A double-blind randomized study of cisapride in the treatment of nonulcer dyspepsia. The Canadian Cisapride Nud Study Group.

Cisapride is a substituted benzamide with gastrointestinal prokinetic effects presumed to be due to the enhancement of the physiological release of acetylcholine at the myenteric plexus. In a multicentre study, 189 patients with nonulcer dyspepsia (NUD) received single-blind placebo treatment for two weeks. A total of 123 patients with no or minimal response to placebo and epigastric pain of at least moderate severity and frequency were randomly assigned to one of the three parallel double-blind treatments for six weeks: cisapride 10 mg tid, cisapride 20 mg tid or placebo. The severity and frequency of individual symptoms (epigastric pain, heartburn, nausea, vomiting anorexia, postprandial discomfort, regurgitation, lower abdominal pain, bloating and constipation) were assessed on a four- and five-point categorical scale, respectively, by the investigator at three on treatment visits and by patients in a daily diary. Analysis of investigator and patient assessments for differences in symptom severity x frequency composite scores among the three treatment groups showed no statistically significant differences for individual symptoms or symptom clusters. As assessed by the investigator, and compared with baseline, cisapride 20 mg tid significantly (P < 0.05) improved epigastric pain, bloating and early satiety as well as improved the total symptom cluster. Investigator evaluation of the five most severe and frequent symptoms for each patient showed statistically significant improvement in each treatment group. For patient diary assessments, statistically significant within-treatment improvement of the total symptom cluster, the five most severe symptoms cluster, bloating and early satiety was observed for both cisapride 20 mg and placebo, whereas epigastric pain significantly (P < 0.05) improved in all three treatment groups. Investigator evaluation of global response (good+excellent) rate at the end of the six week treatment period was 38% for cisapride 20 mg, 47% for cisapride 10 mg and 33% for placebo. No statistically significant difference in this parameter among treatments was noted. Cisapride was well tolerated at both doses with a side effect profile comparable with that of placebo. It is concluded that in this double-blind multicentre study with a single-blind two-week placebo run in phase, cisapride 10 mg tid and 20 mg tid were not effective compared with placebo in improving symptoms in NUD patients. This study re-emphasizes the good prognosis of patients with NUD, with 14% of patients improving in the two-week placebo run-in phase and a further 33% improving in the next six weeks while on placebo. Within-treatment analysis of investigator assessments showed improvement for cisapride 20 mg tid suggesting a trend of efficacy at this dose.

Reevaluation of the balloon in gastrointestinal manometry.

Although the flow-through catheter (FTC) system has been useful and satisfactorily accurate for gastrointestinal manometry, we hypothesized that a cylindrical, liquid-filled balloon would also accurately reflect stress imposed by a sphincter. Latex balloons were fitted over the side ports of a closed-end catheter. The responses of the balloon and FTC system were compared in a cylindrical chamber commonly identified as a Starling resistor. Independent, constant-pressure sources were used to control both the inwardly directed "contact pressure" of the Starling resistor (Ps) and the intraluminal fluid pressure (P(lum)). The balloon transducers responded linearly and accurately (slope = 1) to changes in both Ps and P(lum) within the test range (0-200 mmHg, 0-26.7 kPa). When either P(lum) or Ps was held constant and the other changed, the balloon transducers always accurately measured the higher of the two pressures. Although the performance of the FTC system was improved after the Starling resistor was lubricated, the FTC system sometimes responded inaccurately to changes in Ps. The ability of the balloon transducers to measure the contractions of the lower esophageal sphincter and of the esophagus was demonstrated. We conclude that the balloon transducer can measure sphincter pressure accurately and suggest that, in certain circumstances, it might be advantageous relative to the FTC system.

Treatment of acute colonic pseudoobstruction (Ogilvie's syndrome) with cisapride.

A 73-yr-old white woman admitted with lobar pneumonia and congestive heart failure developed progressive colonic pseudoobstruction (Ogilvie's syndrome) 2 days after admission which was unrelieved by diatrizoate meglumine (Gastrografin, Squibb Canada, Montreal) enema and rectal tube. Cisapride, a new gastrointestinal prokinetic agent, was administered intravenously with full resolution of the syndrome. To the authors' knowledge, this is the first reported case of successful treatment of acute colonic pseudoobstruction with cisapride.

