Differential effects of Na+, K(+)-ATPase inhibition by ouabain on acid secretory responses to histamine and bethanechol in the mouse isolated stomach.

1. The effect of Na+,K(+)-ATPase inhibition by ouabain on gastric acid secretion was studied in the mouse isolated whole stomach preparation. 2. Ouabain caused a transient enhancement of histamine-induced gastric acid secretion followed by an inhibitory phase. On the other hand, ouabain caused a rapid reduction of bethanechol-stimulated acid secretion without an enhancement phase. 3. In dibutyryl cyclic AMP-induced acid secretion, ouabain led to a transient increase in acid secretion followed by a fall, as was seen with the histamine stimulation. Ouabain caused a rapid reduction of A23187-induced acid secretion. 4. Ouabain by itself increased basal acid secretion, and thereafter slowly suppressed the acid secretion. 5. Atropine inhibited both the ouabain-induced enhancement of the stimulated gastric acid secretion and the ouabain-induced stimulation of basal acid secretion. 6. The present study showed that Na+,K(+)-ATPase inhibition by ouabain caused a phasic enhancement of the stimulated gastric acid secretion through release of endogenous acetylcholine when the secretagogues act via an intracellular cyclic AMP pathway. It also inhibited the stimulated acid secretion irrespective of secretagogues, probably through its inhibitory effect on Na+,K(+)-ATPase in the gastric parietal cell.

Bethanechol-induced responses in mudpuppy parasympathetic neurons.

The effect of bethanechol on membrane potential and excitability was determined in mudpuppy parasympathetic postganglionic neurons. Bethanechol induced a large amplitude hyperpolarization, which was followed by a smaller amplitude depolarization, in 115 out of 135 cells tested. In approximately 20% of these cells, a brief depolarization preceded the hyperpolarization. During the bethanechol-induced hyperpolarization, the membrane input resistance decreased markedly, whereas the input resistance was increased during the subsequent depolarization. The hyperpolarization and depolarization were blocked by atropine and were unaffected by d-tubocurarine, thus, both appeared to be mediated by muscarinic receptors. The bethanechol-induced hyperpolarization was inhibited by the M2 muscarinic receptor antagonist AF-DX 116, whereas the bethanechol-induced depolarization was unaffected. Both a nonselective increase in membrane conductance and a decrease in membrane potassium conductance appeared to be involved in the generation of the bethanechol-induced depolarization. Evidence for the first mechanism was obtained in barium-treated cells in which bethanechol initiated a rapid onset depolarization, which was reversed at membrane potentials near 0 mV. Evidence for the second mechanism was obtained when the hyperpolarization was inhibited by AF-DX 116. In AF-DX 116-treated cells, the membrane input resistance was increased during most of the bethanechol-induced depolarization. Mudpuppy neurons initiate repetitive action potential activity in response to long depolarizing current pulses. Following application of bethanechol, with the hyperpolarization negated electrotonically, the number of action potentials produced by a depolarizing current pulse was greater than that produced prior to application of bethanechol. It is suggested that activation of muscarinic receptors on mudpuppy cardiac neurons influences multiple conductance systems and determines the excitability of these neurons.

Effects of drugs acting on Cl(-)-HCO3- and Na(+)-H+ exchangers on acid secretion in the rat gastric mucosa sheet preparation.

The effects of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of the Cl(-)-HCO3- exchanger, and amiloride, an inhibitor of the Na(+)-H+ exchanger, on gastric acid secretion under basal conditions and after stimulation with bethanechol or dibutyryl cyclic AMP were studied in rat gastric mucosa sheet preparation. DIDS inhibited bethanechol-induced acid secretion in a dose-dependent manner, but amiloride had no effect. The stimulation of acid secretion by dibutyryl cyclic AMP plus 3-isobutyl-1-methylxanthine was also inhibited by DIDs, but not by amiloride. DIDS did not reduce basal acid secretion, and neither did amiloride. These results suggest that the Cl(-)-HCO3-exchanger in the basolateral membrane of the parietal cell plays an important role in stimulated gastric acid secretion and that the Na(+)-H+ exchanger is less important. In addition, these data show that DIDS inhibits stimulated gastric acid secretion irrespective of the secretagogue, but not basal gastric acid secretion.

