Role of alterations of carbohydrate metabolism in the mechanism of decreasing the contractile function of the myocardium in patients with diabetes mellitus

Changes in the myocardial contractile function were studied in 44 patients with diabetes mellitus by phasic analysis of the systole of the left ventricle, depending on the level and marked variations in glycemia in the course of 24 hours. The most pronounced phasic shifts by the 1 type of hypodynamia, pointing to reduction of the myocardial contractile function, were revealed in prolonged hyperglycemia, hypoglycemia, and a sharp fall of the blood sugar level at the period of marked 24-hour variations in glycemia. The results of investigations substantiated the fact that stable compensation of diabetes served as the active prophylactic measure of cardiovascular affections in this disease.     

Minimization of hemolysis in centrifugal blood pumps: influence of different geometries

Centrifugal blood pumps are of substantial importance for intraoperative extracorporeal circulation and for temporary cardiac assist. Their development and improvement raises many specific questions, especially on mechanical blood properties, flow distribution, and the resulting biocompatibility. In this comprehensive study the influence of various pump geometries on blood trauma was investigated. For this purpose analytical calculations, hydrodynamic performance, numerical simulation, in vitro hemolysis tests and in vivo experiments were used. The gap between rotor and housing was found to be crucial showing a distinct minimum of hemolysis at a gap of 1.5 mm (in vitro increase of plasma free hemoglobin per 100 ml plasma an hour: delta fHb/hour = 2.4 +/- 0.83 mg%/h at 1.5 mm versus 12 +/- 2.2 mg%/h at 2.5 mm; p < 0.05). Housing diameter and shape of the vanes were of less importance for blood traumatization (d = 60 mm: delta fHb/hour = 6.36 +/- 1.8 mg%/h; d = 70 mm: fHb = 7.1 +/- 1.9 mg%/h; straight radial vanes: 5.2 +/- 1.8 mg%/h; straight inclined vanes: 6.8 +/- 1.2 mg%/h; flexed vanes: 6.1 +/- 2.0 mg%/h). Three animal experiments confirmed the optimization of geometry, with a mean fHb of 2.5 to 3.2 mg% in steady state. Hydrodynamic efficiency revealed to be a necessary, but not a sufficient and sensitive criterion for hemolysis minimization (e.g. changes of eta < 10% for changes of fHb > 500%). Numerical simulation gives an improved insight in flow distribution, but can not yet be applied for quantification of blood trauma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reducing blood pressure and modification of coronary risk factors by therapy with doxazosin

In an open, non-comparative, multicenter trail performed by general practitioners, the efficacy and safety of doxazosin, an inhibitor of postsynaptic alpha 1-adrenoceptors, were studied in 924 patients with mild to moderate hypertension. Under treatment with doxazosin both systolic and diastolic blood pressure decreased significantly from 178.4 +/- 18.2/103.1 +/- 8.6 to 149.1 +/- 12.0/85.6 +/- 7.3 mm Hg; the mean daily dose at the end of the 12 weeks' treatment period was 3.3 +/- 2.6 mg. Heart rate decreased by 5% and body weight by 6%. As compared with baseline values, total cholesterol (255.7 +/- 45.4 vs 232.7 +/- 37.3 mg%), triglycerides (206.3 +/- 97.6 vs 175.2 +/- 70.9 mg%) and blood glucose (101.9 +/- 31.0 vs 97.9 +/- 25.5 mg%) decreased significantly, whilst HDL-cholesterol (47.7 +/- 13.0 vs 51.5 +/- 12.4 mg%) increased. Overall, doxazosin was very well tolerated; only 16% of all patients reported adverse drug reactions. The results of this study confirm the effectiveness of doxazosin as first-line medication in the treatment of hypertension, especially in patients with concomitant metabolic disorders such as hyperlipidemia and diabetes mellitus. Moreover, the patients who appear to benefit most from doxazosin treatment are those who show the highest metabolism-related coronary risk, as calculated according to the Framingham Study equation.     