Isolation, Amino-Acid Sequence, Synthesis and Biological Properties of Urotensin I from Hippoglossoides elassodon.

Abstract A 41-residue urotensin I neuropeptide (H-UI) was isolated from urophyses of the marine teleost Hippoglossoides elassodon (the flathead sole). The peptide was recognized by its partial cross-reactivity in a radioimmunoassay developed for Catostomus (sucker) Ul (S-UI), and was purified by reversed-phase high-performance liquid chromatography. The amino-acid sequence was shown to be H-Ser-Glu-Glu-Pro-Pro-Met-Ser-lle-Asp-Leu-Thr-Phe-His-Met-Leu-Arg-Asn-Met-lle-His-Arg-Ala-Lys-Met-Glu-Gly-Glu-Arg-Glu-Gln-Ala-Leu-lle-Asn-Arg-Asn-Leu-Leu-Asp-Glu-Val-NH(2). H-UI is 66% homologous with S-UI and 63% homologous with Cyprinus (carp) Ul (C-UI). Like S- and C-UI, H-UI is about 50% homologous with the frog skin peptide sauvagine and with Catostomus and mammalian corticotropin-releasing factors. H-UI had similar vasodilatory effects in mammals, and similar adrenocorticotropin-releasing effects (in rat and goldfish) to S-UI, C-UI, sauvagine and the corticotropin-releasing factors, but had relatively low potency (e.g. 10% to 30% of the vasodilatory potency of S- and C-UI) in all the bioassay systems studied.

Differential antagonism of alpha-1 and alpha-2 adrenoceptor-mediated vasoconstrictor responses by a vasodilator peptide, urotensin I: comparison with nifedipine.

We showed previously that in the dog, but not in the rat, Urotensin I, (UI), a neuropeptide with corticotropin releasing factor activity, selectively dilated the mesenteric circulation. Even in the rat, mesenteric arteries tested in vitro exhibited greater vasodilator responsiveness to UI than arterial preparations from elsewhere. In the rat in vivo, UI caused a preferential inhibition of alpha-1 adrenoceptor-mediated vasoconstriction, but it was unclear whether this provided an explanation for selective vasodilatation. The present study was done in the rat 1) to determine whether the effect of UI on alpha-1 adrenoceptors differed in regional vascular beds and 2) to compare the inhibitory action of UI on these responses with that of the calcium antagonist, nifedipine. The inhibitory actions of UI were similar, qualitatively and quantitatively, in both the blood-perfused mesenteric circulation and hindquarters of the urethane-anesthetized rat. In both systems, UI produced a greater inhibition of pressor responses to a selective alpha-1 adrenoceptor agonist, phenylephrine, than to norepinephrine or a selective alpha-2 adrenoceptor agonist, alpha-methylnorepinephrine. Pretreatment with prazosin, a selective alpha-1 adrenoceptor antagonist, reduced the antagonistic action of UI on norepinephrine responses in both vascular beds in vivo and in the rat mesenteric artery in vitro. In contrast, prazosin potentiated the inhibitory actions of nifedipine on pressor responses to norepinephrine in vivo without having significant effects on the antagonistic actions of nifedipine on norepinephrine responses in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Is the hypotension of cirrhosis a GABA-mediated process?

Systolic and diastolic blood pressures were recorded in 176 ambulant patients with chronic liver disease, including 36 patients with compensated cirrhosis (Group I), 119 patients with noncirrhotic chronic liver disease (Group II) and 21 patients with benign structural or functional liver disease (Group III). Group I patients had significantly lower systolic (113.0 +/- 2.2 mm Hg, mean +/- S.E.) and diastolic (65.3 +/- 1.7 mm Hg) pressures than Group II patients (125.8 +/- 3.5 and 76.6 +/- 1.5 mm Hg, respectively (p less than 0.0001) or Group III patients (125.1 +/- 3.4 and 77.5 +/- 2.4 mm Hg, respectively) (p less than 0.0001). Serum levels of GABA, a potent amino acid neurotransmitter with known vasodilatory effects in vitro, were higher in Group I patients (1.12 +/- 0.26 microM, mean +/- S.E.) than in Group II patients (0.41 +/- 0.05 microM) (p less than 0.005) or Group III patients (0.34 +/- 0.03 mM) (p less than 0.05). A constant infusion of GABA into the systemic circulation of six adult dogs, at rates required to achieve serum GABA levels within one order of magnitude of those observed in humans with cirrhosis, resulted in a 17.0 +/- 4.3 mm Hg decrease in systolic pressure (p less than 0.05) and a 10.8 +/- 3.7 mm Hg decrease in diastolic pressure (p less than 0.05). Control amino acids were not vasoactive. The results of this study suggest that, in addition to other vasoactive compounds, a GABA-mediated process might contribute to the hypotension observed in patients with compensated cirrhosis.