Differential sensitivities of the sphincter of Oddi and gallbladder to cholecystokinin in the guinea pig: their role in transsphincteric bile flow.

Cholecystokinin (CCK) is considered to simply contract the gallbladder and relax the sphincter of Oddi with meals. In this study, we examined this hypothesis by investigating the action of CCK on the sphincter of Oddi and gallbladder of the guinea pig. The experimental design used an in vitro preparation of the sphincter of Oddi to measure contraction of the circular muscle. CCK increased tone in both the gallbladder and the sphincter of Oddi in a concentration-dependent manner. The normalized concentration-response curves for CCK, however, revealed that the gallbladder had a greater sensitivity to CCK (ED50 7 nM) than the sphincter of Oddi (ED50 22 nM; p < 0.01). Conversely, the sphincter was more sensitive to bethanechol than was the gallbladder. When the sphincter of Oddi was stimulated maximally with CCK in the presence of atropine (10(-6) M) or tetrodotoxin (10(-6) M), the contractile response was significantly reduced (p < 0.05) although not abolished. Conversely, atropine completely abolished the responses to bethanechol (10(-3) M) and transmural field stimulation (70 V, 10 Hz, 1 ms, for 20 s). Transmural field stimulation of the sphincter that had been precontracted with CCK (26 nM) caused a transient, initial relaxation followed by contraction. Pretreatment with atropine augmented the duration of this relaxation, which could be completely abolished by tetrodotoxin. Thus, CCK contracts the sphincter of Oddi in the guinea pig by a direct (myogenic) and a neural (likely cholinergic) mechanism. Relaxation of the sphincter of Oddi also occurs in the guinea pig via noncholinergic inhibitory nerves.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential inhibition of cholinergic and noncholinergic neurogenic contractions by 5-hydroxytryptamine1A receptor agonists in guinea pig ileum.

Previous studies have shown that 5-hydroxytryptamine1A (5-HT1A) receptors are localized only to a subset of myenteric neurons in guinea pig ileum; the purpose of this study was to determine the possible functional significance of this differential receptor localization. Nerve-mediated contractions of the longitudinal muscle, myenteric plexus of guinea pig ileum were studied in vitro. Contractions were evoked by single transmural electrical stimuli (0.5-msec duration, at 0.1 Hz; cholinergic) or trains of stimuli (10 or 20 Hz for 1 sec; noncholinergic; scopolamine, 1 microM present). The 5-HT1A agonist, 8-hydroxy-2-(n-dipropylamino)tetralin (DPAT), reduced cholinergic contractions by no more than 14% in the concentration range of 0.001 to 0.3 microM. At high concentrations (1 to 100 microM), DPAT inhibited longitudinal muscle, myenteric plexus contractions; the EC50 was 6 microM. 5-Hydroxytryptamine (5-HT) and 5-carboxamidotryptamine (5-CT) reduced longitudinal muscle, myenteric plexus contractions by a maximum of 35% and 24% at 100 and 30 microM, respectively. Spiperone and 1-(2-methoxyphenyl)-4-[4-(2-phthalimidobutyl]piperazine (NAN-190), two 5-HT1A receptor antagonists, did not block DPAT-induced inhibition of cholinergic contractions. DPAT (3, 10 and 30 microM) shifted histamine concentration-response curves to the right in an apparently competitive manner; Schild analysis yielded a pA2 of 5.2. DPAT (3, 10, 30 and 100 microM) also shifted bethanechol concentration-response curves to the right in an apparently competitive manner; Schild analysis yielded a pA2 of 5.5. These data indicate that DPAT blocks histamine and muscarinic receptors on longitudinal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of pinacidil on spontaneous and evoked contractile activity.

