M), the slow-wave pattern became disorganized. Addition of increasing concentrations of [K+]o or bethanechol, but not CCK-OP, stimulated a concentration-dependent increase in the maximum rate of rise (dV/dtmax) of an evoked spike potential. These studies suggest 1) bethanechol decreased the membrane potential without altering the slow-wave activity, whereas CCK-OP has a minimal effect on the membrane potential but distorted the slow-wave shape; 2) an increased amplitude of the spike and dV/dtmax of the spike were associated with an increase in phasic contractions after bethanechol or increased [K+]o; 3) the lack of an increase in the spike amplitude and the dV/dtmax to CCK-OP was associated with no increase in phasic contraction.

Animals↗
PubMed1987

Pyloric contribution to antroduodenal resistance to flow in the conscious dog.

We have developed a pneumatic resistometer to monitor antroduodenal resistance to flow for prolonged periods of time in conscious dogs. To investigate the specific contribution of the pylorus to antroduodenal resistance we compared resistance during fasting in four control dogs and in four dogs with extramucosal pyloric myotomy (1.5 cm long). After pyloric myotomy, as in controls, resistance to flow changed cyclically, being lowest during phase I and highest during phase III of the interdigestive motor cycle. Pyloric myotomy decreased resistance during phase III. Atropine (0.1 mg X kg-1 X h-1) administered during motor quiescence (phase I) reduced resistance in the control group (P less than 0.05) but not in myotomized animals. Bethanechol (0.2 mg X kg-1 X h-1) significantly increased resistance in both groups (P less than 0.05). We conclude that antroduodenal resistance to flow is related to cyclic interdigestive motility. The pylorus is the predominant determinant of antroduodenal resistance during motor quiescence, but its contribution diminishes markedly during motor activity.

Animals↗
PubMed1987

Inhibitory action of peptide YY on gastric acid secretion.

The purpose of this study is to investigate the effect of peptide YY (PYY) on pentagastrin-, histamine-, and bethanechol-stimulated gastric acid secretion and the possible mechanisms by which PYY inhibits gastric acid secretion. Six mongrel dogs with chronic gastric and duodenal fistulas were given an intravenous infusion of pentagastrin (0.5 microgram . kg-1 . h-1), histamine (18 micrograms . kg-1 . h-1), or bethanechol (80 micrograms . kg-1 . h-1) either alone or simultaneously with intravenous PYY (100, 200, 400, pmol . kg-1 . h-1). PYY (100, 200, 400 pmol . kg-1 . h-1) inhibited pentagastrin-stimulated gastric acid secretion in a dose-dependent manner. PYY (400 pmol . kg-1 . h-1) did not depress bethanechol-stimulated gastric acid secretion. PYY (400 pmol . kg-1 . h-1) also failed to inhibit histamine-stimulated gastric acid secretion. Furthermore, PYY inhibit pentagastrin-stimulated gastric acid secretion in the face of atropine, vagotomy, or indomethacin treatment. These findings indicate that the inhibitory action of PYY on gastric acid secretion is in part independent of long and short cholinergic pathways. These findings also indicate that the inhibitory mechanism of PYY is independent of prostaglandin synthesis. Our findings are discussed in relation to previous reports regarding the effects of PYY on gastric acid secretion.

Animals↗
PubMed1987

Synergism between cellular messengers and agonist combinations in pepsinogen secretion.

The esophagus of Rana catesbeiana yielded 20-40 X 10(6) peptic cells that were greater than 80% pure by immunostaining, greater than 90% viable, and had low basal pepsinogen and lactic dehydrogenase (LDH) release. Cellular responses to agents that bypass receptors and act directly on cell messenger systems have been compared with receptor-mediated activation. Pepsinogen secretion was stimulated dose dependently by A23187, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), and forskolin. The combination of any two or all three agents at optimum effective concentrations stimulated secretion to more than double the output of the sum of the individual responses. Incubation in Ca2+-free media reduced responses to A23187 and TPA but not forskolin. Ca2+ deprivation eliminated the synergism of messenger combinations. Secretory responses to combinations of the agonists bethanechol or bombesin with either A23187 or TPA were additive and were synergistic with forskolin. Isoproterenol plus bethanechol or bombesin produced synergistic responses that were significantly smaller than combinations of their putative messengers. The synergistic response to isoproterenol and bethanechol was dependent on extracellular Ca2+. These data suggest that although Ca2+ may function in peptic cells to stimulate secretion directly, it may also act as a gain control for synergistic interaction between other messenger pathways (protein kinase a and c).