Distinct vascular actions of epidermal growth factor-urogastrone and transforming growth factor-alpha.

We compared the effects of epidermal growth factor-urogastrone (EGF-URO) with those of transforming growth factor-alpha (TGF-alpha) on regional blood flow in the anesthetized dog in vivo, and on isolated canine helical coronary artery strips in vitro. Like EGF-URO, TGF-alpha was a potent stimulator of femoral arterial blood flow in vivo; and, when added to the tissue bath in vitro before an agonist, TGF-alpha like EGF-URO was a potent inhibitor of the contractile responses of helical coronary arterial strips to various smooth muscle agonists: norepinephrine (NE), prostaglandin F2 alpha (PGF alpha) and potassium chloride (KCl). Nonetheless, there were marked differences between EGF-URO and TGF-alpha in terms of the two biological responses measured. In terms of blood flow, although the ED50 for the increase in blood flow was similar for EGF-URO and TGF-alpha (ED50 = 0.4 micrograms EGF-URO equivalents per dose), the maximum responsiveness to TGF-alpha (130% increase in flow) was substantially greater than the maximum response to EGF-URO (70% increase in flow). Furthermore, TGF-alpha did not cause tachyphylaxis to subsequent doses of TGF-alpha, whereas a prior dose of either EGF-URO or TGF-alpha desensitized markedly the blood flow preparations to EGF-URO. Different desensitization patterns for the actions of EGF-URO and TGF-alpha also were observed in the arterial strip preparations. The inhibitory action of EGF-URO for agonist (NE, PGF2 alpha or KCl)-mediated contraction was diminished with repeated exposure of the tissue to EGF-URO, whereas the inhibitory action of TGF-alpha persisted with repetitive tissue exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidermal growth factor-urogastrone causes vasodilatation in the anesthetized dog.

Epidermal growth factor-urogastrone (EGF-URO) administered intraarterially was a potent dilator in dog femoral (FEM), superior (cephalic) mesenteric (SMA), celiac (CAC), coronary (COR), carotid (CAR), and renal (REN) vascular beds. The effects of EGF-URO, which exhibited tachyphylaxis, could not be attributed either to recirculating EGF-URO or to the secondary release of other agonists or products of the cyclooxygenase pathway. Two vascular beds (FEM, SMA) showed a high maximum responsiveness to EGF-URO (maximum effect [Emax] approximately equal to 70% increase in flow) whereas another group (CAC, COR, CAR, and REN) exhibited lower responsiveness (Emax approximately equal to 20%). The ED50 for this effect of EGF-URO was in the range of 0.4 micrograms (FEM, SMA, CAR, and COR) to 0.9 micrograms (CAC and REN). In isolated dog COR helical strips, EGF-URO did not exhibit either a direct relaxing or a contractile effect. However, preincubation of strips with EGF-URO caused up to a 66% inhibition of contraction in response to norepinephrine (1 microM), with an ED50 for EGF-URO of 1 nM. This action of EGF-URO also showed marked tachyphylaxis. Our data point to a potential role for EGF-URO (and possibly for the structurally related alpha-transforming growth factor) in the regulation of blood flow in vivo.

Differential antagonism of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses by urotensin I, a selective mesenteric vasodilator peptide.

