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PubMed1983

Mobilization of cellular choline by stimulation of muscarine receptors in isolated chicken heart and rat cortex in vivo.

The effects of cholinesterase inhibitors and muscarinic agonists on efflux of choline were studied in isolated perfused chicken heart and rat cortex in vivo. In the heart, the phospholipase A2 inhibitor mepacrine (10(-4) M) reduced the choline efflux (1.1 nmol g-1 min-1) by 51 +/- 5% (N = 3), whereas several cholinesterase inhibitors (physostigmine, neostigmine and diisopropylfluorophosphate) and muscarinic agonists (acetylcholine, oxotremorine and bethanechol) caused an increase. The muscarinic increase in choline efflux appears to be specific, as the increase caused by 10(-6) M physostigmine (+113%), by 3 X 10(-7) M acetylcholine (+89%) or by 5 X 10(-4) M bethanechol (+29%) was blocked by atropine. Cholinesterase inhibitors and muscarinic agonists also caused a decrease in heart rate by about 50%. Papaverine (10(-5) M) blocked the physostigmine- or bethanechol-evoked increase in choline efflux, but left the decrease in heart rate unchanged. Choline efflux from rat cortex in vivo was studied using the "cup technique." During the experimental period (3 hr), resting efflux declined from 60 to 15 pmol cm-2 min-1. Again choline efflux was increased by physostigmine (+48%) or by bethanechol (+48%) added to the cup solution from 80 to 160 min, whereas a decrease was observed after atropine plus physostigmine (-36%) or atropine plus bethanechol (-26%). In conclusion, stimulation of muscarine receptors increased extracellular choline by mobilization of cellular choline presumably through an effect on phospholipid metabolism. The hypothesis is discussed that synthesis of acetylcholine in the brain may be supported by an autoregulation of precursor availability.

Acetylcholine↗
PubMed1993

Galanin activates an inwardly rectifying potassium conductance in mudpuppy atrial myocytes.

Galanin- and bethanechol-activated K+ currents have been studied in mudpuppy atrial myocytes. The galanin and bethanechol K+ currents were time-dependent and inwardly rectifying. In GTP gamma S, the galanin and bethanechol currents were reduced progressively as G-protein gated K+ channels became activated. GDP beta S inhibited agonist-induced outward currents. We conclude that galanin and bethanechol activate the same or a very similar inwardly rectifying K+ conductance and that activation of a G protein is required.

Animals↗
PubMed1985

Cholinergic control of gastric acid secretion.

In the perfused stomach preparation of the anaesthetized rat the cholinergic agonists acetylcholine (ACh) and bethanechol stimulated gastric acid secretion. Both agonists produced similar maximal acid output (70 mumols/15 min) when infused intravenously. However, bethanechol was more potent, eliciting half maximal stimulation at 1.98 mumols/kg/h, while the corresponding dose of ACh was 10.95 mumols/kg/h. Secretory responses to either agonist were antagonized in a dose related fashion by blockade of muscarinic receptors with atropine. In contrast, inhibition of nicotinic receptors with hexamethonium produced a striking potentiation of ACh stimulated secretion whilst the bethanechol elicited secretion remained unaffected. In the presence of full nicotinic receptor blockade the ACh response curve was shifted to the left sixfold, half maximal stimulation being produced at 1.79 mumols/kg/h. Cimetidine partially inhibited the secretory responses elicited by either ACh or bethanechol while blockade of adrenoceptors (alpha and beta) did not affect acid output induced by cholinergic agonists. Secretion elicited by ACh is interpreted as being the composite effect of pro-secretory action and an inhibitory mechanism due to the activation of nicotinic receptors. Hexamethonium, through nicotinic receptor blockade, inhibits the restricting mechanism and thus reveals the full stimulatory action of ACh.

Acetylcholine↗
PubMed1986

Increasing antidumping effect of intestinal pacing with motor-active agents.