1-Methyl-3-isobutylxanthine↗
PubMed1987

[3H]QNB binding and contraction of rabbit colonic smooth muscle cells.

We used radioligand binding and studies of cell contraction to characterize muscarinic receptors on dispersed smooth muscle cells from rabbit proximal and distal colon. Cells obtained after serial incubations in collagenase were used to measure binding of tritiated quinuclidinyl benzilate [( 3H]QNB). AT 37 degrees C, specific [3H]QNB binding was saturable and linearly related to cell number. Nonlinear regression analysis was used to determine the affinity of [3H]QNB for its receptor. In the distal colon the Kd was 60 pM, and the mean number of receptors was 1.2 X 10(6)/cell. Compared with cells from the distal colon, cells from the proximal colon had a lower affinity (Kd = 337 pM) but similar numbers of receptors. The concentrations of the antagonists atropine, secovorine, and pirenzepine, which were required for inhibition of 50% [3H]QNB binding (IC50), were 8, 5, and 870 nM, respectively, suggesting that the receptors are of the M2-muscarinic subclass. Hill coefficients for these agents were 1.1, 0.9, and 1.1, suggesting binding to a single receptor. The IC50 for the muscarinic agonists bethanechol and oxotremorine were 80 and 0.57 microM, respectively. Hill coefficients were 0.67 for both, suggesting more complex interactions involving receptors of different affinities. In studies of cell contraction, bethanechol stimulated a dose-dependent decrease in cell length with half the maximal contraction occurring at 100 pM. These results suggest that 1) contraction is mediated by binding of bethanechol to M2-muscarinic receptors and that 2) there are a large number of spare receptors in colonic smooth muscle.

Animals↗
PubMed1988

Development of the muscarinic receptor in rabbit gastric smooth muscle.

We used binding of [N-methyl-3H]scopolamine ( [3H]-NMS) to tissue homogenates and isometric contraction of muscle strips to characterize perinatal changes in the muscarinic receptor on rabbit gastric smooth muscle. In homogenates from fetal (28 days of gestation), 1-, 3-, and 7-day, 4- and 11-wk-old rabbits, specific binding was saturable and temperature dependent, achieved equilibrium by 10 min at 30 degrees C, and was linearly related to tissue concentration. Specific binding was 80 +/- 2% of total binding at 0.2 nM [3H]NMS. The number of binding sites was 120,000 receptors/cell, maximal during the first week of life compared with the fetus or older animals. Affinity of [3H]NMS was highest in the first week of life (Kd = 345 +/- 24 pM, 1 day old). Age did not affect Hill coefficients or Ki values; secoverine and 4-diphenylacetoxy-N-methylpiperidine methiodide were 50-fold more potent than pirenzepine. In muscle strips, bethanechol stimulated dose-dependent atropine-inhibitable isometric contraction. The doses required for half-maximal contraction were similar in both age groups (5-6 microM), but maximal contraction was fivefold greater in weanlings compared with neonates. Increasing extracellular potassium concentration resulted in similar differences, suggesting that the differences were not receptor related. These results suggest that well-differentiated M2-muscarinic receptors are functional on rabbit gastric smooth muscle during the perinatal period.

Animals↗
PubMed1988

Sources of calcium for contraction of distal circular muscle or taenia coli in the rabbit.

