Biomedical subjects

W L Hasler

Publications and source records attributed to W L Hasler.

53 records · Page 3Linked to original sources

PubMed1995

Hyperglycemia inhibits mechanoreceptor-mediated gastrocolonic responses and colonic peristaltic reflexes in healthy humans.

BACKGROUND/AIMS: The effects of hyperglycemia on colonic motor function are unknown. Therefore, colonic neuromuscular function was tested in normal volunteers as a model for constipation in diabetes. METHODS: Extended (gastrocolonic response) and local (peristaltic reflex) neural responses and colonic muscle contractility were tested under control, hyperglycemic clamp, and euglycemic, hyperinsulinemic clamp conditions with placement of barostat-regulated balloons in the descending colon to measure changes in tone as differences in balloon volume. RESULTS: Hyperglycemic clamping to 274 +/- 3 mg/dL blunted increases in colon tone evoked by gastric distention (gastrocolonic response) (100-300 mL) but did not affect gastric tone. Three descending colonic balloons in series assessed the peristaltic reflex. Inflation of the middle stimulus balloon increased proximal tone, an increase that was blunted by hyperglycemia, but produced distal relaxation followed by increases in tone that were unaffected by hyperglycemia. Euglycemic, hyperinsulinemic clamping had no effect on the gastrocolonic response or peristaltic reflex. Tonic increases evoked by bethanechol (5 mg administered subcutaneously) were unaffected by hyperglycemic clamping. CONCLUSIONS: Hyperglycemia blunts mechanoreceptor-mediated gastrocolonic responses and ascending contractions but not descending components of the peristaltic reflex in humans, effects not caused by hyperinsulinemia or direct muscle actions. These inhibitory effects on long and short neural reflexes that modulate colonic motility may contribute to constipation in diabetes.

Adult↗

PubMed1995

Hyperglycemia alters perception of rectal distention and blunts the rectoanal inhibitory reflex in healthy volunteers.

BACKGROUND/AIMS: Acute hyperglycemia has been shown to alter gastrointestinal motility. The effects of hyperglycemia on rectal afferent neural and anal sphincter function were studied. METHODS: Perception of rectal balloon distention, pressure-volume relationships, volumes necessary to induce reflex internal anal sphincter relaxation, resting anal sphincter pressure, and maximal anal sphincter squeeze pressure were measured under basal, hyperglycemic clamp, and euglycemic, hyperinsulinemic clamp conditions in 9 healthy volunteers. RESULTS: Hyperglycemic clamping (258 +/- 14 mg/dL) significantly blunted threshold perception and the urge to defecate in response to rectal distention without altering perception of maximally tolerated distention. In contrast, euglycemic, hyperinsulinemic clamping had no effect on perception of rectal distention. Rectal pressure-volume relationships after hyperglycemic clamping were unchanged compared with basal conditions. Hyperglycemic clamping caused a significant increase in the distention necessary to induce the rectoanal inhibitory reflex. This effect was not observed under euglycemic, hyperinsulinemic clamp conditions. Hyperglycemia did not significantly affect resting internal anal sphincter pressure or maximal external anal sphincter squeeze pressure. CONCLUSIONS: Acute hyperglycemia but not secondary hyperinsulinemia reduces sensation of rectal distention and blunts the onset of the rectoanal inhibitory reflex, suggesting effects both on visceral afferents projecting to the cortex and intrinsic afferents mediating local reflex activity.

Adult↗

PubMed1995

Mediation of hyperglycemia-evoked gastric slow-wave dysrhythmias by endogenous prostaglandins.

