Sergio Cardoso

Predominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities

BACKGROUND/AIMS Irritable bowel syndrome may be influenced by the autonomic nervous system. Abnormalities in autonomic function, colon transit time, and psychological profiles in 21 patients were assessed. METHODS Using modified Manning criteria for irritable bowel syndrome, patients were classified as constipation-predominant or diarrhea-predominant. Autonomic function was determined by one vagal cholinergic and two sympathetic adrenergic measures. Colon transit was assessed by radiopaque markers, and psychological profiles were determined by three inventories. RESULTS Autonomic function tests showed that diarrhea-predominant subgroup values for one sympathetic adrenergic measure (postural adjustment ratio) were significantly different from controls (P < 0.01). Constipation-predominant subgroup values were significantly lower for the vagal cholinergic measure R-R interval (P < 0.05). Colon transit measures differed by subgroup in left, right, rectosigmoid, and total colon transit times. Both subgroups differed significantly from controls on psychological measures; the constipation subgroup showed more psychological distress. CONCLUSIONS Irritable bowel syndrome specific-symptom subgroups had different patterns of autonomic functioning, colonic transit, and psychological measures. The constipation subgroup is associated with a cholinergic abnormality and the diarrhea-predominant subgroup with an adrenergic abnormality. These findings suggest specific associations between the autonomic nervous system, predominant physical symptoms, colon transit time, and psychological factors in patients with irritable bowel syndrome.

Increased Tolerance of Leukemic Mice to Arabinosyl Cytosine with Schedule Adjusted to Circadian System

Mice (BDF1) inoculated with L1210 leukemia survive for a statistically significantly longer span when four courses of arabinosyl cytosine are administered at 4-day intervals-not in courses consisting of eight equal doses at 3-hour intervals, but in sinusoidally increasing and decreasing 24-hour courses, the largest amount being given at previously mapped circadian and circannual times of peak host resistance to the drug. This finding relates to the many therapeutic situations involving rhythmic, and thus predictable, cycles in the hosts tolerance of undesired effects from the agent used.

Changes in Gastric Emptying in Recipients of Successful Combined Pancreas-Kidney Transplants

Gastroparesis causes gastric emptying disorders in patients with chronic diabetes mellitus and it results from reduced smooth muscle contractility secondary to autonomic dysfunction. Today there has been little objective evidence of improvement in gastric emptying following correction of both uremia and diabetes by combined kidney-pancreas transplantation. We used gastrointestinal symptom scores, solid gastric emptying tests and electrogastrography to evaluate the effect of combined kidney-pancreas transplantation on gastric emptying in 8 uremic diabetic patients. The mean age of the patients was 40 years (range: 30-51 years) and the mean duration of diabetes was 24 years (range: 16-30 years). The patients had been on dialysis up to 24 months. The pretransplant A1 mean was 6.5 before improving to 4.3 after transplantation. All patients were receiving exogenous insulin. Our study data indicate that uremic diabetics have a high prevalence of symptomatic gastrointestinal dysfunction including abnormalities of gastric emptying and gastric electrical activity. Following transplantation, the gastrointestinal symptomatology improved significantly. Significant improvement in the rate of gastric emptying also correlated with improvement in the symptom complex. Gastric electrical activity also improved during the follow-up period.