Studies were performed on proximal taenia coli and distal circular muscle from the rabbit to determine if the source of Ca2+ required for bethanechol stimulation of contraction was similar after permeabilizing the tissues with saponin. The EC50 for Ca2+ stimulation of contraction was pCa 6.1 +/- 0.1 for both tissues. The peak response occurred at pCa 4.5. The addition of 1 microM calmodulin did not alter the Ca2+ EC50 or the peak response. Caffeine (20 mM) stimulated contraction of both taenia coli and distal circular muscle. The caffeine-stimulated contractile response was threefold greater in the taenia than in the distal circular muscle (P less than 0.05). Perfusion of thin strips of colonic muscle with buffer, containing 10(-7) M Ca2+, reduced the amplitude of bethanechol-stimulated contraction. The perfusion time to reduce the contraction by 50% was greater in the proximal muscle (2.4 +/- 0.1 min) than in the distal muscle (1.1 +/- 0.5 min) (P less than 0.001). These data suggest that 1) the intracellular Ca2+ concentration necessary for contraction is similar in the proximal and distal colon and 2) the intracellular Ca2+ stores appear to be greater in proximal taenia coli compared with distal circular muscle.

Animals↗
PubMed1988

Developmental regulation of rat intrinsic factor mRNA.

Using a full-length rat intrinsic factor (IF) cDNA clone, we have examined gene expression of IF in selected tissues from the adult rat and during postnatal development in the rat stomach. IF mRNA was expressed only in the rat stomach, and in situ hybridization revealed that the expression was limited to the chief cells at the base of the oxyntic glands. IF mRNA concentration in the stomach increased with postnatal age and reached a peak at the 30th day. Postnatally the amount of IF mRNA hybridized increased in both individual cells and in total number of cells. Administration of cortisol to, or adrenalectomy of, rats between 5 and 12 days of age resulted in increase or decrease of IF mRNA levels, respectively. Other hormones tested (pentagastrin, thyroxine, and triiodothyronine) had no significant effect. During the suckling period, IF bound well to the ileal receptor, despite lower than adult levels of activity and different glycosylation, as assessed by binding to concanavalin A-Sepharose beads. These results show that developmental expression of IF activity in rat is closely related to the expression of its mRNA and that corticosteroids play an important role in such an expression.

Adrenalectomy↗
PubMed1988

Cholecystokinin in the regulation of intestinal motility and pancreatic secretion in dogs.

Peptidal (CR-1409) and nonpeptidal (L-364,718) cholecystokinin (CCK) receptor antagonists were used to determine the possible involvement of CCK in the fasted and fed intestinal motility patterns and the related alterations in pancreatic secretion. Dogs were implanted with electrodes along the small bowel and with chronic pancreatic fistulas. In fasted dogs, the typical migrating motor complex (MMC) cycles and accompanying fluctuations in pancreatic secretion were recorded. Neither of the CCK antagonists affected these motor and secretory components of the MMC. Feeding interrupted the MMC and increased spike activity at all levels of the small bowel, and this was accompanied by a significant increase in pancreatic secretion and in plasma hormone [gastrin, CCK, and pancreatic polypeptide (PP)] levels. Both CCK antagonists significantly reduced the postprandial spike activity but failed to restore the fasted pattern. Exogenous gastrin and CCK, as well as bombesin, induced fedlike motility patterns accompanied by marked pancreatic protein secretion. These effects were completely reversed to the fasted patterns during intravenous infusion of CCK antagonists. In contrast, cholinergic stimulation (bethanechol) induced a fedlike pattern that was more resistant to CCK antagonists. We conclude that CCK does not play a major role in the fasted motility pattern and related fluctuations in pancreatic secretion but may be partly involved (by itself and by released PP) in the induction of the fed motility pattern and the postprandial stimulation of the exocrine pancreas.

Animals↗
PubMed1988

Effect of prostaglandin E2 on rabbit colonic smooth muscle cell contraction.

Isolated circular smooth muscle cells from the rabbit distal colon were used to study the effect of prostaglandin E2 (PGE2) on bethanechol-stimulated smooth muscle cell contraction. Contraction was expressed as the percentage decrease in mean cell length compared with unstimulated cells. Incubation with different concentrations of PGE2 (10(-10)-10(-6) M) did not cause contraction or relaxation of unstimulated smooth muscle cells. Bethanechol stimulated a dose-dependent contraction that was maximal at 30 s. The threshold for bethanechol-stimulated contraction was 10(-11) M; the ED50 was 10(-10) M; and the maximum contraction (23.0 +/- 1.8%) occurred at 10(-8) M. Preincubation with PGE2 reduced both the efficacy and potency of bethanechol-stimulated contraction. Preincubation with 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) or dibutyryl-cAMP reduced the efficacy of bethanechol-stimulated contraction without affecting potency. Increasing concentrations of PGE2 stimulated a dose-dependent increase in the production of intracellular cAMP (P less than 0.05). These studies show that PGE2 inhibits bethanechol-stimulated contraction of isolated colonic circular myocytes and is associated with increased production of intracellular cAMP. There is also a cAMP-independent effect of PGE2 on the potency of bethanechol stimulation.