BACKGROUND/AIMS: Antral hypomotility and gastric dysrhythmias occur in diabetic gastroparesis. This study tested the hypothesis that acute hyperglycemia suppresses fed antral contractions and disrupts slow-wave rhythmicity via prostaglandin pathways. METHODS: Six normal volunteers underwent electrogastrography and antroduodenal manometry under control, hyperglycemic clamp, and euglycemic, hyperinsulinemic clamp conditions before and after administration of indomethacin (50 mg orally three times daily for 3 days). RESULTS: Hyperglycemic clamping to 230 mg/dL evoked a 4-fold increase in tachygastric activity and a 2.6-fold increase in arrhythmic activity (P < 0.05), whereas 140 and 175 mg/dL did not induce dysrhythmias. Antral motility indexes were reduced by 58% +/- 14% at 175 mg/dL and 70% +/- 8% at 230 mg/dL after a 750-kcal meal. Euglycemic, hyperinsulinemic clamping to insulin levels observed with the highest glucose infusions did not produce tachyarrhythmias or hypomotility. After indomethacin, hyperglycemic clamping to 230 mg/dL did not induce tachyarrhythmias. In contrast, indomethacin did not prevent the reduction in motility evoked by hyperglycemic clamping. CONCLUSIONS: Acute hyperglycemia, but not hyperinsulinemia, inhibits fed antral motility and induces gastric dysrhythmias at higher plasma glucose levels. Induction of dysrhythmias, but not hypomotility, is dependent on endogenous prostaglandin synthesis. These findings offer insight into the myoelectric disturbances of diabetic gastroparesis and suggest a possible therapeutic role for prostaglandin synthesis inhibitors for gastric dysrhythmias in this condition.

Adult↗

PubMed1995

Central cholinergic and alpha-adrenergic mediation of gastric slow wave dysrhythmias evoked during motion sickness.

Motion sickness is associated with gastric slow wave disruption. Animal models of slow wave disturbances show dependence on neural and prostaglandin pathways. Roles of these pathways in circular vection-evoked gastric dysrhythmias and nausea were tested. Eight volunteers with histories of motion sickness underwent vection (60 degrees/s), during which nausea (0 = none to 3 = severe) and electrogastrographic parameters were assessed. Tachygastric activity was expressed as the signal percentage at frequencies of > 4.5 cycles/min. Circular vection induced a maximal nausea score of 2.8 +/- 0 at 513 +/- 66 s. Tachygastric activity increased from 18 +/- 2 to 37 +/- 4% (P < 0.05) and peaked before maximal nausea. Atropine reduced nausea scores to 0 +/- 0 (P < 0.01) with no increase in tachygastric activity (14 +/- 6%). In contrast, the peripheral muscarinic antagonist methscopolamine did not reduce tachygastric activity (46 +/- 4%), nausea (1.8 +/- 0.5), or time to maximal tachygastric activity (504 +/- 80 s) with vection. Phentolamine reduced nausea (1.5 +/- 0.3, P < 0.01) and tachygastric activity, and delayed their onset, whereas propranolol and naloxone had no effect. Pretreatment with oral indomethacin (50 mg) three times daily for 3 days had no effect on vection-evoked tachygastric activity or nausea. To conclude, circular vection evokes gastric dysrhythmias that correlate temporally with maximal nausea and are suppressed by atropine, but not methscopolamine, and are reduced by phentolamine. In contrast to other models of slow wave disruption, endogenous prostaglandins play no role. Thus central cholinergic pathways mediate vection-evoked dysrhythmias with additional modulation by alpha-adrenergic pathways.

Adult↗

PubMed1995

Octreotide reduces perception of rectal electrical stimulation by spinal afferent pathway inhibition.

Octreotide reduces perception of rectal distension in normal volunteers and irritable bowel patients. To localize octreotide's site of action, perceptual and evoked potential responses to rectal electrical stimulation were tested in seven normal volunteers after double-blind octreotide (100 micrograms 2) or placebo. After octreotide, the currents needed to elicit threshold perception of square-wave impulses delivered to the rectum were 29% higher than after placebo. When electrical stimulation was delivered at constant currents 50% above threshold, rectal perception scores were significantly reduced after octreotide compared with placebo. Rectal electrical stimulation led to characteristic and reproducible cerebral evoked potentials. Octreotide had no effect on latencies, but reduced peak-to-peak amplitudes by 35% compared with placebo. Rectal electrical stimulation also led to characteristic and reproducible spinal evoked potentials. Octreotide had no effect on spinal latencies, but reduced peak-to-peak amplitudes by 51%. In conclusion, octreotide reduces perception of rectal electrical stimulation, which is associated with inhibition of cerebral and spinal evoked potential amplitude, indicating effects on spinal afferent pathways.