The aim was to determine whether cholecystokinin-octapeptide (CCK-OP), bethanechol Cl, or metoclopramide HCl would increase the antidumping effect of intestinal pacing in five dogs with truncal vagotomy and Roux gastrectomy. While recording electrical activity from the conscious animals, the amount of a 100-ml, 25% dextrose gastric instillate emptied in 20 min was determined during control tests, during tests with CCK-OP (500 ng/kg/hr), bethanechol (80 micrograms/kg/hr), or metoclopramide alone (600 micrograms/kg/hr) given intravenously or during tests using combinations of pacing and drugs. In other tests, intraluminal gastrointestinal pressure was measured during control and drug infusions. CCK-OP, which relaxed the proximal stomach, slowed emptying of the dextrose instillates (mean +/- SEM emptied, no pacing, no drug = 74 +/- 5 ml; CCK-OP alone = 34 +/- 5 ml; P less than 0.05). CCK-OP also enhanced the slowing effect produced by pacing (pacing alone = 41 +/- 7 ml; pacing plus CCK-OP = 19 +/- 8 ml; P less than 0.05). In contrast, bethanechol and metoclopramide, which did not alter proximal gastric motility, did not alter emptying or augment or diminish the effect of pacing. The conclusion was that the combination of pacing and CCK-OP slowed gastric emptying of the dextrose more than pacing alone and thus had a greater antidumping effect. In contrast, neither bethanechol nor metoclopramide enhanced the pacing effect.

Action Potentials↗
PubMed1986

Cholinergic stimulation of human pancreatic secretion.

The effect of graded doses of bethanechol on pancreatic secretion and plasma levels of pancreatic polypeptide and somatostatin was investigated in six healthy volunteers. In other studies the effect of a bethanechol background on the secretin-CCK stimulation of pancreatic secretion was also studied. Bethanechol caused a moderate stimulation of amylase secretion with a weak stimulation of bicarbonate secretion. These effects were not associated with significant changes in the plasma level of pancreatic polypeptide and somatostatin. Bethanechol enhanced the response to secretin and CCK. These results confirm a cholinergic pathway in the stimulation of pancreatic secretion in man.

Adult↗
PubMed1988

Effect of various prokinetic agents on post Roux-en-Y gastric emptying. Experimental and clinical observations.

The effect of various prokinetic drugs was assessed in animals with Roux-en-Y gastrojejunostomy. The agents tested were (1) bethanechol 2.5 mg subcutaneously at 0 min and 30 min postprandially (pp); (2) metoclopramide 20 mg intravenous bolus at 0 min pp; (3) a combination of 1 and 2; (4) oxytocin 5 mg intramuscularly at 0 min and 240 min pp; (5) motilin at 100 ng/kg/hr; or (6) 300 ng/kg/hr continuous intravenous infusion from 0 to 270 min pp. Only bethanechol administration resulted in significantly less gastric retention (65 +/- 6% vs 32 +/- 5% retention at 5 hr). (P less than 0.002). The animal results with parenteral bethanechol were confirmed in humans with chronic delayed gastric emptying following Roux-en-Y gastrojejunostomy, with a decrease in gastric retention on radionuclide scan from 78.5 +/- 5% to 26 +/- 12% at 2 hr pp (P less than 0.01). Initially all patients responded with symptomatic improvement. However, subsequently 3/6 (50%) of patients required total or near total gastrectomy for recurrent symptoms of gastric stasis. Nevertheless, 2/6 (33%) of patients have no further evidence of gastric stasis, and a trial of bethanechol is recommended prior to considering further gastrectomy in patients with the Roux-stasis syndrome.

Animals↗
PubMed1994

Effect of CGRP antagonist, alpha-CGRP 8-37, on acid secretion in the dog.