Uninhibited bladder contractions have been associated with a variety of bladder dysfunctions including outlet obstruction, neurogenic bladder, incontinence, and other neurologic and nonneurogenic bladder disorders. One class of compounds that is gaining popularity and support for the treatment of hyperreflexia is potassium channel openers, such as pinacidil and cromakalim. In general, these agents act by hyperpolarizing the smooth muscle membrane, resulting in an increase in membrane stability which in turn would be expected to inhibit spontaneous and evoked contraction. It is the purpose of this study to compare the potency and selectivity of pinacidil at inhibiting both hyperreflexia in vivo, and several forms of in vitro contractile stimulation in the rabbit. The following is a summary of the results. (1) Pinacidil is an effective inhibitor of hyperreflexia in the in vivo rabbit model. (2) Pinacidil is a substantially more potent inhibitor of the amplitude of the hyperreflexia than the frequency. (3) Pinacidil was substantially more potent at inhibiting the contractile response to 2-Hz stimulation than to 32-Hz stimulation, but was equally effective at inhibiting field stimulation of the bladder base and body. (4) Pinacidil was significantly more potent at inhibiting the peak response to field stimulation than the rate of tension generation. (5) Pinacidil was equally potent and effective at inhibiting the phasic and tonic components of the response to field stimulation. (6) Pinacidil was a more potent inhibitor of methoxamine stimulation of the bladder base than bethanechol stimulation of the bladder body. (7) Pinacidil was a noncompetitive or mixed inhibitor of both methoxamine and bethanechol stimulation, whereas it was a competitive inhibitor of KCl stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence of a direct TRH effect on the rat exocrine pancreas.

In the present study, the effect of TRH on amylase secretion was determined both in vivo, by cannulating the pancreatic duct of rats, as well as in vitro, by using isolated lobules and dissociated acini. The results show that TRH inhibited both basal and stimulated in vivo amylase secretion. Nevertheless, the in vitro experiments failed to show a TRH-related inhibitory effect when TRH was used alone, although the hormone did blunt the secretion elicited by CCK8 and bethanechol from isolated lobules and dissociated acini. Results suggest that TRH can inhibit stimulated amylase secretion in rats through a direct effect on acinar cells.

Effects of locus coeruleus activation on electroencephalographic activity in neocortex and hippocampus.

Experiments were conducted to examine the hypothesis that increased neuronal discharge activity of noradrenergic neurons of the locus coeruleus (LC) above resting discharge rates can alter forebrain electroencephalographic (EEG) activity. Small infusions (70-135 nl) of the cholinergic agonist bethanechol within 500 microns of the LC were used to activate this nucleus reversibly in halothane-anesthetized rats. A combined recording-infusion probe allowed verification of this electrophysiological activation. Simultaneously, EEG activity was recorded from sites in the frontal cortex and hippocampus and subjected to power-spectrum analyses. The findings were (1) LC activation was consistently followed, within 5 to 30 sec, by a shift from low-frequency, high-amplitude to high-frequency, low-amplitude EEG activity in frontal neocortex and by the appearance of intense theta-rhythm in the hippocampus; (2) forebrain EEG changes followed LC activation with similar latencies whether infusions were made lateral or medial to the LC; (3) infusions placed outside the immediate vicinity of the LC were not followed by these forebrain EEG effects; (4) following infusion-induced activation, forebrain EEG returned to preinfusion patterns with about the same time course as the recovery of LC activity (10-20 min for complete recovery). These infusion-induced effects on EEG activity were blocked or severely attenuated by pretreatment with the alpha 2-agonist clonidine, which inhibits LC discharge and norepinephrine release, or the beta-antagonist propranolol. These observations indicate that enhanced LC discharge activity is the crucial mediating event for the infusion-induced changes in forebrain EEG activity observed under these conditions and suggest that LC activation may be sufficient to induce EEG signs of cortical and hippocampal activation.

[Effects of NIK-228 on gastric acid secretion in rats using the congo red sprayed method].