Adult↗

PubMed1995

Bradykinin acting on B2 receptors contracts colon circular muscle cells by IP3 generation and adenylate cyclase inhibition.

Receptor subtypes and intracellular signaling events involved in bradykinin-evoked contraction of colonic circular muscle are unknown. We studied the roles of inositol trisphosphate (IP3) and cyclic AMP generation and the selectivity for B1 and B2 receptors in guinea pig colon. Bradykinin induced concentration-dependent contraction of circular muscle strips with an EC50 of 2 x 10(-8) M that was inhibited by the B2 antagonist D-Argo-(Hyp3,Thi5,8,D-Phe7)-bradykinin but not the B1 antagonist des-Arg9-[Leu8]bradykinin. The B1 agonist des-Arg9-bradykinin did not evoke contraction or relaxation. Bradykinin induced concentration-dependent shortening of isolated myocytes from circular muscle with an EC50 of 2 x 10(-11) M that was inhibited by the B2 but not the B1 antagonist, confirming the myogenic nature of the bradykinin receptors. Persistence of myocyte contraction in a calcium-free medium with EGTA confirmed the lack of dependence on extracellular calcium. In colon muscle tissue, bradykinin evoked concentration-dependent IP3 generation with an EC50 of 10(-7) M and a maximal level of 58 +/- 17 pmol/mg of protein at 10(-4) M that was inhibited by the B2 but not the B1 antagonist. Bradykinin, acting on B2 receptors, inhibited cyclic AMP formation after forskolin (10(-5) M) with an EC50 of 3 x 10(-8) M and maximal inhibition of 48% at 10(-5) M. In conclusion, bradykinin induces colon muscle contraction via myogenic non-B1 receptors, which are likely of the B2 subtype, with phosphoinositide turnover activation and adenylate cyclase inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗

PubMed1994

Somatostatin analog inhibits afferent response to rectal distention in diarrhea-predominant irritable bowel patients.

Irritable bowel syndrome (IBS) patients exhibit enhanced sensitivity to rectal distention. The somatostatin analog reduces perception of rectal distention in healthy volunteers without modifying rectal resistance. We evaluated whether octreotide has similar effects on rectal perception and resistance in diarrhea-prone IBS patients. Octreotide (100 micrograms s.c.) and placebo were injected in double-blind fashion in eight IBS patients. Rectal balloons measured volumes that evoked increasing levels of perception and intrarectal pressures. After placebo, threshold perception, pressure, urgency and maximal tolerated volume were reported at 18 +/- 5, 46 +/- 8, 72 +/- 7 and 102 +/- 10 ml by the IBS patients, values less than we have observed in healthy volunteers. With octreotide, these sensations were perceived at higher volumes (40 +/- 10, 89 +/- 16, 167 +/- 20 and 202 +/- 25 ml, P < .05) that approximated responses in healthy volunteers. IBS patients exhibited higher rectal pressures at each volume and showed a trend to higher rectal resistance (0.13 +/- 0.02 mmHg/ml) than we have observed in healthy volunteers. These abnormalities were normalized by octreotide. Octreotide did not block the rectoanal inhibitory reflex confirming a lack of effect on local rectal reflex arcs. As with healthy volunteers, IBS patients with diarrhea experience reduced perception of rectal distention after octreotide. Octreotide also reduces elevated rectal pressures in IBS patients, in contrast to healthy volunteers. Thus, octreotide shows potential therapeutic benefit in IBS via dual effects on visceral afferent pathways and rectal wall stiffness.

Adult↗

PubMed1993

A somatostatin analogue inhibits afferent pathways mediating perception of rectal distention.