The recently synthesized calcitonin gene-related peptide (CGRP) antagonist, human alpha-CGRP 8-37, was used to study its effects on gastric acid secretion. Four dogs with gastric fistula were used to measure the antagonist's physiologic effects in the stomach. All dogs received a bactopeptone dextrose meal (intragastric titration to pH 5.5) with either continuous CGRP 8-37 (1000 pmol/kg/hr) or saline (control). Additionally, intravenous bombesin (75-600 ng/kg/hr) and bethanechol (12.5-100 micrograms/kg/hr) was tested in the presence of the antagonist. Plasma gastrin levels also were measured via radioimmunoassay (RIA) in control and CGRP 8-37-stimulated animals. Gastric acid secretion increased by 100% with infusion of 1000 pmol/kg/hr CGRP 8-37 when compared to the control. Acid output increased 98% with both intravenous antagonist and 600 ng/kg/hr bombesin when compared to bombesin alone. However, no augmentation of acid secretion by CGRP 8-37 was shown with 25 micrograms/kg/hr bethanechol. RIA of plasma gastrin demonstrated no effect with the antagonist when given alone and did not increase bombesin-stimulated gastrin release. We conclude that CGRP 8-37 blocks native CGRP inhibitory effects on gastric acid secretion. Our findings of potentiation of acid secretion by bombesin as well as no change in gastrin levels in the presence of the antagonist is likely due to a blockage in a noncholinergic neuron to the somatostatin cell. Furthermore, CGRP 8-37 did not increase bethanechol-stimulated acid secretion, most likely due to bethanechol's (acetylcholine) nearly ubiquitous positive effects on acid secretion.

Animals↗
PubMed1986

The role of striatal cholinergic mechanisms for the development of limb rigidity: an electromyographic study in rats.

The muscarinic cholinergic agonist bethanechol (0.25-1.0 micrograms) injected bilaterally into various parts of the rat neostriatum induced a tonic electromyogram (EMG) activity in the gastrocnemius muscle which is considered to be a measure of limb rigidity. This tonic EMG activity was found to be dose-dependent and muscarine-specific since it could be blocked by coadministration of the muscarinic antagonist N-methylscopolamine (1.0 micrograms). Tonic EMG activity of comparable amount was observed after injections of bethanechol (1.0 microgram) into all regions of the neostriatum but not into the globus pallidus, thalamus, zona incerta or cortex. The tonic EMG activity induced by intrastriatal injection of bethanechol (1.0 microgram) was abolished by a subsequent injection of the GABAmimetic drug muscimol (25 ng) into the posterior part of the substantia nigra pars reticulata suggesting that bethanechol-induced limb rigidity is mediated via impairment of GABAergic transmission within the substantia nigra pars reticulata.

Animals↗
PubMed1987

Calcium dependence of neurotensin stimulation of circular colonic muscle of the rabbit.

The effect of neurotensin on smooth muscle contraction was compared in strips from rabbit proximal and distal circular colonic muscle. The effective dose for neurotensin stimulation that caused a 50% response in both tissues was similar (1.3 X 10(-10) M). The maximal isometric stress, however, was greater in the distal colon than in the proximal colon (p less than 0.01). Neurotensin stimulation of both proximal and distal colon was unaffected by tetrodotoxin, phentolamine, propranolol, naloxone, or atropine. Neurotensin-stimulated contraction was inhibited by "Ca2+-free" (pCa = 5.1) or La3+ buffer. Verapamil (10(-6) M) or nitroprusside (10(-4) M) decreased neurotensin stimulation of proximal and distal colon by approximately 40% (p less than 0.05). Removal of Ca2+ from the buffer inhibited stimulation of muscle contraction by high extracellular potassium [( K+]o) more than bethanechol stimulation (p less than 0.01). La3+ (1 mM) inhibited the contraction stimulated by bethanechol or increased [K+]o. Although verapamil inhibited contraction by bethanechol and increased [K+]o by approximately 50%, nitroprusside had no effect on the contraction mediated by these stimulants. 8-Bromo-guanosine 3',5'-cyclic monophosphate (cGMP) inhibited neurotensin, but not [K+]o or bethanechol-stimulated contraction. These data suggest (a) neurotensin stimulated colonic contractions at a concentration that is potentially physiologic, (b) neurotensin stimulated colonic smooth muscle directly without neural mediation, (c) neurotensin stimulation of colonic muscle is controlled by [Ca2+]o and [cGMP]i.