In order to characterize the hemodynamic actions of urotensin I, a vasodilator peptide with selectivity for the mesenteric vascular bed, we studied its hypotensive effects and interference with alpha-1 and alpha-2 adrenergic vasoconstrictor responses in the rat. After i.v. administration in anesthetized rats, urotensin I (0.06-6 nmol/kg) produced a dose-dependent lowering of arterial blood pressure. At hypotensive doses, urotensin I was about 3 times more potent in antagonizing systemic pressor responses to the selective alpha-1 adrenoceptor agonist, phenylephrine, than responses to the nonselective adrenoceptor agonist, norepinephrine. Additional studies were performed on the blood-perfused mesenteric bed of the anesthetized rat and on the isolated rat superior mesenteric artery, using as tools phenylephrine, norepinephrine and the relatively selective alpha-2 adrenoceptor agonist, alpha-methylnorepinephrine. The selectivity of the three agonists for vascular alpha-1 and alpha-2 adrenoceptors in the blood-perfused mesenteric bed was confirmed using prazosin and yohimbine as selective antagonists of alpha-1 and alpha-2 adrenoceptors, respectively. Urotensin I diminished the maximum increase in perfusion pressure and shifted the log dose-response curves to the right for all three agonists. A marked selectivity of urotensin I for alpha-1 adrenoceptor-mediated responses was observed: IC30 values of the peptide for pressor responses to phenylephrine, norepinephrine and alpha-methylnorepinephrine were 0.05, 0.83 and greater than 6 nmol/kg, respectively. A less pronounced selectivity of urotensin I for alpha-1 adrenoceptor-mediated contractions could be demonstrated in isolated strips of the superior mesenteric artery of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Residual stalks of pedunculated adenomas. An underrecognized type of colonic polyp.

Variable lengths of stalk of colonic pedunculated adenomas may be left behind at polypectomy. At follow-up endoscopy, a residual stalk is a smooth-surfaced, sessile polyp, without a distinct head, and may be difficult to remove. It may be mistaken endoscopically for either a recurrent adenoma or a polyp missed at the original procedure. Histologically, it has a coat of normal mucosa and a core of submucosa in which recanalized blood vessels, scarring, and hemosiderin deposition (consequences of thermocautery) may be seen. We present four cases illustrating the clinicopathologic problem and the pathologic appearances. One caused clinical concern because of its size and location at the site of former polypectomy. One was histologically confusing and raised the question of a vascular malformation. The third, seen at segmental colectomy after endosocopic biopsy of an adenoma, illustrates the gross appearances. The fourth contained regenerative mucosa and recanalized submucosal blood vessels.

Comparison of an intravenous selective mesenteric vasodilator with intraarterial papaverine in experimental nonocclusive mesenteric ischemia.

Acute nonocclusive mesenteric ischemia was produced in dogs anesthetized with pentobarbital by reversible pericardial tamponade, which reduced cardiac output and mesenteric blood flow by approximately 42% and 53%, respectively. Papaverine, infused into the cephalic (superior) mesenteric artery at an average dose of 100 micrograms/kg X min, was completely effective in restoring mesenteric blood flow and correcting altered intestinal oxygen kinetics. However, the same dose of papaverine given intravenously to other dogs was ineffective in correcting the deranged hemodynamics and oxygen kinetics. Larger doses of intravenous papaverine returned mesenteric blood flow toward control values but caused systemic arterial hypotension. In comparison, synthetic urotensin I, a highly selective mesenteric vasodilator peptide, produced results identical to those produced by intraarterial papaverine, even though it was given intravenously in small doses (average dose: 13 ng/kg . min). Moreover, it produced no systemic effects. These results suggest that intravenous urotensin I is as effective as intraarterial papaverine in a model of severe mesenteric ischemia, and that it should be examined for a possible clinical role in the treatment of acute mesenteric ischemia in humans.

Use of selective mesenteric vasodilator peptides in experimental nonocclusive mesenteric ischemia in the dog.