BACKGROUND: Octreotide, a somatostatin analogue, has antinociceptive activity in several models. We studied whether octreotide modifies perception of rectal distention in healthy volunteers and examined its mechanism of action. METHODS: Octreotide (100 micrograms, subcutaneously) and placebo were injected in double-blind fashion. Rectal balloons measured volumes that evoked increasing levels of perception. Octreotide's effects on rectal sensation were compared with actions on rectal resistance, rectal motor activity, afferent and efferent anal activity, and somatic perception. RESULTS: After octreotide administration, threshold perception, pressure, urgency, and maximal tolerated volume were reported at 62 +/- 4, 185 +/- 11, 269 +/- 17, and 362 +/- 25 mL, which were greater than after administration of placebo (25 +/- 4, 95 +/- 9, 153 +/- 10, and 211 +/- 13 mL, P < 0.01). Rectal pressures, which increased from 9.2 +/- 1.2 mm Hg at 30 mL to 20.2 +/- 1.7 mm Hg at 180 mL after administration of placebo, were not modified by octreotide; this shows a lack of effect on rectal resistance. However, in addition to enhancing volumetric tolerance, maximally tolerated pressures were increased to 42.4 +/- 5.1 mm Hg (P < 0.01) by octreotide. Octreotide increased phasic rectal contractions but did not change anal pressures or block the rectoanal inhibitory reflex, confirming that local rectal reflex arcs are unaffected. Perception of thermal or electrical cutaneous stimulation was unaffected by octreotide showing selectivity for visceral afferent pathways. CONCLUSIONS: Octreotide reduces sensation of rectal distention via inhibition of visceral afferent pathways. In contrast, afferent pathways involved in local reflexes and cutaneous perception are not inhibited by octreotide.

Adult↗

PubMed1993

GABA mediation of the dual effects of somatostatin on guinea pig ileal myenteric cholinergic transmission.

Somatostatin (SS) has both excitatory and inhibitory actions on myenteric cholinergic transmission, which are mimicked by gamma-aminobutyric acid (GABA). We hypothesized that both effects of SS are mediated by neural GABA pathways. In guinea pig ileal longitudinal muscle-myenteric plexus, SS evoked [3H]-GABA release verifying GABA neural activation. SS (10(-9)-10(-5) M) stimulation of atropine-sensitive ileal contraction and evocation of tetrodotoxin-sensitive [3H]acetylcholine (ACh) release was mimicked by the GABAA agonist muscimol but not the GABAB agonist baclofen. SS (10(-7) M)-evoked contraction and [3H]ACh release were markedly reduced by the GABAA antagonist bicuculline (10(-5) M) but not the GABAB antagonist phaclofen. Cholecystokinin (CCK) evokes ileal contraction via an atropine-sensitive pathway and stimulates ACh release via adenylate cyclase activation. SS inhibited contraction and release evoked by CCK (10(-7) M). These inhibitory actions were reversed by phaclofen but not bicuculline and were mimicked by baclofen but not muscimol. Pertussis toxin (200 ng/ml for 3 h) reversed the inhibitory effects of SS and baclofen on CCK-stimulated contraction and release. In conclusion, SS modulates ileal cholinergic pathways by stimulation of GABA neural pathways. The excitatory action of SS is mediated by GABAA receptors, whereas the inhibitory action utilizes GABAB receptors via a pertussis toxin-sensitive G protein.

Acetylcholine↗

PubMed1993

Down-regulation of motilin receptors on rabbit colon myocytes by chronic oral erythromycin.

Acutely, erythromycin stimulates colonic smooth muscle contraction via action on motilin receptors, but the effects of chronic erythromycin exposure are unknown. Thus contraction and motilin binding studies were performed on rabbit colonic smooth muscle after 2 weeks of oral erythromycin ethyl succinate (25 mg/kg, twice a day). Isolated colon myocytes from untreated rabbits contracted to erythromycin with an EC50 of 30 +/- 17 pM and peak shortening of 24.1 +/- 0.8% at 10 nM. Motilin evoked similar contractions with an EC50 of 63 +/- 13 pM and peak shortening of 26.8 +/- 0.9% at 10 nM. Myocytes from treated rabbits exhibited reduced contractile responses to erythromycin with an EC50 of 203 +/- 27 pM (P < .002) and decreased peak shortening to 20.1 +/- 2.9% at 100 nM (P < .05). Motilin responses were also blunted [EC50 of 326 +/- 16 pM, peak shortening of 16.2 +/- 1.2% at 1 microM (P < .002)]. [125I]motilin binding to untreated colon smooth muscle homogenates was saturable and specific with a Kd of 0.53 +/- 0.10 nM and a Bmax of 48 +/- 6 fmol/mg protein. Muscle from treated rabbits exhibited no change in motilin receptor affinity (Kd = 0.50 +/- 0.08 nM) but showed a 63% reduction in receptor density (Bmax = 18 +/- 4 fmol/mg protein; P < .03). In conclusion, chronic erythromycin administration results in decreased contractile potency and efficacy of motilin and erythromycin on colonic myocytes, associated with decreased motilin receptor density but no change in receptor affinity. Thus chronic erythromycin exposure leads to tolerance to its colonic smooth muscle motor effects via motilin receptor down-regulation.

