Effects of a kappa-opioid agonist,asimadoline, on satiation and GI motor and sensory functions in humans

To compare the effects of the kappa-opioid agonist asimadoline and placebo on visceral sensation and gastrointestinal (GI) motor functions in humans, 91 healthy participants were randomized in a double-blind fashion to 0.15, 0.5, or 1.5 mg of asimadoline or placebo orally twice a day for 9 days. We assessed satiation (nutrient drink test), colonic compliance, tone, perception of colonic distension (barostat), and whole gut transit (scintigraphy). Treatment effect was assessed by analysis of covariance. Asimadoline increased nutrient drink intake (P = 0.03). Asimadoline decreased colonic tone during fasting (P = 0.03) without affecting postprandial colonic contraction, compliance, or transit. Gas scores in response to colonic distension were decreased with 0.5 mg of asimadoline at low levels (8 mmHg above operating pressure) of distension (P = 0.04) but not at higher levels of distension. Asimadoline at 1.5 mg increased gas scores at 16 mmHg of distension (P = 0.03) and pain scores at distensions of 8 and 16 mmHg (P = 0.003 and 0.03, respectively) but not at higher levels of distension. Further studies of this compound in diseases with altered satiation or visceral sensation are warranted.     

Effect of the α2δ ligand, pregabalin, on colonic sensory and motor functions in healthy adults

Pregabalin, an α2δ ligand, is used clinically to treat somatic pain. A prior study suggested that pregabalin reduces distension-induced pain while increasing rectal compliance. We aimed to quantify effects of pregabalin on colonic sensory and motor functions and assess relationships between sensory effects and colonic compliance. We conducted a randomized, double-blind, placebo-controlled, parallel-group study of a single oral administration of 75 or 200 mg of pregabalin in 62 healthy adults (aged 18-75 yr). Subjects underwent left colon intubation. We assessed "stress-arousal symptoms", compliance, sensation thresholds, sensation ratings averaged over four levels of distension, fasting and postprandial colonic tone, and phasic motility index (MI). Analysis of covariance (adjusted for age, sex, body mass index, and corresponding predrug response) and proportional hazard models were used. There were no clinically important differences among treatment groups for demographics, predrug compliance, tone, MI, and sensation. Treatment was associated with reduced energy and increased drowsiness but no change in tension or relaxation. Sensation ratings averaged over the four distension levels were lower for gas sensation [overall effect P = 0.14, P = 0.05 (pregabalin 200 mg vs. placebo)] and for pain sensation [overall effect P = 0.12, P = 0.04 (pregabalin 200 mg vs. placebo)]. The magnitude of the effect of 200 mg of pregabalin relative to placebo is on average a 25% reduction of both gas and pain sensation ratings. Pregabalin did not significantly affect colonic compliance, sensation thresholds, colonic fasting tone, and MI. Thus 200 mg of pregabalin reduces gas and pain sensation and should be tested in patients with colonic pain.     

Rectal and colonic distension elicit viscerovisceral reflexes in humans

Colonic transit is slowed in patients with disordered rectal evacuation, but the mechanism of this phenomenon is unclear. Our objective was to investigate rectocolonic inhibitory reflexes in humans to provide potential insight into patients with obstructed defecation. In 30 healthy subjects, a barostat-manometric assembly recorded colonic tone and phasic activity in the descending colon during rectal distension and recorded rectal tone during colonic distension. Phasic distensions were 8, 16, and 32 mmHg above balloon operating pressure, and staircase inflations were comprised of balloon inflation then deflation in 2-mmHg increments at 30-s intervals from 0 to 36 mmHg. Colonic balloon volumes increased to a similar extent during phasic rectal distensions 8, 16, and 32 mmHg above operating pressure, reflecting reduced colonic tone; balloon volumes also increased and phasic pressure activity decreased during staircase rectal distensions. In contrast, rectal balloon volume declined, reflecting increased tone during phasic and staircase colonic distensions. Thus rectal distension inhibited colonic motor activity, indicative of a viscerovisceral inhibitory reflex.     