Three structurally related peptides, ovine corticotropin-releasing factor, sauvagine, and urotensin I are selective mesenteric vasodilators in dogs. To assess the possible benefit of these peptides in nonocclusive mesenteric ischemia, they were compared with a nonselective vasodilator, sodium nitroprusside, in the anesthetized dog. Mesenteric blood flow was reduced by approximately 30%, without lowering of systemic arterial pressure, by either digoxin or pericardial tamponade. In the digoxin model, i.v. infusions of corticotropin-releasing factor, sauvagine, and urotensin I restored intestinal vascular resistance and mesenteric blood flow to control values, without causing a fall in systemic arterial blood pressure. In the tamponade model, only urotensin I was assessed, and it produced the same restoration of hemodynamic variables. On the other hand, in both models, i.v. infusions of nitroprusside, which were effective in correcting intestinal vascular resistance, produced a fall in arterial blood pressure (presumably because of systemic dilatation), which prevented restoration of mesenteric blood flow. Intestinal oxygen uptake was not altered by tamponade, but was reduced by 23% in the digoxin model, where it was restored to control values by both the peptides and nitroprusside. The increased oxygen extraction seen in both models was corrected by the peptides but not by nitroprusside, suggesting that nitroprusside may have a direct and offsetting metabolic effect on the gut.

Reticuloendothelial system Fc receptor-mediated clearance of IgG-tagged erythrocytes from the circulation of patients with idiopathic ulcerative colitis and chronic liver disease.

Immune complexes may be important in the pathogenesis of the liver disease associated with idiopathic ulcerative colitis. In the present study, we documented Fc receptor-mediated clearance by the reticuloendothelial system of immune complex-like material from the systemic circulation of 25 healthy control subjects, 19 patients with ulcerative colitis alone, 9 patients with ulcerative colitis and elevated liver enzyme tests and 8 patients with various other forms of chronic liver disease. Following an intravenous infusion of IgG-tagged 51Cr-labeled autologous erythrocytes, serial blood samples were drawn over a 2-hr period of time, and computer-generated clearance curves were obtained. The time required for clearance of 50% of infused erythrocytes (T1/2) was then calculated. Serum immunoglobulin (IgA, IgG and IgM), complement (C3 and C4) and immune complex-like activity (IgG and IgM types) were also determined. Sixteen of 19 (84%) ulcerative colitis patients and 7 of 8 (88%) chronic liver disease patients had normal clearance T1/2's (when compared to 25 healthy controls). Conversely, only 1 of 9 (11%) ulcerative colitis + chronic liver disease patients demonstrated normal clearance function. Aside from serum IgM levels, the results of serum immunoglobulin, complement and immune complex-like determinations were similar in ulcerative colitis and ulcerative colitis + chronic liver disease patients. Serum IgM levels, however, were significantly decreased in ulcerative colitis patients and increased in ulcerative colitis + chronic liver disease patients (p less than 0.001). The results indicate that the reticuloendothelial system of patients with ulcerative colitis and chronic liver disease is impaired in its ability to dear immune complex-like material from the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of selective mesenteric dilator peptides to examine the role of the intestine in experimental hemorrhagic shock.

If mesenteric vasoconstriction sets in motion the chain of events that leads to shock, then the administration of a selective mesenteric vasodilator (which has no other known cardiovascular actions) should prevent, or at least modify, the hemodynamic events in a standardized shock preparation. We used the Wiggers model of experimental hemorrhagic shock in 20 pentobarbital-anesthetized dogs, giving half the dogs a selective mesenteric dilator peptide, sauvagine, to produce selective dilatation of the superior (cephalic) and inferior (caudal) mesenteric circulations. (Sauvagine does not dilate the coeliac vascular bed.) A third, sham-operated group of four dogs served as a time control. Sauvagine produced no observable beneficial effect in terms of hemodynamic measurements, intestinal oxygen kinetics, or intestinal histology. Since we took the precaution of delivering the peptide close-arterially (to ensure delivery during hypoperfusion), we conclude that mesenteric vasoconstriction per se is not the prime event in initiating shock. Since reduced cardiac output during hypovolemia led to diminished mesenteric flow (in spite of vasodilation), these experiments do not exclude the possibility of diminished intestinal blood flow being a central event in shock.

Corticotropin releasing factor-like peptides produce selective dilatation of the dog mesenteric circulation.