Animals↗
PubMed1994

Comparative studies on the ontogeny and autonomic responses of the fetal calf bladder at different stages of development: involvement of nitric oxide on field stimulated relaxation.

This initial study correlates the passive length-tension relationship, contractile and relaxant responses to field stimulation and contractile responses to specific autonomic agonists and antagonists with gestational age. Fetal bovine bladders were separated into three groups based on the head-rump length (FL): 30 to 45 cm. (early gestation), 50 to 65 cm. (middle gestation) and 70 to 85 cm. (late gestation). Each bladder was separated into upper and lower bladder segments; longitudinal strips of smooth muscle were isolated and placed in individual muscle baths. Passive length-tension studies demonstrated that compliance was greatest in the bladder of late gestation and lowest in the bladder of early gestation period. Field stimulation (FS) elicited frequency-dependent contractile responses in all strips. In the upper bladder, the maximal response and maximal rate of tension generation to FS was lowest in the youngest fetuses and increased in proportion to the gestational age. In the lower bladders, there were no gestational age-related differences in the maximal response or maximal rate of tension generation in response to field stimulation. The maximal response of the upper bladder to bethanechol increased significantly from the youngest gestational age to mid-gestation, with no further changes between mid- and late gestation. The maximal response to field stimulation and bethanechol were equal between upper and lower bladder segments for the youngest gestational bladders, whereas for the oldest gestational ages, the maximal response of the upper bladder to FS and bethanechol were significantly greater than the responses of the lower bladder. In the presence of maximal precontraction with bethanechol, FS induced a rapid and marked decrease in tension. The magnitude of the relaxation was substantially greater for the strips of lower bladder than for the strips of upper bladder at late gestation. In lower bladders, the magnitude of the field stimulated relaxation was greater in the strips from the older fetuses than in the strips from younger fetuses. In all strips, field stimulated relaxations were completely inhibited by pretreatment with L-NAME (an inhibitor of nitric oxide synthesis), indicating that the FS-induced relaxation was due to nitric oxide. In addition to nitric oxide-induced relaxation, beta adrenergic stimulation also induced a significant relaxation of the isolated strips. In summary, these data suggest that, in the tubular shaped fetal bovine bladder, there were distinct differences in the autonomic responses between the upper bladder segment and the lower bladder segment in the late gestation period.

Adenosine Triphosphate↗
PubMed1989

Pharmacological responses of rabbit urinary bladder after subtotal cystectomy.

Partial cystectomy is used clinically in specific circumstances. There have been some reports indicating that the bladder following subtotal cystectomy can regenerate to a certain degree. The present study investigates the physiology and pharmacology of bladder regeneration at eight weeks after resection of a major part of the bladder body in rabbits. The following studies were performed on control and cystectomy bladders: 1) in vivo cystometry (prior to and four weeks after the operation, and before the sacrifice at eight weeks); 2) sequential muscle strip study (the strips were obtained by dividing bladder transversely into upper body, lower body, mid-bladder, upper base and lower base); and 3) in vitro whole bladder studies. The results can be summarized as follows: 1) grossly there was no regeneration of the bladder body; the cystometric capacity was increased slowly after the operation primarily due to increased size and capacity of the bladder base. 2) The contractile response of the subtotal cystectomized bladder body to field stimulation and bethanechol stimulation was less than the response of normal bladder body. 3) The contractile response to epinephrine showed that the ratio of alpha/beta adrenergic response was much greater in the cystectomy bladder than in the normal bladder. 4) In the whole bladder study, the intravesical pressure response to field stimulation was about the same in both groups, the response to bethanechol was less for cystectomized bladder, and the response to methoxamine was greater for the cystectomized bladder. 5) The ability of cystectomy bladder to empty in response to both field stimulation and bethanechol was impaired whereas the control bladder fully emptied to both field stimulation and bethanechol. In conclusion, over the eight week period following subtotal cystectomy the capacity increased via distention (and hypertrophy) of the bladder base area as opposed to regeneration of the bladder body.