Administration, Oral↗

PubMed1992

Angiodysplasia and von Willebrand's disease type IIB treated with estrogen/progesterone therapy.

The association between angiodysplasia and von Willebrand's disease was first reported in 1967. The cases reported to date have involved patients with type I and IIA von Willebrand's disease. We report a patient with type IIB von Willebrand's disease who suffered gastrointestinal bleeding attributable to gastric angiodysplasia. The patient underwent endoscopic electrocautery acutely and has been treated long-term with estrogen/progesterone therapy. She has suffered no recurrent gastrointestinal bleeding at over 11 months of follow-up. We suggest hormonal therapy as an alternative to repeated blood product transfusion or extensive surgical resection in patients with von Willebrand's disease and gastrointestinal bleeding from angiodysplasia.

Arteriovenous Malformations↗

PubMed1992

Erythromycin contracts rabbit colon myocytes via occupation of motilin receptors.

Erythromycin stimulates gastroduodenal motility via action on motilin receptors. We evaluated erythromycin as a colonic muscle motilin agonist using in vitro rabbit colon studies. Isolated myocytes contracted to erythromycin with a half-maximal effective concentration of 2 pM and peak shortening of 22.4 +/- 2.5% at 1 nM, which was superimposable with the response to motilin. 125I-labeled motilin binding to colon muscle homogenates was saturable and specific with a dissociation constant (Kd) of 0.39 nM and maximal binding (Bmax) of 41 +/- 3 fmol/mg protein. Motilin displaced specifically bound 125I-motilin, with a Kd of 0.31 nM. Erythromycin displaced 125I-motilin but was less potent, with an inhibitory constant of 84.0 nM. Bmax values from displacement studies were similar to the Scatchard data. Motilin receptor protection from alkylation by N-ethylmaleimide preserved contraction to motilin and erythromycin but not acetylcholine or cholecystokinin, whereas protection with erythromycin preserved contraction to motilin but not other agonists. In conclusion, erythromycin binds to colon muscle motilin receptors present in densities similar to reported values for the upper gut. Furthermore, erythromycin contracts colonic myocytes via specific action on motilin receptors. Thus erythromycin may have colonic motor-stimulating properties by action on motilin receptors.

Animals↗

PubMed1992

Cholecystokinin at physiological levels evokes pancreatic enzyme secretion via a cholinergic pathway.

The mechanism by which physiological concentrations of cholecystokinin (CCK) evoke pancreatic exocrine secretion in humans was investigated. CCK octapeptide (CCK-8) dose dependently increased trypsin and lipase output in healthy humans. Atropine inhibited CCK-8 (10 ng.kg-1.h-1)-stimulated trypsin output by 84.0 +/- 7.7% and lipase output by 78.6 +/- 9.2%. The inhibition with atropine was much less with a CCK-8 dose of 40 ng.kg-1.h-1 (41.8 +/- 6.6% for trypsin and 46.3 +/- 7.3% for lipase). CCK-8 at 10 ng.kg-1.h-1 produced plasma CCK levels similar to postprandial levels (6.0 +/- 1.3 vs. 6.9 +/- 0.8 pM), whereas the 40-ng.kg-1.h-1 dose produced supraphysiological levels (18.4 +/- 3.1 pM). To evaluate if CCK might act via stimulation of cholinergic nerves, in vitro studies were performed using rat pancreas. CCK-8 (10 nM-10 microM) stimulated [3H]acetylcholine release from pancreatic lobules that was blocked by tetrodotoxin, a calcium-free medium, and the CCK antagonist L364,718. In conclusion, CCK-stimulated pancreatic enzyme secretion is dependent on cholinergic neural and noncholinergic pathways. In humans, CCK infusions, which produce plasma CCK levels similar to those seen postprandially, stimulate the pancreas predominantly via a pathway dependent on cholinergic innervation. Correlative in vitro experiments suggest that CCK may act by stimulation of neural acetylcholine release. In contrast, supraphysiological CCK infusions act in part via noncholinergic pathways.