Three synthetic peptides, ovine corticotropin-releasing factor, sauvagine, and urotensin I, contain homologous amino acid residues. In the anesthetized dog, all three produce marked and selective dilatation of the mesenteric circulation; none of the peptides influenced blood flow in the renal, femoral, carotid, or even celiac arteries. The mesenteric vasodilatation appeared to be unrelated to the common ability of these peptides to release corticotropin and beta-endorphin, and cannot be abolished or attenuated by conventional blocking agents or inhibitors. The unique action of these peptides suggests that there may be a related peptide in the intestine that acts to regulate intestinal blood flow. The peptides may also prove useful therapeutically in nonocclusive ischemia, if this unusual action is also present in humans.

Decreased nutrient blood flow during dopamine- and epinephrine-induced intestinal vasodilation.

Mesenteric blood flow returned to control values promptly upon termination of i.a. infusions of vasodilator doses of acetylcholine (ACh) and isoproterenol (Iso) into the canine superior mesenteric artery (SMA). However, termination of vasodilator infusions of dopamine (DA) and epinephrine (Epi) into the SMA resulted in an additional increase in flow resembling the reactive hyperemic response observed upon termination of norepinephrine infusion into the SMA. In experiments that measured the effect of these agents on intestinal oxygen kinetics, i.a. ACh and Iso increased oxygen uptake but did not affect percent oxygen extraction. Equivasodilator i.a. infusions of DA and Epi decreased percent oxygen extraction. DA decreased oxygen uptake whereas Epi did not alter oxygen uptake. After administration of phenoxybenzamine, the effects of i.a. DA and Epi on oxygen kinetics became identical to those produced by equivasodilator infusions of ACh or Iso. Moreover, the reactive hyperemia-like response on cessation of DA and Epi infusions was abolished. In experiments that utilized 125I absorption from the jejunum as a measure of intestinal mucosal blood flow, i.a. ACh and Iso were found to increase mucosal blood flow in proportion to the increase in total SMA flow. In contrast, i.a. doses of DA and Epi that increased SMA flow nevertheless decreased mucosal flow. It was concluded that vasodilator doses of dopamine and Epi decrease oxygen delivery to the intestine at least in part due to a decrease in mucosal blood flow; this probably involves action on alpha adrenoreceptors.

A study of efficacy, tolerance and compliance of once-daily versus twice-daily metoprolol (Betaloc) in hypertension. Betaloc Compliance Canadian Cooperative Study Group.

The effects of metoprolol (Betaloc tablets) in a group of 193 hypertensives were compared with the effects of a slow-release formulation (Betaloc Durules) in a further group of 196 patients. Patients were selected at random for treatment. There were no differences between the groups in terms of age, weight, sex, blood pressure, concurrent illness or concomitant therapy. Blood pressure control and apparent adverse effects were similar for both groups; the overall withdrawal rate from each group was similar. Compliance, assessed by tablet counts, was significantly improved in the group receiving once-daily therapy. Simplification of the dosage regimen to once-daily therapy appears to improve the patient's willingness to comply with the physician's instructions.

Isolation, analysis of structure, synthesis, and biological actions of urotensin I neuropeptides.

The 41-residue neuropeptide urotensin I (UI), from the urophyses of two teleost fish species (Cyprinus carpio and Catostomus commersoni), was isolated and purified, and its amino acid sequence was determined and confirmed by synthesis of a fully active peptide. The UI peptide was found to be a close structural and biological homologue of the ovine hypothalamic corticotropin-releasing factor (CRF) and the frog skin peptide sauvagine; UI is, therefore, a phylogenetic prototype of this group of peptides. Extraction of urophyses in hot acetic or hydrochloric acid cleaves an amino terminal tripeptide yielding a fully active UI(4-41). The UI peptides are equipotent with the other two naturally occurring peptides (CRF and sauvagine) in the release of mammalian pituitary corticotropin (ACTH), but UI is several times more potent than the mammalian homologue in the stimulation of release of fish pituitary ACTH. The UI peptide and its mammalian or amphibian homologues have a long-lasting hypotensive action in mammals, via a uniquely selective vasodilatation in the superior (anterior) mesenteric vascular bed only. The significantly lower hypotensive vasodilatory action of the mammalian homologue (CRF) suggests a change in the unknown physiological role of the haemodynamic actions of the UI peptides in the mammalian gastrointestinal tract during phylogenetic progression from fishes to mammals.