Effects of a cannabinoid receptor agonist on colonic motor and sensory functions in humans: a randomized, placebo-controlled study

Cannabinoid receptors (CBR) are located on cholinergic neurons in the brain stem, stomach, and colon. CBR stimulation inhibits motility in rodents. Effects in humans are unclear. Dronabinol (DRO), a nonselective CBR agonist, inhibits colonic motility and sensation. The aim of this study was to compare effects of DRO and placebo (PLA) on colonic motility and sensation in healthy volunteers. Fifty-two volunteers were randomly assigned (double-blind) to a single dose of 7.5 mg DRO or PLA postoperative with concealed allocation. A balloon-manometric assembly placed into the descending colon allowed assessment of colonic compliance, motility, tone, and sensation before and 1 h after oral ingestion of medication, and during fasting, and for 1 h after 1,000-kcal meal. There was an overall significant increase in colonic compliance (P = 0.045), a borderline effect of relaxation in fasting colonic tone (P = 0.096), inhibition of postprandial colonic tone (P = 0.048), and inhibition of fasting and postprandial phasic pressure (P = 0.008 and 0.030, respectively). While DRO did not significantly alter thresholds for first gas or pain sensation, there was an increase in sensory rating for pain during random phasic distensions at all pressures tested and in both genders (P = 0.024). In conclusion, in humans the nonselective CBR agonist, DRO, relaxes the colon and reduces postprandial colonic motility and tone. Increase in sensation ratings to distension in the presence of relaxation of the colon suggests central modulation of perception. The potential for CBR to modulate colonic motor function in diarrheal disease such as irritable bowel syndrome deserves further study.     

Attenuation of the colorectal tonic reflex in female patients with irritable bowel syndrome

Alterations in normal intestinointestinal reflexes may be important contributors to the pathophysiology of irritable bowel syndrome (IBS). Our aims were to compare the rectal tonic responses to colonic distension in female IBS patients with predominant constipation (IBS-C) and with predominant diarrhea (IBS-D) to those in healthy females, both fasting and postprandially. Using a dual barostat assembly, 2-min colonic phasic distensions were performed during fasting and postprandially. Rectal tone was recorded before, during, and after the phasic distension. Colonic compliance and colonic sensitivity in response to the distension were also evaluated fasting and postprandially. Eight IBS-C patients, 8 IBS-D patients, and 8 age- and sex-matched healthy subjects (group N) participated. The fasting increments in rectal tone in response to colonic distension in both IBS-C (rectal balloon volume change -4.6 +/- 6.1 ml) and IBS-D (-7.9 +/- 4.9 ml) were significantly reduced compared with group N (-34 +/- 9.7 ml, P = 0.01). Similar findings were observed postprandially (P = 0.02). When adjusted for the colonic compliance of individual subjects, the degree of attenuation in the rectal tonic response in IBS compared with group N was maintained (fasting P = 0.007; postprandial P = 0.03). When adjusted for colonic sensitivity there was a trend for the attenuation in the rectal tonic response in IBS patients compared with group N to be maintained (fasting P = 0.07, postprandial P = 0.08). IBS patients display a definite attenuation of the normal increase in rectal tone in response to colonic distension (colorectal reflex), fasting and postprandially. Alterations in colonic compliance and sensitivity in IBS are not likely to contribute to such attenuation.     