Animals↗
PubMed1989

Opioid receptors and the initiation of migrating myoelectric complexes in dogs.

The role of endogenous opioids and opioid receptors in the control of migrating myoelectric complexes (MMCs) was studied in conscious dogs implanted with silver-silver chloride electrodes. In normal fasted dogs, MMC cycle times were 103 +/- 7 min in the duodenum. During naloxone infusion (1-2 mg/kg iv, then 0.2-1.0 mg.kg-1.h-1 iv) cycle times increased to 219 +/- 29 min (P less than 0.01). Naloxone (2 mg/kg iv, then 1 mg.kg-1.h-1 iv) had no effect on the response of the small intestine to bethanecol (5 mg sc) or to feeding. Pretreatment with naloxone (2 mg/kg iv) 5 min before the administration of motilin (400-500 micrograms/kg iv) did not block the initiation of MMCs by motilin. In separate experiments, animals were pretreated with the positive or negative isomer of the opioid receptor antagonist WIN-44,441 (0.2 mg/kg iv) 5 min before morphine administration. The negative isomer binds to opioid receptors whereas the positive isomer does not. The negative but not the positive isomer antagonized all effects of morphine on intestinal myoelectric activity. These studies suggest that endogenous opioids and opioid receptors may play a role in control of the initiation of MMCs and that motilin and exogenous opioids act via different mechanisms to initiate MMCs.

Animals↗
PubMed1989

Inhibitory regulation of rat exocrine pancreas by peptide YY and pancreatic polypeptide.

Peptide YY (PYY) and pancreatic polypeptide (PP) have been shown to inhibit exocrine pancreatic secretion in vivo in a variety of species. This study evaluates the type of stimulation inhibited by PYY and PP by examining, in urethan-anesthetized rats, the inhibition of pancreatic secretion when stimulated to a comparable extent by cholecystokinin (CCK), 2-deoxy-D-glucose (2DG), bethanecol, and electrical vagal nerve stimulation. PYY at maximal infusion rates inhibited stimulation by CCK by 83%, bethanecol by 55%, and electrical nerve stimulation by 40%. The inhibition of CCK stimulation was half maximal at 250 pmol.kg-1.h-1. By contrast, PYY totally inhibited 2DG-stimulated secretion with half-maximal inhibition at 10 pmol. kg-1.h-1. PP acted similarly to PYY in inhibiting CCK and 2DG-stimulated pancreatic protein secretion but was fivefold weaker in each case. These findings indicate that PYY and PP have multiple actions but preferentially inhibit neurally mediated pancreatic secretion at a preacinar cell locus, possibly at a central site of action.

Animals↗
PubMed1989

Neural mechanisms of pancreatic polypeptide release in conscious dogs.

L364,718, a potent and specific antagonist for peripheral cholecystokinin (CCK) receptors, was used to determine its effect on plasma levels of pancreatic polypeptide (PP) after administration of 2-deoxy-D-glucose (2-DG, a central vagal activator) and of bethanechol (a cholinergic receptor agonist). Six conscious dogs were used in this study. Intravenous injection of 2-DG (75 mg/kg) caused significant increases in plasma levels of PP and gastrin, but there was no significant rise in plasma levels of immunoreactive and bioactive CCK. Intravenous injection of L364,718 (20 nmol/kg) significantly inhibited the PP response stimulated by 2-DG injection by approximately 60% but did not affect gastrin. Plasma levels of PP were increased dose dependently by bethanechol infusion and were not altered significantly by injections of L364,718. The results indicate that L364,718 inhibits PP response stimulated by a central vagal activator (2-DG) but not by cholinergic receptor agonist (bethanechol). This study suggests that CCK might be involved in the neural control of PP release as a neurotransmitter but probably not as a final activator of PP cells in dogs.