We have reported the antiulcer activities of a new compound that we named NIK-228 (3-hydroxy-methyl-2-methylimidazo [2, 1-b] benzothiazole). In the present report, we studied the antisecretory effects of NIK-228 on basal and stimulated gastric acid secretion using the Congo red sprayed method. Male Wistar rats (200 to 250 g) were used after 24 hr of fasting (without water). NIK-228, atropine and cimetidine were administered orally or intravenously 1 hr before operation for Congo red spraying. NIK-228 (100 mg/kg, p.o.), atropine (5 mg/kg p.o.) and cimetidine (100 mg/kg, p.o.) all inhibited basal gastric acid secretion. Oral administration of NIK-228 and atropine inhibited gastrin, 2-deoxy-D-glucose (2-DG) and bethanechol-induced acid secretion, but didn't inhibit histamine-induced acid secretion. Cimetidine inhibited all of histamine, gastrin, 2-DG and bethanechol-induced acid secretion. In vagotomized rats, oral and intravenous administration of atropine both inhibited bethanechol-induced acid secretion, but NIK-228 was not inhibited. These results suggested that antisecretory effects of NIK-228 were caused by the central vagal systems.

Comparison of the contractile and metabolic effects of muscarinic stimulation with those of KCl.

Urinary bladder emptying is mediated primarily by a coordinated contraction of the bladder body in response to parasympathetic stimulation and muscarinic receptor activation. In previous studies we presented evidence that the contractile response to bethanechol stimulation could be dissociated from the metabolic response through the use of diltiazem (calcium channel blockade). The conclusion from these studies was that muscarinic stimulation resulted in a significant increase in metabolic activity which was not directly associated with contraction. KCl stimulates contraction in isolated strips by directly depolarizing the membrane rather than from binding to specific membrane receptors. The current study directly compares the metabolic and contractile activity of bethanechol (muscarinic stimulation) with KCl (direct membrane depolarization). Isolated strips of rabbit urinary bladder body were monitored in vitro for changes in intracellular-free calcium, NADH/NAD ratio, and contraction. Intracellular-free calcium was monitored by preincubation of isolated bladder smooth muscle strips with FURA-2 AM and continuously measuring the fluorescence with an MB2 surface spectrofluorometer using excitation wavelengths of 340 and 380 nm, and an emission wavelength of 510 nm. The NADH/NAD ratio was monitored with the MB2 surface spectrophotometer using an excitation wavelength of 366 nm and an emission wavelength of 450 nm. Contraction was monitored using a isometric force transducer connected to a Grass model D polygraph. The results can be summarized as follows. (1) Both bethanechol and KCl stimulate a sharp decrease in the NADH/NAD ratio, a rapid increase in intracellular-free calcium, and a slower increase in contractile force.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of magnesium chloride on rabbit bronchial smooth muscle.

STUDY OBJECTIVE: The objective of this study was to determine the extent to which magnesium relaxes bronchial smooth muscle during induced contraction. DESIGN: An in-vitro model using bronchial rings from New Zealand White rabbits stimulated to contract by electrical stimulation, histamine, or bethanechol. INTERVENTIONS: Magnesium chloride 1, 6, 16, 36, and 86 mM was added to each tissue bath and resting tension was measured. Electrical stimulation 100 V/100 ms, histamine 10 mM, or bethanechol 6.25 mM was added to washed tissues to induce contraction. This was followed with magnesium chloride 5, 10, and 50 mM, and the response of bronchial smooth muscle was measured. MEASUREMENTS AND MAIN RESULTS: Magnesium chloride 1, 6, 16, 36, and 86 mM decreased the mean +/- SEM resting tension of bronchial rings by 40 +/- 16, 100 +/- 11, 110 +/- 10, 170 +/- 9, and 275 +/- 22 mg, respectively. Electrical stimulation (4) of 100 V/100 ms increased the mean +/- SEM resting tension by 168 +/- 52 mg. Magnesium chloride 5, 15, and 50 mM added to the tissue bath decreased the response to 100 V/100 ms to 65 +/- 27, 40 +/- 23, and 1 +/- 0 mg, respectively. Histamine 10 mM (4) increased mean +/- SEM resting tension by 490 +/- 121 mg. Magnesium chloride 5, 15, and 50 mM decreased the histamine response by 80 +/- 56, 250 +/- 74, and 475 +/- 131 mg, respectively. Bethanechol 6.25 mM (14) increased the mean +/- SEM resting tension by 495 +/- 74 mg. Magnesium chloride (5, 15, 50 mM) decreased bethanechol-induced tension by 52 +/- 18, 184 +/- 26, and 506 +/- 64 mg, respectively. CONCLUSION: Magnesium chloride produced dose-dependent relaxation of bronchial smooth muscle at rest and when stimulated by histamine, bethanechol, or electrical impulse. Calcium chloride was unable to significantly reverse magnesium-induced relaxation. These data support the hypothesis that magnesium relaxes smooth muscle and dilates bronchial rings.