Modulatory influences on antegrade and retrograde tonic reflexes in the colon and rectum

Tonic reflexes in the colon and rectum are likely to be important in health and in disorders of gastrointestinal function. The aim of this study was to evaluate the fasting and postprandial "colorectal" and "rectocolic" reflexes in response to 2-min isobaric distensions of the colon and rectum, accounting for enteric sensation, compliance, and distending balloon volume. In 14 healthy fasting subjects, a dual barostat assembly was positioned (descending colon and rectum). A 2-min phasic distension was performed in the colon and rectum in random order while the opposing balloon volume was recorded. Sensation (phasic distension) and compliance (ramp distension) were also determined. The experiment was repeated postprandially. Colonic distension resulted in significant rectal tonic contraction in the fasting (rectal volume change: -35.4 +/- 8.4 ml, P < 0.01) and postprandial (-22.2 +/- 8.4 ml, P < 0.01) states. After adjustment for colonic sensitivity, for compliance, and for distending balloon volume, the rectal volume change remained significant; the extent of the tonic response, however, correlated significantly with increasing pain score (P < 0.01). In contrast, rectal distension did not produce a significant tonic response in the colon (fasting: -6.5 +/- 7.3 ml; postprandial: 2.7 +/- 7.3 ml), either unadjusted or adjusted for rectal sensitivity, compliance, and distending balloon volume. In conclusion, the colorectal reflex, but not the rectocolic reflex, can be readily demonstrated both before and after a meal in response to a 2-min isobaric distension in the colon and rectum, respectively. Although the presence of the colorectal reflex does not depend on colonic sensitivity or the volume of the distending colonic balloon, these factors modulate the reflex, especially in the fasting state.     

Cholinergic stimulation enhances colonic motor activity, transit, and sensation in humans

The cholinesterase inhibitor neostigmine indirectly stimulates muscarinic M(1)/M(2)/M(3) receptors, thereby reducing colonic distension in acute colonic pseudo-obstruction. We investigated the dose-response profile for the colonic sensorimotor effects of neostigmine and bethanechol, a direct muscarinic M(2)/M(3) agonist in humans. A barostat-manometric assembly recorded phasic pressures, tone, and pressure-volume relationships (compliance) in the descending colon and rectum of 30 healthy subjects who received intravenous neostigmine (0.25, 0.75, or 1.5 mg; n = 15) or subcutaneous bethanechol (2.5, 5, or 10 mg; n = 15). Sensation to luminal distension was also assessed. Thereafter, the effects of neostigmine and bethanechol on colonic transit (geometric center) were compared with those of saline by scintigraphy in 21 subjects. Both drugs increased colonic phasic pressure activity, reduced rectal compliance, and enhanced urgency during rectal distension. Neostigmine also reduced colonic and rectal balloon volumes, reflecting increased tone by an average of 12% and 25% for the highest dose, respectively. Only neostigmine reduced colonic compliance, accelerated colonic transit [mean geometric center at 90 min 2.5 vs. 1.0 (placebo)], and increased pain perception during colonic distension. We conclude that neostigmine has more prominent colonic motor and sensory effects than bethanechol. Moreover, neostigmine induces coordinated colonic propulsion, perhaps by stimulating muscarinic M(1) receptors in the myenteric plexus.     

Candidate genes and sensory functions in health and irritable bowel syndrome

Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (GI) function; these effects are mediated through G protein transduction. Candidate genetic variations in ADR-SER were significantly associated with somatic scores in irritable bowel syndrome (IBS) and gastric emptying but not small bowel or colonic transit. Our aim was to assess whether candidate ADR-SER genes are associated with motor and sensory GI functions in IBS and subgroups on the basis of bowel dysfunction. In 122 patients with IBS and 39 healthy controls, we assessed gastrointestinal somatic symptoms and affect by validated questionnaires. We measured: gastric volume (GV), maximum tolerated volume, rectal compliance, sensation thresholds and ratings, and genetic variations including alpha2A (C-1291G), alpha2C (Del 332-325), GNbeta3 (C825T), and 5-HTTLPR. Demographics and genotype distributions were similar in the patients with IBS subgrouped on bowel function. There were significant associations between 5-HTTLPR SS genotype and absence of IBS symptoms and between 5-HTTLPR LS/SS genotype and increased rectal compliance and increased pain ratings, particularly at 12 and 24 mmHg distensions. GNbeta3 was associated only with fasting GV; we did not detect associations between alpha2A genotype and the gastrointestinal sensory or motor functions tested. We concluded that 5-HTTLPR LS/SS genotype is associated with both increased pain sensation and increased rectal compliance though the latter effect is unlikely to contribute to increased pain sensation ratings with LS/SS genotype. The data suggest the hypotheses that the endophenotype of visceral hypersensitivity in IBS may be partly related to genetic factors, and the association of GNbeta3 with fasting GV may explain, in part, the reported association of GNbeta3 with dyspepsia.     