Acetylcholine↗

PubMed1991

Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma.

BACKGROUND: Patients with scleroderma may have abnormal motility of the small intestine, with pseudoobstruction and bacterial overgrowth. Standard stimulatory agents are often ineffective in such patients. Because the somatostatin analogue octreotide evokes intestinal motor activity in normal subjects, we hypothesized that it might increase motility in patients with scleroderma. METHODS: We studied the effects of octreotide on intestinal motility and plasma motilin concentrations in five fasting patients with scleroderma who had bacterial overgrowth and in six fasting normal subjects. The motor effects of octreotide were correlated with its effects on abdominal symptoms and bacterial overgrowth as determined by the level of breath hydrogen excretion. RESULTS: In the normal subjects, octreotide (10 micrograms subcutaneously) increased the mean (+/- SD) frequency of intestinal migrating complexes, which reflect intestinal motility, from 1.5 +/- 1.0 to 4.1 +/- 1.1 every three hours. In the patients with scleroderma, who had no spontaneous migrating complexes, octreotide (100 micrograms) induced 3.6 +/- 2.3 complexes every three hours. These complexes propagated at the same velocity and had two-thirds the amplitude of the spontaneous complexes in normal subjects. Plasma motilin concentrations, which were higher in the patients with scleroderma (229 +/- 74 pmol per liter) than in the normal subjects (112 +/- 37 pmol per liter), were inhibited by octreotide, suggesting that intestinal activity evoked by octreotide is independent of motilin. Treatment of the patients with scleroderma with octreotide (50 micrograms every evening) for three weeks reduced breath hydrogen excretion while they were fasting from 25 +/- 5 to 4 +/- 2 ppm (P = 0.001) and breath hydrogen excretion after they ingested 50 g of glucose from 46 +/- 24 to 8 +/- 7 ppm (P = 0.015); these reductions were accompanied by a significant decrease in nausea, bloating, and abdominal pain and by less frequent emesis. CONCLUSIONS: Octreotide stimulates intestinal motility in normal subjects and in patients with scleroderma. In such patients, the short-term administration of octreotide reduces bacterial overgrowth and improves abdominal symptoms. This agent may be useful for the treatment of intestinal dysmotility in patients with scleroderma.

Adult↗

PubMed1991

Cisapride acts on muscarinic (glandular M2) receptors to induce contraction of isolated gastric myocytes: mediation via a calcium-phosphoinositide pathway.

The effects of cisapride on guinea pig gastric smooth muscle were characterized. Cisapride induced concentration-dependent contraction of isolated myocytes with an EC50 of 10(-11) M, which was antagonized in concentration-dependent fashion by atropine. 4-Diphenylacetoxy-N-methylpiperidine-methiodide (4-DAMP) (10(-6) M), a selective M2 glandular receptor antagonist, inhibited contraction to cisapride (10(-10) M), whereas pirenzepine, an M1 receptor antagonist, had no effect. For comparison, carbachol induced contraction with an EC50 of 5 x 10(-11) M, which was also atropine-sensitive. Cisapride-induced contraction was not blocked by methysergide (10(-6) M), a nonselective serotonin antagonist. Cisapride displaced specific binding of [3H]N-methylscopolamine at a single receptor population with a Ki of 6.51 x 10(-5) M and a Bmax of 351.0 fmol/mg protein. Cisapride (10(-6) M) evoked a 73.8 +/- 7.6% increase in inositol 1,4,5-trisphosphate at 30 sec and a maximal increase of greater than 130% at 2 min, which was significantly reduced by atropine (10(-6) M). In contrast, cisapride did not enhance or inhibit basal levels of cyclic AMP. Thus, cisapride induces contraction via specific interaction at smooth muscle M2 glandular muscarinic receptors, which is associated with inositol trisphosphate generation, but not adenylyl cyclase activation.