Effects of two new pirenzepine analogs on the contractile response of the guinea-pig oesophageal muscularis mucosae to acetylcholine, bethanechol, histamine and high potassium.

The guinea-pig oesophageal muscularis mucosae was used to determine the affinity for muscarinic receptors of two new tricyclic compounds, DF 545 and DF 594, which are structurally related to pirenzepine. Both acetylcholine and bethanechol induced a concentration-dependent contraction of the muscularis mucosae. This contraction was competitively antagonized by DF 545 and DF 594 over the dose range 10(-7)-10(-5) M, while at higher concentrations both antagonists caused a depression of the maximal response to the cholinomimetics. The potency of DF 545 and DF 594 appeared to be comparable to that of pirenzepine and approximately 50 times lower than that of atropine. By comparing the affinities of DF 545 and DF 594 with those of selective antagonists (methoctramine and 4-DAMP) which discriminate between M2/M3 muscarinic receptor subtypes, it emerged that pirenzepine as well as DF 545 and DF 594 might act on M3 receptors, which seem to be predominant in the guinea-pig oesophageal muscularis mucosae. McN-A-343 exhibited no agonist activity while it acted as a competitive antagonist against acetylcholine and bethanechol. None of the compounds exhibited calcium antagonist properties. DF 545 inhibited the contractile responses to histamine, but DF 594 and pirenzepine did not.

The effects of the antimuscarinic drugs pirenzepine and atropine on plasma portal levels of somatostatin and gastrin in the dog.

The effects of the antimuscarinic drugs pirenzepine and atropine on somatostatin and gastrin portal levels under basal conditions and during bethanechol infusion have been investigated in anesthetized dogs. Iv bolus administration of pirenzepine (1 mg/kg) or atropine (0.1 mg/kg), decreased gastrin concentrations, but did not affect basal somatostatin levels. During 120 min of bethanechol infusion (160 micrograms/kg/h) gastrin levels increased but somatostatin levels were unchanged. Pirenzepine (1 mg/kg iv bolus), administered at the 60th min of bethanechol infusion, decreased the gastrin concentrations, and markedly enhanced somatostatin levels. Under the same conditions atropine (0.1 mg/kg iv bolus) decreased gastrin levels, but had little or no effect on somatostatin levels. These results indicate that muscarinic receptors with similar affinity for pirenzepine and atropine mediate excitatory cholinergic influences on gastrin release. By contrast, muscarinic receptors with higher affinity for pirenzepine seem to be involved in the cholinergic inhibition of somatostatin release: by selectively blocking these receptors, pirenzepine may increase portal somatostatin levels.

Subtypes of muscarinic receptors in canine pancreatic secretion in vivo and in vitro.