Genetic variation in endocannabinoid metabolism, gastrointestinal motility, and sensation

Cannabinoid agonist inhibits gastrointestinal motility. The endocannabinoid, anandamide, is inactivated by fatty acid amide hydrolase (FAAH). A single nucleotide polymorphism in the human FAAH gene (C385A) reduces FAAH expression. Our aim was to evaluate associations between FAAH genotype variation and symptom phenotype, gastric emptying and volume, colonic transit, and rectal sensation in patients with functional gastrointestinal disorders (FGID). 482 FGID patients [Rome II positive, 159 constipation disorders, 184 diarrhea disorders (D-IBS), 86 mixed bowel function (M-IBS), 20 chronic abdominal pain (CAP), 33 functional dyspepsia], and 252 healthy volunteers (HV) underwent questionnaires and studies of phenotype and genotype from 2000 to 2007: 250 gastric emptying, 210 fasting and postprandial gastric volume, 152 colonic transit, and 123 rectal sensation. All had FAAH genotype [CC vs. polymorphic (CA/AA)] determined by TaqMan. FAAH genotype distribution of FGID patients and HV did not deviate from Hardy-Weinberg equilibrium. There was a significant association of FAAH genotype with FGID phenotype (overall chi(2), P = 0.011) and with specific individual phenotypes (P = 0.048). Thus FAAH CA/AA increases the odds (relative to HV) for D-IBS (P = 0.008), M-IBS (P = 0.012), and, possibly, CAP (P = 0.055). There was a significant association of FAAH CA/AA genotype with accelerated colonic transit in D-IBS (P = 0.037). There was no association of FAAH genotype with rectal sensation thresholds or ratings. The association of genetic variation in metabolism of endocannabinoids with symptom phenotype in D-IBS and M-IBS and with faster colonic transit in D-IBS supports the hypothesis that cannabinoid mechanisms may play a role in the control of colonic motility in humans and deserve further study.     

Increases in weight and body size increase the odds for hypertension during 7 years of follow-up

Changes in BMI and body size were compared to incident hypertension in 24,550 men and 10,111 women followed prospectively as part of the National Runners' Health Study to test whether long-term weight change affects hypertension risk. Incident hypertensions were reported by 2,143 men and 430 women during (mean +/- s.d.) 7.8 +/- 1.8 and 7.5 +/- 2.0 years of follow-up, respectively. Despite being active, men's and women's BMI increased 1.15 +/- 1.70 and 0.95 +/- 1.89 kg/m(2), respectively, and their waist circumferences increased 2.97 +/- 5.02 and 3.29 +/- 6.67 cm, respectively. Compared to those whose BMI declined, those who gained >or=2.4 kg/m(2) had an odds ratio (95% confidence interval) of 1.68 (1.45, 1.94) for becoming hypertensive if male and 1.42 (1.05, 1.92) if female. Men whose waist circumference increased >or=6 cm had an odds ratio of 1.22 (1.01, 1.47) for becoming hypertensive compared to those whose waists decreased. In both sexes, the odds for hypertension were significantly related to BMI at follow-up when adjusted for baseline BMI, but generally not to baseline BMI when adjusted for follow-up BMI. In the subset whose weights remained relatively unchanged during follow-up (+/-0.4 kg/m(2)), each kg/m(2) increment in BMI was associated with an odds ratio for becoming hypertensive of 1.19 (1.14, 1.24) in men and 1.11 (1.02, 1.20) in women. Thus, even among lean, physically active individuals: (i) weight gain increases hypertension risk; (ii) higher body weight increases the hypertension risk in a dose-dependent manner in the absence of any weight change; and (iii) there is no advantage carried forward to having been previously lean.     