Adenylyl Cyclases↗

PubMed1991

Characterization of receptors mediating the effects of dopamine on gastric smooth muscle.

The effects of dopamine on circular and longitudinal smooth muscle from the body of the guinea pig stomach were examined. In circular muscle, dopamine (10(-6)-10(-3) mol/L) induced contractions that were tetrodotoxin-insensitive with a concentration of half-maximal effect (EC50) of 6.3 x 10(-6) mol/L for dopamine vs. 1.4 x 10(7) mol/L for norepinephrine. The efficacies of dopamine- and norepinephrine-induced contraction were similar. The alpha-adrenoceptor antagonist phentolamine competitively inhibited dopamine-induced circular contractions (Ki = 2.5 x 10(-8) mol/L slope 1.06), whereas the dopamine antagonist haloperidol had no effect. The alpha 1-antagonist prazosin competitively inhibited dopamine-induced contractions (Ki = 1.8 x 10(-8) mol/L, slope 1.03), whereas the alpha 2 antagonist yohimbine was slightly less potent (Ki = 2.2 x 10(-7) mol/L, slope 1.15). In longitudinal muscle, dopamine produced relaxation with an EC50 of 2.9 x 10(-5) mol/L vs. 2.4 x 10(-6) mol/L for norepinephrine. Tetrodotoxin reduced relaxation to dopamine by one third at low doses of dopamine (10(-5)-10(-4) mol/L) and had no effect above 10(-3) mol/L. Phentolamine did not inhibit dopamine-induced relaxation, whereas haloperidol demonstrated potent competitive inhibition (Ki = 5.8 x 10(-7) mol/L, slope 0.90). The selective DA1 antagonist Sch 23390 (Research Biochemicals Inc., Natick, MA) showed competitive antagonism (Ki = 6.3 x 10(-6) mol/L, slope 0.98), whereas the selective DA2 antagonist domperidone had no effect. The effect of Sch 23390 was tetrodotoxin resistant. It is concluded that in the body of the guinea pig stomach, dopamine induces contraction in circular muscle through smooth muscle alpha adrenoceptors, whereas in longitudinal muscle, dopamine induces relaxation through smooth muscle DA1 receptors.

Adrenergic alpha-Antagonists↗

PubMed1990

Regional cholinergic differences between distal and proximal colonic myenteric plexus.

We investigated differences in myogenic and neural response of proximal vs. distal guinea pig colon in longitudinal and circular muscle. Spontaneous phasic contractions were more intense in distal colon in both layers. Phasic contractile frequency was also greater in distal colon in both layers. In both longitudinal and circular muscle, acetylcholine induced greater contractions in distal than in proximal colon (maximal response: longitudinal, 7.00 +/- 1.04 X 10(4) vs. 3.50 +/- 0.49 X 10(4) N/m2; circular, 3.29 +/- 0.82 X 10(4) vs. 8.92 +/- 1.30 X 10(3) N/m2). Compared with proximal colon, electric field stimulation induced greater atropine-sensitive contractions in distal colon in both muscle layers (maximal response: longitudinal, 4.22 +/- 0.53 X 10(4) vs. 7.53 +/- 1.97 X 10(3) N/m2; circular, 2.14 +/- 0.79 X 10(3) vs. -5.28 +/- 2.04 X 10(2) N/m2). In contrast, there were no regional differences in atropine-insensitive relaxations. Veratridine (10(-5) M) stimulated greater [3H]acetylcholine release from distal longitudinal muscle-myenteric plexus than from proximal preparations (11.44 +/- 2.03 vs. 5.84 +/- 1.26% of total tissue radioactivity). These data suggest the greater contractile responses in the distal colon are because of enhanced cholinergic response to neural stimuli and increased muscle sensitivity to acetylcholine, whereas there are no differences in the inhibitory responses to neural stimuli.

Acetylcholine↗