sincalide and Constipation

Topics: Analgesics, Opioid; Colonic Diseases, Functional; Constipation; Diarrhea; Diverticulum, Colon; Electromyography; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Manometry; Parasympatholytics; Prostaglandins; Receptors, Cholecystokinin; Serotonin Antagonists; Sincalide; Somatostatin

Distal colonic motor activity was measured in 12 control subjects and seven constipation-predominant irritable bowel syndrome patients to examine the effects of intravenous administration of cholecystokinin. In the basal state, no significant motility differences were noted between these two groups. Following the intravenous administration of the hormone cholecystokinin, a statistically significant reduction in colonic motility in control subjects and a non-significant decrease in motility in irritable bowel syndrome patients was seen. Our results do not suggest an exaggeration of the colonic motor response to cholecystokinin occurs in irritable bowel syndrome.

Topics: Abdominal Pain; Adult; Cholecystokinin; Colon; Colonic Diseases, Functional; Constipation; Female; Gastrointestinal Motility; Humans; Informed Consent; Injections, Intravenous; Male; Manometry; Sincalide

The slow transit time of the colon in females with constipation is due to impairment of agonist-induced contraction. The impairment is associated with downregulation of G proteins that mediate contraction and upregulation of Gs proteins that mediate relaxation. These changes are caused by overexpression of progesterone (P4) receptors in the colon, rendering its muscle cells sensitive to physiological P4 concentrations. Downregulation of Gq/11 is mediated by P4 receptor B (PR-B). We examined whether upregulation of Gs proteins increased the inhibition of contraction and whether the increase is mediated by the P4 receptor A (PR-A). These studies were conducted in colon-isolated colon muscle cells from human control and slow-transit constipation (STC) females and from guinea pigs. Muscle cell contraction was induced by CCK-8. Inhibition of contraction was induced by vasoactive intestinal polypeptide (VIP), and 8'bromo-c'AMP (8B-c'AMP) G protein levels were determined by Western blot. VIP-induced inhibition of contraction was greater in muscle cells from STC and P4-treated muscle cells. There were no differences in the inhibition induced by 8B-c'AMP between muscle cells from STC and P4-treated controls. The increased VIP-induced inhibition of muscle cells treated with P4 was blocked by pretreatment with PR-A antibodies and unaffected by PR-B antibodies. These antibodies had no effect on 8B-c'AMP induced-inhibition. The P4 upregulation of Gs proteins was blocked by PR-A antibodies and unaffected by PR-B antibodies. Similar results were obtained in muscle cells from guinea pig colons. We concluded that P4 upregulation of Gs proteins increases VIP-induced inhibition of contraction mediated by PR-A.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adult; Animals; Antibodies; Cells, Cultured; Colon; Constipation; Cyclic AMP; Female; GTP-Binding Protein alpha Subunits, Gq-G11; GTP-Binding Proteins; Guinea Pigs; Humans; Male; Middle Aged; Muscle Contraction; Myocytes, Smooth Muscle; Progesterone; Receptors, Progesterone; Sincalide; Vasoactive Intestinal Peptide

Colon muscle strips and cells from female patients with slow-transit constipation (STC) exhibit impaired motility, signal transduction abnormalities characterized by downregulation of Gq/11 and upregulation of Gs proteins, decreased cyclooxygenase (COX)-1 and thromboxane (Tx)B2 levels, increased COX-2 and PGE2 levels, and overexpression of progesterone receptors (PGR). Progesterone (P4) treatment of normal cells reproduced these motility and signal transduction abnormalities. The purpose of the study was to examine whether overexpression of PGR-B reproduces these abnormalities by rendering the cells more sensitive to physiological concentrations of P4. Cultured human colon muscle was transfected with a plasmid DNA expressing PGR-B. The mRNAs of PGR, COX-1, COX-2, and Gq/11 were determined by quantitative real-time PCR. Their protein expression was determined by Western blot, and prostaglandins were measured by radioimmunoassay. Cultured muscle cells maintained their phenotypic features determined with myosin light chain (MLC) and h-caldesmon antibodies. Control and transfected muscle cells responded to 10(-6) M P4. In contrast, muscle cells transfected with PGR-B responded to lower P4 concentration (10(-7) M). This P4 concentration reduced MLC phosphorylation induced by CCK-8 (10(-8) M), downregulated Gq/11, and decreased COX-1 and TxB2 levels. It upregulated Gs proteins. It also increased COX-2 and PGE2 levels. We conclude that overexpression of PGR-B renders the cells more sensitive to physiological concentrations of P4. These results are consistent with the hypothesis that overexpression of PGR-B contributes to the motility and signal transduction abnormalities observed in female patients with STC and normal serum levels of P4.

Topics: Calmodulin-Binding Proteins; Cells, Cultured; Colon; Constipation; Cyclooxygenase 1; Cyclooxygenase 2; Female; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Middle Aged; Myocytes, Smooth Muscle; Myosin Light Chains; Phenotype; Phosphorylation; Progesterone; Prostaglandins; Receptors, Progesterone; RNA, Messenger; Signal Transduction; Sincalide; Time Factors; Transfection; Up-Regulation

We compared responses of the gallbladder to graded intravenous infusions of cholecystokinin octapeptide (CCK-OP) in normal controls (n = 8) and patients with irritable bowel syndrome (IBS) with predominant constipation (n = 8) or diarrhea (n = 8). The doses of CCK-OP ranged from subphysiological (negligible contraction of the gallbladder) to supraphysiological (90% contraction of gallbladder and abdominal side effects) amounts. All gallbladders contracted progressively in response to CCK-OP, and a Weibull model (power exponential function) described precisely the gallbladder's response to CCK-OP. Patients with IBS responded differently from normal patients; those with constipation contracted their gallbladders more and those with diarrhea contracted less in response to the peptide. Gallbladders were also stimulated with a high-fat, liquid meal; all patients' gallbladders contracted, but clear differences between groups could not be demonstrated postprandially. The results suggest that the smooth muscle of the gallbladder in IBS has an abnormal sensitivity to CCK-OP, and the results support the concept that IBS can be a generalized abnormality of the smooth muscle of the digestive tract.

Topics: Adult; Colonic Diseases, Functional; Constipation; Diarrhea; Dietary Fats; Female; Gallbladder; Humans; Male; Muscle Contraction; Muscle, Smooth; Sincalide; Ultrasonography