Associations between obesity and changes in adult BMI over time and colon cancer risk

Obesity has been associated with increased colon cancer risk in epidemiological studies; however, the specific time periods during which obesity may be most relevant as well as how changes in adult body size over time affect colon cancer risk have not been well explored. We evaluated potential associations between BMI in each age decade(20s, 30s, 40s, 50s, and 2 years before study recruitment ("recruitment period")) and in BMI changes over timeand colon cancer risk in a population-based case-control study comprising 438 cases and 491 controls. We found that obese (BMI>or=30.0 kg/m2) compared to normal (BMI>or=18.5 to <25.0 kg/m2) body size at the recruitment period was associated with increased colon cancer risk (odds ratio (OR)=1.54; 95% confidence interval (CI)=1.03-2.31; P=0.03). No associations were observed for obese body size in the other age decades. An increased risk was found for changes in BMI between the 30s decade and the recruitment period of 5-10 kg/m2 (OR=1.54; 95%CI=1.02-2.34; P=0.04) and >10 kg/m2 (OR=2.40; 95% CI=1.23-4.66; P=0.01) (P trend=0.01). Stratification by gender revealed that BMI changes>10 kg/m2 increased risk in women but not men. Similar results were found for BMI changes between the 20s decade and the recruitment period but effect sizes were smaller. Our results provide additional support to obesity's role in colon cancer and suggest large body size increases exceeding 10 kg/m2 may potentially be more important after age 30, particularly among women; however, prospective studies with sex hormone, growth factor, and pro-inflammatory biomarkers are needed to provide insights to the underlying biological mechanism(s).     

Intra-abdominal adipose tissue is independently associated with sex-hormone binding globulin in premenopausal women

Lower serum concentrations of sex-hormone binding globulin (SHBG) are associated with increased risk for several obesity-related diseases in women including hormone-sensitive cancers, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Previous investigations have reported that body composition, specifically central obesity, and/or higher insulin concentrations are key factors associated with lower SHBG in overweight and obese women; however, these studies were limited by their cross-sectional design. We hypothesized that intra-abdominal adipose tissue (IAAT), a fat depot linked with an abnormal metabolic profile, is inversely and independently associated with SHBG. Therefore, we determined the longitudinal associations among SHBG, insulin, and IAAT in 107 premenopausal women enrolled in a weight loss study. Overweight (BMI 27-30 kg/m(2)) women were weight reduced until BMI of ≤ 24 was achieved. Body composition and IAAT were measured at baseline and after weight loss with dual-energy X-ray absorptiometry and computed tomography, respectively. Serum concentrations of insulin and SHBG were determined. Paired t-test showed that insulin and IAAT decreased significantly and SHBG increased significantly following weight loss (P < 0.0001 for all). Simple correlations from baseline showed no association with insulin and SHBG (r = -0.142, P = 0.143) and a significant inverse association between IAAT and SHBG (r = -0.43, P < 0.0001). Repeated measures mixed-model showed that after adjusting for age and time (weight loss), IAAT was significantly inversely associated with SHBG (P = 0.0002) and there was no association with insulin and SHBG (P = 0.180). We conclude that SHBG concentrations are influenced by IAAT and not insulin in premenopausal women.     