Adenosine Triphosphate↗
PubMed1990

Comparison of urinary bladder function in sexually mature and immature male and female rats.

Although studies exist using both male and female rats, there are virtually no studies that compare male and female bladder function. In this initial study, in-vivo and in-vitro urinary bladder function was investigated in two age groups of male and female rats (sexually immature and sexually mature). These studies compare in-vivo micturition behavior (water intake, urine output, frequency and volume per micturition); and in-vitro whole bladder function (bladder volume/pressure relationships, the ability of the in-vitro bladders to generate pressure and empty in response to bethanechol and field stimulation). The results can be summarized as follows: 1) The 24 hour water intake, urine output, and volume per micturition for the mature male rats was significantly greater than that of the mature females with no significant differences among the immature females, mature females, or immature males. 2) There were no significant differences in the frequency of micturition between the 4 groups. 3) Although the average plateau pressures (cystometrograms) of the immature and mature female bladders were greater than that of the immature and mature male bladders, the compliance was similar for all groups. 4) The maximum pressure response of the mature female bladder was significantly greater than pressures generated by bladders in the other three groups; there were no age or sex related differences in the bethanechol log ED50 values. 5) There were no age or sex-related differences in the bethanechol log ED50 values or maximal expulsion responses. 6) Field stimulated bladders from mature animals generated significantly greater intravesical pressures than bladders from immature animals, but, there were no significant differences in maximal pressures attained between mature male and female bladders nor between immature male and female bladders. In conclusion, micturition behavior, and the maximal pressure response to bethanechol changed dramatically with sexual maturity. These results are consistent with the idea that estrogen and other hormones may have a marked influence on bladder function and micturition behavior.

Animals↗
PubMed1986

Inhibitory effects of beta-adrenergic agonists on gastric acid secretion in dogs.

We evaluated the effect of two beta-adrenergic agonists, isoproterenol (nonselective agonist) and terbutaline (selective beta 2-agonist), on gastric acid secretion stimulated by intravenous pentagastrin, bethanechol, or histamine in dogs with gastric fistulas. Intravenous infusion of isoproterenol or terbutaline inhibited pentagastrin-stimulated acid secretion to a significantly greater extent than they inhibited bethanechol- or histamine-stimulated acid secretion. For example, isoproterenol (12 micrograms X kg-1 X h-1) reduced mean pentagastrin-, bethanechol-, and histamine-stimulated acid output by 86, 63, and 14%, respectively. Percent inhibition of acid secretion with terbutaline (30 micrograms X kg-1 X h-1) averaged 60, 17, and 24% for pentagastrin, bethanechol, and histamine, respectively. Terbutaline also inhibited pentagastrin-stimulated acid secretion from vagally denervated fundic pouches in a dose-related manner. Plasma somatostatin-like immunoreactivity was significantly higher during infusion of terbutaline plus pentagastrin than during infusion of pentagastrin alone. However, an intravenous infusion of 0.3 microgram X kg-1 X h-1 somatostatin-14 had no effect on pentagastrin-stimulated acid secretion from the gastric fistula, even though this infusion increased plasma somatostatin-like immunoreactivity to the same extent as terbutaline plus pentagastrin infusion. Thus the amount of somatostatin released during terbutaline infusion was not sufficient to explain the inhibition of pentagastrin-stimulated acid secretion observed.