In conscious dogs with esophageal, gastric and pancreatic fistulae, sham-feeding and meat feeding increased the pancreatic protein secretion to a peak, reaching about 39% and 69% of CCK8 maximum, and raised plasma pancreatic polypeptide (PP) levels. Pirenzepine given intravenously (i.v.) (30 nmol.kg-1 or 3 mumol.kg-1) reduced dose-dependently the pancreatic protein and plasma PP responses to sham-feeding and meat feeding, being about 100 times less potent as an inhibitor than atropine. Neither pirenzepine nor atropine affected near-maximal pancreatic bicarbonate and protein responses to secretin (164 pmol.kg-1.h-1) and CCK8 (170 pmol.kg-1.h-1), but both antimuscarinic agents significantly inhibited pancreatic responses to lower doses of these secretagogues. When added to the incubation medium of dispersed canine pancreatic acini, pirenzepine reduced dose-dependently the amylase responses only to urecholine, and not to CCK or gastrin, being about 1000 times less potent as an inhibitor than atropine. This report provides an evidence that pirenzepine inhibits pancreatic secretion in a similar manner to atropine, but that pirenzepine, in both in vivo and in vitro studies, is 2-3 orders of magnitude less potent as an inhibitor than atropine, indicating that the muscarinic pathway of the exocrine pancreas has a low affinity for pirenzepine and may thus involve M2-receptors.

Some profiles of transmucosal potential difference in rat stomach determined in situ with special reference to effects of timoprazole, a H+,K+-ATPase inhibitor.

Gastric transmucosal potential difference (PD) is referred to an index of function and integrity of the mucosa. The features of gastric PD were studied in association with gastric acid secretion. The gastric PD was measured at the forestomach, glandular portion and pylorus in the rat in in situ preparations. Secretagogues such as bethanechol (BeCh, 50 micrograms/kg, i.v.), tetragastrin (TG, 30 micrograms/kg, i.v.), and histamine (Hist, 10 mg/kg, s.c.) produced a decrease in PD at the three regions of the stomach. These PD reductions did not occur with the combined treatment with timoprazole (30 mg/kg, i.d.); a marked increase in PD was noted, especially, in the case of Hist plus timoprazole. Similarly, BeCh induced PD decrease was antagonized by atropine (30 micrograms/kg, i.v.) and Hist induced PD decrease was attenuated by cimetidine (10 mg/kg, i.v.), while TG induced PD decrease was not affected by either of them. Of the antisecretory drugs, only cimetidine produced an increase in basal PD, probably via a mechanism unrelated to acid secretion. These results suggest that the PD decrease by each secretagogue seen at oxyntic and non-oxyntic gland regions of the stomach primarily originates from secretory activation of the parietal cells and that its action on function unrelated to acid secretion also exerts a minor influence on gastric PD.

Effect of serotonin on bethanechol-stimulated gastric acid secretion and gastric antral motility in dogs.

The purpose of the present study was to evaluate the effect of serotonin on bethanechol-stimulated gastric acid secretion and antral motility in conscious dogs with gastric fistula. Bethanechol stimulated the acid secretion dose-dependently and maintained the frequency and strength of the antral contractions at a high level. Serotonin inhibited the acid secretion dose-dependently, whereas the antral motility was stimulated. The acid inhibition was blocked by propranolol, and dose-response analysis showed inhibition of a non-competitive type. This study thereby shows that serotonin inhibits bethanechol-stimulated gastric acid secretion similarly to salmefamol (beta 2-adrenergic agonist)--that is, dose-dependently and non-competitively. Serotonin has been proposed to be a mediator of the beta-adrenergic influence on gastric function in vivo, but the counteracting effect of propranolol and the stimulatory effect of serotonin on motility contradict this hypothesis.

[Effects of somatostatin and its analogue, des (Ala1, Gly2) [D-Trp8, D-Asu3,14]-somatostatin (SS-1), on gastric mucosal blood flow and gastric secretion].

The inhibitory effects of somatostatin and its analogue (SS-1) on gastric mucosal blood flow (MBF) and gastric secretion were studied using bethanechol and pentagastrin as stimulants in anesthetized rats. In the present study, the inhibitory action of SS-1 was particularly investigated, regarding somatostatin as the control compound. Pretreatment with SS-1 at 1, 10, 30, or 100 micrograms/kg, i.v. (single dosing), inhibited the increase of MBF and gastric secretion stimulated by bethanechol in a dose-dependent manner. SS-1 showed no marked difference from somatostatin in terms of the degree and manner of the inhibition until 30 min after treatment. At 90 min, however, SS-1 still showed an inhibitory action, which was more prominent in gastric secretion than in MBF. Thus, SS-1 had a longer duration of action than somatostatin. Generally, SS-1 and somatostatin inhibited MBF to the same degree, whereas SS-1 inhibited gastric secretion more strongly than somatostatin. When pentagastrin was used to stimulate MBF and gastric secretion, SS-1 inhibited MBF and gastric secretion to the same degree as did somatostatin, but again, SS-1 had a longer duration of action than somatostatin.