Hypotension During Hemodialysis: Role For Nitric Oxide*

Hypotensive episodes during hemodialysis are a frequent complication in patients with end-stage renal disease. The possibility that nitric oxide (NO), a major regulator of cardiovascular hemodynamics, could be a factor was explored. Pre and postdialysis plasma samples from 17 hemodialysis patients were analyzed for the stable end products of NO,nitrite + nitrate (NO2 + NO3), by the Greiss method. Predialysis NO2 + NO3 levels were significantly higher in end-stage renal disease than in nine age-matched controls (44.08 +/- standard error of mean 5.74 versus 18.67 +/- 3.56 uM, P = 0.017). In more than half of the patients, postdialysis values dropped markedly, whereas in others the value change was far less; several rose above predialysis values. Depending on the nitrite + nitrate reduction ratio (pre minus postdialysis NO2 + NO3 divided by the predialysis value) patients were separated into two groups, A (n = 9 where nitrate + nitrate reduction ratio was > 0.5 and B (n = 8 where nitrate + nitrate reduction ratio was < 0.5). Whereas the mean predialysis NO2 + NO3 values between groups A and B did not differ significantly, postdialysis levels fell from a predialysis mean of 50 uM to 12 uM in group A but rose from 37 uM to 45 uM in group B. The difference between the postdialysis values of group A and group B was significant (P = 0.0264). In group B, mean systolic blood pressure dropped more than in group A, (57.8 mm Hg compared with 21.2 mm Hg, P = 0.0078). When measured by analysis of variance for repeated measures, skin and core temperatures and blood pressures were lower in group B than in group A. The volume of the ultrafiltrate was removed and dialysis duration and mean weight loss did not differ. Thus, in group B, apparently NO formation increased during hemodialysis exceeding the rate of removal or metabolism of the end products, whereas in group A, NO2 + NO3 removal or metabolism was without apparent increase in the formation of NO. The basis for this difference is unknown. Because vasodilation is a major effect of NO, the strong association of severe reduction in blood pressures and increased NO synthesis in subset B suggests a role for NO in hypotensive episodes during hemodialysis.

Prevention of arteriolar rarefaction in the spontaneously hypertensive rat by exposure to simulated high altitude.

Microvascular alterations associated with reversal of hypertension by exposure to simulated high altitude were investigated in the gracilis muscle of the spontaneously hypertensive rat (SHR). Male, 4-week-old SHR were either placed in a hypobaric chamber (SHR-HA) at 430 mmHg or maintained at ambient barometric pressure (SHR-SL) for 8-10 or 12-14 weeks. Measurements of microvascular diameter and density were made by closed-circuit television microscopy. Mean arterial blood pressure was significantly lower in the SHR-HA groups. Functional arteriolar rarefaction occurred in SHR-SL at 8-10 weeks while structural arteriolar rarefaction occurred after 12-14 weeks. In contrast, neither functional nor structural rarefaction of arterioles was observed in the SHR-HA groups. Although functional rarefaction of capillaries did occur in SHR-HA, it was less than that in SHR-SL. Total capillary density, however, was similar in SHR-SL and SHR-HA after 12-14 weeks. Vasoconstriction was decreased in SHR-HA and vasodilated arteriolar diameters were greater than those of SHR-SL. These results show that simulated high altitude lowered blood pressure in SHR and resulted in a microcirculatory bed resembling that seen in a normotensive animal.

Diabetic gastroparesis is associated with an abnormality in sympathetic innervation

Objective To investigate the hypothesis that diabetic gastroparesis might be associated with sympathetic, as well as parasympathetic, autonomic nervous system abnormailites. Patients We evaluated 12 consecutive patients with diabetes mellitus who presented with symptoms of gastroparesis. Methods The autonomic function tests included two measurments of sympathetic adrenergic function [reflex vasoconstriction to cold stress and the postural adjustment ratio (PAR)], and measurement of sympathetic cholinergic function (resting skin temperature) and vagal cholinergic function [EKG R-R interval (RRI)]. Gastric emptying was also measured and analysed by a power exponential model to estimate the solid gastric emptying slope. Patients were separated into delayed and nondelayed solid gastric emptying subgroups, the latter including two patients with rapid gastric emptying. Results All autonmic function measures were significantly lower in the diabetes mellitus group than in normal controls (P <0.001); diabetic patients as a group had slower solid gastric emptying slopes than nondiabetic controls (P ≤0.01). There was no significant correlation between measures of vagal cholinergic function by RRI, the sympathetic cholinergic function by PAR, or sympathetic cholinergic function by skin temperature and solid gastric emptying, but a statistically significant correlation was found between the sympathetic adrenergic measure of vasoconstriction to cold stress and the slope of solid gastric emptying (r = 0.79, P 7ge; 0.01). Diagnostic values for the autonomic function tests when compared to solid gastric emptying revealed sensitivites of 50% for the RRI, 88% for vasoconstriction, 63% for PAR and 71% for skin temperature. Conclusion We recommend that autonomic function measurements in patients with diabetes mellitus and upper gut symptoms should incude tests of sympathetic function as well as traditional tests of vagal cholinergic function.

Assessment of gastric electrical activity and autonomic function among diabetic and nondiabetic patients with symptoms of gastroesophageal reflux.