Animals↗
PubMed1989

Characterization of cholinergic receptors mediating pepsinogen secretion from chief cells.

By use of a highly enriched preparation of chief cells (greater than 90% pure) prepared from guinea pig stomach, the cholinergic receptors regulating pepsinogen secretion were studied. Each of five different muscarinic cholinergic agonists, but not the nicotinic cholinergic agonist nicotine, stimulated pepsinogen release. Carbamylcholine-stimulated pepsinogen release was inhibited by each of seven different cholinergic receptor antagonists with relative potencies of N-methylscopolamine greater than scopolamine = 4-diphenylacetoxy-N-methylpiperidine methiodide = atropine much greater than pirenzepine greater than AF-DX-116 much greater than tetraethylammonium. Binding of [N-methyl-3H]scopolamine ([3H]NMS) was time and temperature dependent, reversible, saturable, and specific. Analysis of [3H]NMS binding demonstrated a Kd of 1.3 nM for NMS with a binding capacity of 61 fmol/mg protein or 5,920 sites/chief cell. With the agonists carbamylcholine, acetylcholine, or muscarine, the receptor population could be divided into two classes of receptor sites: a class with high affinity (Kd, 12-53 microM) representing 73% of the binding sites and a class with low affinity (Kd, 2-5 mM) representing 27% of the binding sites. Each of the antagonists had equal affinity for both receptor populations. There was a close correlation between the ability of antagonists to inhibit [3H]NMS binding and carbamylcholine-stimulated pepsinogen release. Each agonist was 29- to 63-fold more potent at stimulating pepsinogen release than interacting with high-affinity receptors and 2,000- to 11,000-fold more potent than interacting with low-affinity receptors, suggesting spare receptors. Studies with the alkylating agent, propylbenzilylcholine mustard, demonstrated that there was a receptor reserve of 50-80%.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Cholinergic control of smooth muscle peristalsis in the cat esophagus.

The aim of this study was to examine in detail the effects of selective cholinergic and other pharmacological antagonists on primary and secondary peristalsis in the smooth muscle of the cat esophagus in order to fully characterize the cholinergic contribution to peristalsis in this species. Primary and secondary peristalsis in the smooth muscle part of the feline esophagus was completely abolished by atropine, 4-dephenylacetoxy-N-methylpiperidine methiodide (4-DAMP) (a selective M2 muscarinic antagonist), hexamethonium, and high doses of nicotine. Pirenzepine (a selective M1 muscarinic antagonist), propranolol, and phentolamine were without effect, as were naloxone, methysergide, and pyrilamine. From these findings we conclude that primary and secondary peristalsis in feline esophageal smooth muscle involves nicotinic ganglionic neurotransmission as well as postganglionic release of acetylcholine that acts directly on muscarinic receptors located on the smooth muscle. Peristalsis in esophageal striated muscle does not involve either synaptic transmission or muscarinic receptors.

Animals↗
PubMed1990

Structural and functional characteristics of muscle from diabetic rodent small intestine.

After 30 days of streptozotocin-induced diabetes, the small intestine from untreated diabetic, insulin-treated diabetic, and nondiabetic rodents was excised in toto and measured. Despite a net loss in body weight, the diabetic animals showed a near twofold increase in small intestinal weight. This was characterized by a 148% increase in mucosal mass as well as a 39% increase in intestinal smooth muscle mass (P less than 0.05, respectively). The diabetic intestine was significantly longer and had a greater diameter and surface area. Diabetes significantly increased mucosal mass per unit surface area but produced an insignificant decrease in smooth muscle mass per unit surface area. Insulin treatment of the diabetic animals prevented the increase in total mucosal mass and mucosal mass per unit surface area. Insulin treatment also prevented the increase in smooth muscle mass, but reduced smooth muscle mass per unit surface area to a level significantly less than that found in nondiabetic intestine. In vitro dose-response studies of circular and longitudinal small intestinal muscle from the diabetic animals showed normal tension development and sensitivity to both bethanechol chloride and physostigmine. These observations show that the diabetic state produces alterations in not only mucosal but also smooth muscle mass in the small intestine. However, despite these morphological changes, diabetic intestinal smooth muscle retains its sensitivity to cholinergic stimulation and its capacity for tension generation.

Animals↗