Adrenergic beta-Agonists↗
PubMed1992

Chronic nicotine intake increases the responses to muscarinic receptor stimulation.

Chronic nicotine administration depresses the autonomic ganglia, but its effects on the muscarinic receptors at the neuroeffector sites remain unclear. The present study, using rats, examines the influence of chronic treatment with nicotine (25 micrograms/ml drinking water) for 10 or 15 days on muscarinic receptor responses, as reflected by bethanechol-evoked gastric secretion or by acetylcholine-induced decreases in mean blood pressure. Bethanechol, 0.4, 0.8, 1.6 or 3.2 mg/kg injected subcutaneously, dose-dependently increased the basal gastric secretory volume and acid output in pylorus-ligated control animals which normally drank tap water. Rats given nicotine in their drinking water for 10 or 15 days showed a further marked increase in both the volume of gastric secretion and acid output in response to bethanechol injections. Although bethanechol dose-dependently increased acid secretion, the ulcer index was very small and there was no significant difference between the control and nicotine-treated groups. The basal mean blood pressure remained normal after the 10-day nicotine treatment. Acetylcholine, 0.1, 0.3, 1 or 3 micrograms/kg given intravenously, decreased the mean blood pressure; this acetylcholine-evoked blood pressure fall was intensified by nicotine pretreatment. The findings suggest that the responses to muscarinic receptor stimulation are increased by chronic nicotine treatment for 10 or 15 days. These exaggerated effects are possibly the consequence of persistent autonomic ganglion blockade by chronic nicotine treatment.

Acetylcholine↗
PubMed1994

Comparative pharmacology of the male and female rabbit bladder neck and urethra: involvement of nitric oxide.

The present study compared the contractile and relaxant responses of male and female rabbit bladder neck and urethra to field stimulation (FS) and various contractile and relaxant agents, with special attention paid to the involvement of nitric oxide (NO) in the mediation of field-stimulated relaxation. FS at basal tension elicited a frequency-dependent contractile response in all preparations. The maximal response to high frequency FS was significantly greater in the bladder neck strips isolated from male rabbits than in those from female rabbits. There were no significant differences in the response to bethanechol or phenylephrine between strips isolated from males and females. Field-stimulated responses of the strips from male bladder neck and urethra were greater than the response to phenylephrine. The responses of all strips to FS were greater than those to bethanechol. In addition, the response to phenylephrine was generally greater than that to bethanechol. Phentolamine was a significantly more effective inhibitor of the response of the female bladder neck and urethral strips to FS than of the response of the male strips. The contractile response of all strips to phenylephrine was generally greater than that to bethanechol for both sexes and for both bladder neck and urethral strips. NG-nitro-L-arginine methylester (L-NAME) inhibited totally the field-stimulated relaxation of all strips. Isoproterenol stimulated a slowly developing but significant inhibition of phenylephrine prestimulated contractions. In conclusion, significant differences exist in the magnitude of field-stimulated relaxation between the bladder neck and urethra of both male and female rabbits, and, for all tissues, field-stimulated relaxation could be completely inhibited by pretreatment with L-NAME, an NO synthesis inhibitor.

Animals↗
PubMed1993

Adenosine and cholinergic-induced gastric contraction in rats.