Gastroesophageal reflux disease (GERD) may present differently in patients with diabetes mellitus (DM) than in nondiabetics (NDM). We compared three tests in two patient groups with GERD symptoms: a DM group (n = 10) and a NDM group (n = 13). The tests were 24-hr esophageal pH, autonomic function testing (AFT), and electrogastrography (EGG). Analysis of the 23 patients revealed the DM group had normal 24-hr pH values (9 of 10 patients, mean pH 3.1 ± 1.7), while NDM displayed abnormal pH values (9 of 13 patients, mean pH 21.2 ± 5.9). AFT results were abnormal in DM (demonstrating cholinergic/adrenergic dysfunction), but normal in NDM. EGG values were abnormal in both groups (mean 3.31 ± 0.1 in each). We conclude that in GERD-symptomatic patients, those with DM frequently have normal 24-hr pH, but abnormal autonomic functioning, in contrast to NDM, who have abnormal 24-hr pH but normal autonomic function. Both groups had identically abnormal mean EGG values.

Reproducibility of exercise-induced modulation of cardiovascular responses to cold stress

The modulation of cardiovascular responses to the cold pressor test (CPT) as produced by exercise was studied in 13 volunteers. The reproducibility of the measurements selected for the study, i.e. heart rate (HR), blood pressure (BP), blood flow (BF) and skin temperature (ST), was investigated through repeat experiments in the fall of 1994 and the winter of 1995. HR was monitored before, during and after a 10-min period of bicycling at 70% of reserve HR. BP, cutaneous BF and ST were measured before and after exercise. Two CPTs (hand into ice-cold water for 1 min) were performed: one preceding exercise and another at 3 min after exercise. The results obtained allow us to conclude that in non-hypertensive volunteers (1) the pronounced cardiovascular responses (ST, BF and BP) induced by CPT are reproducible (p>0.2) when compared to basal level values and (2) cardiovascular responses to cold stress are significantly attenuated by exercise (p<0.03). Our study, therefore, supports and validates the use of our coupled exercise-CPT method in ongoing epidemiological studies attempting to identify individuals at risk for the development of hypertension as well as those most likely to benefit from preventative exercise programs.

Autonomic and Enteric Nervous System Dysfunction May Play a Role in Hyperemesis Gravidarum

Background Nausea and vomiting, seen in 70-85% of all pregnancies, becomes intractable in hyperemesis gravidarum (HG). We aimed to investigate the relationship between HG and autonomic nervous system functioning and gastric electrical activity. Methods Twenty-seven pregnant patients, 21 with HG and six normal, were studied with sympathetic adrenergic; percent vasoconstriction (%VC) and postural adjustment ratio (PAR); parasympathetic vagal cholinergic functions by R-to-R intervals (RRIs), a total autonomic score; and enteric nervous system measured by electrogastrography (EGG). Results Significant differences were found in parasympathetic measures (RRI for HG 29.98 ± 2.95 vs. control 40.91 ± 2.38, P < 0.05); sympathetic PAR was significantly lower in patients (PAR for HG 24.5 ± 5.0 vs. 67.6 ± 11.4 for controls, P < 0.01); mean total autonomic score was significantly lower in HG (131.75 ± 9.61 vs. 196.87 ± 12.8, P < 0.05). EGG results were borderline different (normal < 3.3, HG 3.4 vs. controls 3.0, P = 0.07). Conclusion Autonomic and enteric nervous system dysfunction may play a role in the pathophysiology of HG.

Platelet Alpha-2 Receptors in Normotensive and Hypertensive Pregnancies in Blacks

It is known that hypertension among blacks starts at earlier ages and has a higher mortality rate as compared to other populations. Alpha-2 receptors were compared in the platelets of normotensive (n=19) and hypertensive pregnant black women (n=29). Characterization and identification of alpha-2 receptors were performed by radio receptor assay. Platelet membranes were incubated with various concentrations of [3H]yohimbine as an alpha-2 antagonist. The maximum number of binding sites (Bmax) and dissociation constant (Kd) were determined by Scatchard analysis. The maximum number of binding sites were 331 fM/mg (normotensive n=19), 286 fM/mg (chronic hypertension n=12), and 357 fM/mg (preeclampsia n=17). These values were not statistically significant. Conclusions: alpha-2 platelet receptors are not altered in hypertensive pregnancies.