Pirenzepine and propantheline effects on esophageal pressure responses to bethanechol.

Pirenzepine is an antisecretory anticholinergic type drug that has recently been shown to be relatively free of usual anticholinergic side effects on esophageal smooth muscle. It has also been suggested that this drug might release some of the inhibitory control of the esophagus and allow increased muscle contractions. To test this hypothesis, we compared the response of the lower esophageal sphincter (LES) and esophageal peristaltic contractions to bethanechol in 12 healthy controls after background oral doses of placebo, pirenzepine (50 mg), and propantheline (30 mg). After baseline placebo, bethanechol (40 micrograms/kg subcutaneously) produced the expected significant increases in LES pressure and amplitude of peristaltic contractions. Maximal increases were 51.9 +/- 14.9 and 29.5 +/- 7.0%, respectively. Also as expected, propantheline inhibited the cholinergic stimulation from bethanechol, allowing only a 10.1 +/- 13.6% increase in LES pressure and a decrease in peristaltic contraction amplitudes (-44.1 +/- 5.0%) after bethanechol. After background pirenzepine, the responses to bethanechol were intermediate between the other two drugs. A significant increase (44.2 +/- 16.4%) in LES pressure occurred after bethanechol while no significant changes (6.9 +/- 5.8%) were noted in peristaltic amplitudes with this drug. Typical side effects of dry mouth were noted in six of the 12 subjects with propantheline and in only three subjects after pirenzepine. These studies once again confirm the absence of usual anticholinergic side effects with oral pirenzepine compared to oral propantheline in the doses studied. We could find no evidence for a release of cholinergic inhibition after pirenzepine administration.

Effect of omeprazole on gastric acid secretion by the rat isolated stomach.

The inhibitory effect of omeprazole has been investigated on the isolated gastric fundus from immature rats. Omeprazole (10(-7)-10(-5) M) inhibited basal acid secretion, conversely from H2-receptor antagonists, antimuscarinic compounds and calcium antagonists; the effect was mimicked only by KSCN (3 X 10(-4)-3 X 10(-2) M). Omeprazole (10(-6)-10(-5) M) caused an insurmountable antagonism of the hypersecretion induced by histamine and bethanechol, whereas it competitively antagonized the secretory response to isoprenaline and dibutyryl cAMP. Experiments carried out in low calcium media showed that calcium ions did not significantly affect the inhibitory potency of omeprazole when tested on basal acid secretion, whereas low calcium solutions enhanced the action of omeprazole against histamine-induced hypersecretion. The above data confirmed the potent antisecretory activity of omeprazole in different experimental conditions in which the common antisecretagogues are without effect and pointed out the novel site of action in the control of gastric acid secretion at intracellular level.

Somatostatin increases the ratio between gastric mucosal blood flow and gastric acid and pepsin secretion in dogs.

The effects of somatostatin on gastric mucosal blood flow (GMBF), acid secretion, and pepsin secretion were evaluated. Conscious gastric fistula dogs were used, with neutral red clearance as the method for estimating the mucosal blood flow. Somatostatin inhibited the pentagastrin- and bethanechol-stimulated gastric acid and pepsin secretion and resulted in an absolute decrease in mucosal blood flow. The ratios between GMBF and secretion (acid and pepsin) were increased during somatostatin infusion, which suggests a relative increase in mucosal blood flow and independent inhibition of gastric secretion. It may be concluded from this study that the acid- and pepsin-inhibitory effects of somatostatin are not mediated by changes in the GMBF.