Electroacupuncture at ST-36 accelerates colonic motility and transit in freely moving conscious rats

Acupuncture is useful for functional bowel diseases, such as constipation and diarrhea. However, the mechanisms of beneficial effects of acupuncture on colonic function have scarcely ever been investigated. We tested the hypothesis that electroacupuncture (EA) at ST-36 stimulates colonic motility and transit via a parasympathetic pathway in conscious rats. Hook-shaped needles were inserted at bilateral ST-36 (lower limb) or BL-21 (back) and electrically stimulated at 10 Hz for 20 min. We also studied c-Fos expression in response to EA at ST-36 in Barrington's nucleus of the pons. EA at ST-36, but not BL-21, significantly increased the amplitude of motility at the distal colon. The calculated motility index of the distal colon increased to 132 +/- 9.9% of basal levels (n = 14, P < 0.05). In contrast, EA at ST-36 had no stimulatory effects in the proximal colon. EA at ST-36 significantly accelerated colonic transit [geometric center (GC) = 6.76 +/- 0.42, n = 9, P < 0.001] compared with EA at BL-21 (GC = 5.23 +/- 0.39, n = 7). The stimulatory effect of EA at ST-36 on colonic motility and transit was abolished by pretreatment with atropine. EA-induced acceleration of colonic transit was also abolished by extrinsic nerve denervation of the distal colon (GC = 4.69 +/- 0.33, n = 6). The number of c-Fos-immunopositive cells at Barrington's nucleus significantly increased in response to EA at ST-36 to 8.1 +/- 1.1 cells/section compared with that of controls (2.4 +/- 0.5 cells/section, n = 3, P < 0.01). It is concluded that EA at ST-36 stimulates distal colonic motility and accelerates colonic transit via a sacral parasympathetic efferent pathway (pelvic nerve). Barrington's nucleus plays an important role in mediating EA-induced distal colonic motility in conscious rats.     

The association between glycemia and endothelial function in nondiabetic individuals: the importance of body weight

The aim of this study was to examine the association between glycemia and markers of early atherosclerosis in healthy nondiabetic individuals. In 309 individuals without diabetes or symptomatic cardiovascular disease, we assessed long-term glycemia by glycosylated hemoglobin (HbA1c) and endothelial function by flow-mediated dilatation (FMD) in the brachial artery. HbA1c was negatively associated with FMD (r = -0.162, P = 0.004). Multivariate linear regression analysis after adjusting for common risk factors of cardiovascular disease showed that BMI was an effect modifier of the association between HbA1c and FMD (P = 0.034 for the HbA1c x BMI interaction). We stratified the FMD outcome data into two groups separated by the median BMI (group 1: BMI < or = 26.1 kg/m(2) and group 2: BMI > 26.1 kg/m(2)). In the lower BMI group, HbA1c was an independent predictor of FMD even when adjusted for confounding factors associated with impaired glucose metabolism (r = -0.215, P = 0.009), but in the higher BMI group HbA1c was not associated with FMD (r = -0.051, P = 0.5). In a nondiabetic population, long-term glycemia was associated with endothelial dysfunction only in lean individuals. In the overweight individuals, this association was not apparent, possibly because some of the mechanisms that mediate the effect of glycemia on vascular function are shared by obesity.     

Fueling the Obesity Epidemic? Artificially Sweetened Beverage Use and Long‐term Weight Gain