Adenosine is known for its modulatory effects on gastric secretory function and mucosal blood flow in rats. However, its action on gastric motility has not been defined. The influence of adenosine on gastric contractions provoked by cholinergic drugs and direct vagal stimulation have, therefore, been examined. Bethanechol (25, 50 or 100 micrograms/kg i.v.) and electrical vagal stimulation dose and voltage dependently increased the number and the amplitude of gastric contractions. An adenosine-A1-receptor agonist, L-phenylisopropyladenosine (10 or 50 micrograms/kg s.c.), given 30 min beforehand, did not affect the changes in gastric parameters but decreased the basal mean blood pressure and lessened the reduction in blood pressure evoked by bethanechol. The adenosine-A2-receptor agonist N-ethylcarboxaminoadenosine (1 or 5 micrograms/kg s.c.), 30 min beforehand, however, significantly increased the number but not the force of gastric contractions; a lower dose of this drug increased the basal blood pressure and potentiated the depressive action of bethanechol on systemic blood pressure. Adenosine administration (7.5 mg/kg s.c.) significantly increased its plasma levels at 30 and 60 min after injection; pretreatment with it (2.5, 7.5 or 12.5 mg/kg s.c.), 30 min beforehand, did not affect the gastric and vascular actions of bethanechol. The highest dose of adenosine potentiated the contractile response of vagal stimulation. In the isolated fundus preparation, adenosine added to the organ bath (10(-6), 10(-4), 10(-2) M) also did not affect the contractions induced by acetylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1992

Evidence for postjunctional release of ATP evoked by stimulation of muscarinic receptors in ileal longitudinal muscles of guinea pig.

The origin of the ATP release evoked by muscarinic agonists and veratridine from longitudinal muscles of the guinea pig was assessed with muscarinic antagonists. Acetylcholine (ACh) (1 microM) and bethanechol (10 microM) produced an immediate and marked ATP release, which was almost completely blocked by atropine (0.3 microM) and by the M3 muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) (1 microM); release was only slightly affected by tetrodotoxin (0.6 microM). The bethanechol-evoked release of ATP was partly, but not significantly, inhibited by pirenzepine, a M1 muscarinic antagonist. Veratridine, an ACh releaser, also elicited a delayed ATP release, in a concentration-related manner. This ATP release was greatly antagonized by atropine and by Ca++ removal from the medium, implying mediation by endogenous ACh released after depolarization. In contrast, electrically evoked ACh release was enhanced by atropine and 4-DAMP. Bethanechol, unlike veratridine, failed to elicit measurable ACh release from the tissue. The contraction evoked by bethanechol was notably inhibited by atropine and 4-DAMP, but not by pirenzepine and AFDX-116, a M2 muscarinic antagonist, at a concentration of 0.3 microM. These findings suggest strongly that ATP is postjunctionally released from the ileal smooth muscles after stimulation of postsynaptic muscarinic receptors, presumably M3 receptors.

Acetylcholine↗
PubMed1986

Desensitization within and between secretagogues of canine gastric acid and pepsin secretion.

Two types of desensitization, autodesensitization and cross-desensitization, of gastric secretory responses to cholinergic (bethanechol and vagal excitation) and noncholinergic stimuli (histamine and pentagastrin) were studied in groups of three to six conscious dogs with gastric fistula. Autodesensitization was manifested as fade of both acid and pepsin secretory responses by 10 to 20%/hr from peak output with all stimuli, histamine, pentagastrin and bethanechol. At the end of 4 hr of pentagastrin, 1.5 micrograms/kg X hr, doubling the dose of pentagastrin for 75 min reversed partly the trend of the acid fade, whereas adding an equipotent dose of histamine was much more effective, i.e., pentagastrin does not desensitize the stomach to histamine. When the three stimuli were given in sequence in random order for 2.5, 1.5 and 1.5 hr, respectively, to study cross-desensitization, histamine and pentagastrin reduced markedly the response of the parietal cells to either direct (bethanechol) or indirect (vagal) subsequent cholinergic stimulation. However, the parietal cells unresponsive to bethanechol remained fully responsive to histamine or pentagastrin, i.e., cholinergic stimulation did not desensitize the stomach to noncholinergic stimuli. From present and published data, neither auto- nor cross-desensitization is due to general, e.g. electrolyte and water depletion, or local, e.g. pH or osmolality, homeostatic consequences of secretion or to the drugs used, e.g. fall in blood pressure with histamine, but to cellular events. Inasmuch as the cell unresponsive to one stimulus may respond to another, a working hypothesis involving receptors is presented.

Animals↗