We have examined the relationship between artificially sweetened beverage (ASB) consumption and long-term weight gain in the San Antonio Heart Study. From 1979 to 1988, height, weight, and ASB consumption were measured among 5,158 adult residents of San Antonio, Texas. Seven to eight years later, 3,682 participants (74% of survivors) were re-examined. Outcome measures were incidence of overweight/obesity (OW/OB(inc)) and obesity (OB(inc)) (BMI > or = 25 and > or = 30 kg/m(2), respectively), and BMI change by follow-up (DeltaBMI, kg/m(2)). A significant positive dose-response relationship emerged between baseline ASB consumption and all outcome measures, adjusted for baseline BMI and demographic/behavioral characteristics. Consuming >21 ASBs/week (vs. none) was associated with almost-doubled risk of OW/OB (odds ratio (OR) = 1.93, P = 0.007) among 1,250 baseline normal-weight (NW) individuals, and doubled risk of obesity (OR = 2.03, P = 0.0005) among 2,571 individuals with baseline BMIs <30 kg/m(2). Compared with nonusers (+1.01 kg/m(2)), DeltaBMIs were significantly higher for ASB quartiles 2-4: +1.46 (P = 0.003), +1.50 (P = 0.002), and +1.78 kg/m(2) (P < 0.0001), respectively. Overall, adjusted DeltaBMIs were 47% greater among artificial sweetener (AS) users than nonusers (+1.48 kg/m(2) vs. +1.01 kg/m(2), respectively, P < 0.0001). In separate analyses--stratified by gender; ethnicity; baseline weight category, dieting, or diabetes status; or exercise-change category--DeltaBMIs were consistently greater among AS users. These differences, though not significant among exercise increasers, or those with baseline diabetes or BMI >30 kg/m(2) (P = 0.069), were significant in all 13 remaining strata. These findings raise the question whether AS use might be fueling--rather than fighting--our escalating obesity epidemic.     

Effect of nifedipine on anorectal sensorimotor functions in health and fecal incontinence

The mechanisms of increased rectal stiffness in women with fecal incontinence (FI) and rectal urgency are not understood. Our hypothesis was that distention-induced activation of mechanosensitive L-type calcium channels in smooth muscle contributes to increased rectal stiffness in FI. Anal pressures, rectal distensibility (compliance, capacity, and contractile response to sinusoidal oscillation), and rectal sensation were assessed before and after oral nifedipine (30 + 10 mg) or placebo in 16 women with FI and 16 asymptomatic women. At baseline, FI patients had a lower anal pressure increment during squeeze (health, 66.9 ± 7.6: FI, 28.6 ± 5.9, mean ± SE, P ≤ 0.01), lower rectal capacity (P = 0.052), and higher rectal pressures during sinusoidal oscillation (health, 13.7 ± 3.2: FI, 21.7 ± 1.4, mean ± SE, P = 0.02) than the healthy women, which suggests an exaggerated rectal contractile response to distention. Nifedipine decreased mean BP, increased heart rate (P = 0.01 vs. placebo), and reduced anal resting pressure (P ≤ 0.01) but did not significantly modify rectal distensibility in health or FI. Plasma nifedipine concentrations (health, 103 ± 21 ng/ml: FI, 162 ± 34 ng/ml) were correlated with increased rectal compliance (r = 0.6, P = 0.02) in all study participants and, in healthy subjects, with decreased rectal pressures during sinusoidal oscillation (r = 0.86, P = 0.01), indicative of reduced stiffness. No consistent effects on rectal perception were observed. These observations confirm that FI is associated with anal weakness and increased rectal stiffness. At therapeutic plasma concentrations, nifedipine reduced anal resting pressure but did not improve rectal distensibility in FI, outcomes that argue against a predominant contribution of myogenic L-type calcium channels to reduced rectal distensibility in FI.     

Effects of selective opioid agonists on feline colonic transit.

The mu agonist morphine and the non-specific opioid antagonist naloxone both may accelerate feline colonic transit; the effects of morphine are dose dependent. Kappa and delta receptor function was studied in the present work. Colonic transit of a radionuclide marker instilled into the cecum was quantitated for 6 hr in a crossover study. The delta agonist [D-Pen2,D-pen5]enkephalin (1 mg/kg, i.m.) prolonged the cecum and ascending colon half-emptying time by 337% (P less than 0.05), and delayed the progression of the geometric center over time. The kappa agonist U-50,488 (1 mg/kg, i.m.) had no apparent effect on the cecum and ascending colon, but delayed filling of the descending colon. Loperamide, an antidiarrheal agent, also delayed colonic transit. Thus, selective opioid agonists have both site and functional differences in their effect on feline colonic transit.     

Role of extrinsic innervation in modulating nitrergic transmission in the canine ileocolonic region

The human colon can dilate, often to life-threatening proportions. Our aim was to explore nitrergic mechanisms underlying colonic dilation in conscious dogs with enterically isolated ileocolonic loops either extrinsically innervated (n = 4) or extrinsically denervated (n = 4). We recorded phasic pressures in ileum and ileocolonic sphincter (ICS), colonic tone, compliance, and relaxation during ileal distension. By NADPH-diaphorase histochemistry, we assessed effects of extrinsic denervation and enteric isolation on nitrergic fibers. Extrinsic denervation increased phasic pressures in ileum, ICS, and colon and abolished ICS and colonic relaxation in response to ileal distension. The nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine (L-NNA) increased phasic pressures at all sites and ICS tone but did not abolish colonic relaxation during ileal distension in innervated loops. L-NNA reduced compliance and induced colonic high-amplitude propagated contractions in denervated loops. The NOS substrate donor L-arginine reversed effects of L-NNA. The number of NADPH-diaphorase fibers increased in both enterically isolated preparations. Nonnitrergic extrinsic nerve pathways mediate reflex colonic relaxation during ileal distension. Enteric isolation augments the number of NOS fibers, an effect not modified by extrinsic denervation.     

Effect of obesity on repeat revascularization in patients undergoing percutaneous coronary intervention with drug-eluting stents

Obesity is a major risk factor for developing coronary artery disease. The impact of obesity on prognosis among those with established coronary disease is less clear. The objective of this study was to evaluate the effect of obesity on repeat revascularization in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). We examined 6,083 patients who were divided into three groups according to BMI: normal (BMI 18.5-24.9 kg/m(2), n = 1,592); overweight (BMI 25-29.9 kg/m(2), n = 3,026) and obese (BMI >30 kg/m(2), n = 1,465). The follow-up focused on clinical-driven repeat revascularization, including target lesion revascularization (TLR) and nonTLR. Median follow-up was 26 months (interquartile range 20-32). There was no significant difference in the incidence of TLR among normal, overweight, and obese patients (6.3% vs. 6.1% vs. 7.1%; P = 0.423). In contrast, the incidence of nonTLR was significantly higher in obese patients compared with normal and overweight (8.4% vs. 6.0% vs. 5.8%, P = 0.003). Multivariate analysis showed that obesity was an independent predictor of nonTLR during follow-up (hazard ratio = 1.39; 95% confidence interval = 1.06-1.83; P = 0.019), along with diabetes and hypercholesterolemia. Concomitant use of statins was independently associated with decreased risk of nonTLR (hazard ratio = 0.75; 95% confidence interval = 0.62-0.92; P = 0.005). In conclusion, among patients undergoing PCI with DES, obesity was not associated with TLR, but was associated with a higher risk of nonTLR.     

Common variants in the CRP gene are associated with serum C-reactive protein levels and body mass index in healthy individuals in Mexico

Variants in the C-reactive protein (CRP) gene have been found to be associated with various phenotypic traits. We evaluated the effect of four SNPs in the CRP gene on serum levels of protein and body mass index (BMI) in 150 unrelated Mexican subjects from 18 to 25 years old, without hypertension, non-overweight, and without inflammatory diseases, non-smoking and non-consumers of alcohol. Subjects were measured for BMI, waist circumference, blood pressure, and serum glucose and triglycerides. The identification of SNPs was performed by PCR-RFLP. Three of the four SNPs were associated with variation in serum levels of CRP, increased in TT (rs1130864) and GG (rs2794521) genotypes, and decreased in the AA genotype of rs1205. The TT genotype was associated with a significant increase in BMI (β = 1.1 kg/m(2), P = 0.04). Two haplotypes were significantly associated with increased serum levels of CRP, but not with BMI. We conclude that variation in the CRP gene affects serum protein levels.