The effect of stevioside on glucose metabolism in rat

This study was conducted to determine the effect of stevioside (SVS) on glucose metabolism. The experiments were performed in male Wistar rats treated with SVS either by intravenous infusion or feeding. SVS infusion (150 mg/mL) was carried out in doses of 0.67, 1.00, and 1.33 mL.kg-1 body weight.h-1. The plasma glucose level significantly increased both during and after SVS infusion, whereas it was not affected by SVS feeding (13.3 mL.kg-1 body weight). The glucose turnover rate (GTR) of [14C(U)]glucose and [3(-3)H]glucose was not significantly different between control and SVS infusion animals. Percent glucose carbon recycling and glucose clearance were reduced from 28.7 +/- 1.3 to 23.0 +/- 1.6% (p < 0.05) and from 6.46 +/- 0.34 to 4.99 +/- 0.20 mL.min-1.kg-1 body weight (p < 0.01), respectively. The plasma insulin level did not change, whereas the plasma glucose level significantly increased from 120.3 +/- 5.9 to 176.8 +/- 10.8 mg% (p < 0.01) during SVS infusion. Animals pretreated with angiotensin II and arginine vasopressin showed no significant effect, while animals pretreated with prazosin had an attenuated hyperglycemic effect of SVS infusion. Pretreatment with indomethacin or N omega-nitro-L-arginine methyl ester (L-NAME) alleviated the plasma glucose level during the second period of SVS infusion. Pretreatment with the combination infusion of indomethacin and L-NAME reduced the plasma glucose level from 117.0 +/- 1.8 to 109.0 +/- 1.7 mg% (p < 0.001), and normalized the plasma glucose level in the second period of SVS infusion. Insulin infusion inhibited the hyperglycemic effect of SVS infusion. The present results show that the elevation of the plasma glucose level during SVS infusion is not due to the reduction of the insulin level. It is probably the effect of SVS on glucose transport across the cell. Insulin response to a high plasma glucose level is suppressed during SVS infusion. Several interactions among norepinephrine, prostaglandin, and nitric oxide are involved in modulating the hyperglycemia during SVS infusion.     

Glomerular filtration and tubular reabsorption of albumin in preproteinuric and proteinuric diabetic rats

Microalbuminuria (26-250 mg/d) is considered to be an indicator of incipient diabetic nephropathy in humans in insulin-dependent diabetes (IDD). However, before microalbuminuria is observed, glomerular alterations, such as glycosylation of the glomerular basement membrane and glomerular hyperfiltration, in IDD may result in increased filtration of albumin before any observed increase in albumin excretion. Glomerular and tubular albumin kinetics were examined in streptozotocin (65 mg/kg body wt, i.v.) diabetic, Munich-Wistar rats at 7-10 (untreated) and 50-70 d (poorly controlled with small doses of insulin) after the onset of diabetes and compared with nondiabetic controls. Additional rats in each condition received acute lysine treatment to prevent tubular protein reabsorption. Urinary albumin excretion and nonvascular albumin distribution volumes were measured in the renal cortex and compared with morphometric measurements of interstitial space and the proximal tubule to assess intracellular uptake of albumin in the proximal tubule. Urinary albumin excretion under anesthesia was not different in 7-10-d IDD versus controls (19 +/- 3 vs. 20 +/- 3 micrograms/min) but increased in the 50-70-d IDD (118 +/- 13 micrograms/min, P < 0.05). Lysine treatment resulted in increased albumin excretion compared with respective nontreatment in 7-10-d IDD (67 +/- 10 micrograms/min, P < 0.05) but not in controls (30 +/- 6 micrograms/min) or in 50-70-d IDD (126 +/- 11 micrograms/min). Glomerular filtration rate was increased both in 7-10-d IDD (2.7 +/- 0.1 ml/min, P < 0.05) and in 50-70-d IDD (2.6 +/- 0.1 ml/min, P < 0.05) compared with control (2.2 +/- 0.1 ml/min). Calculated urinary space albumin concentrations increased early in IDD with 2.5 +/- 0.4 mg% in 7-10-d IDD and 4.9 +/- 0.6 mg% in 50-70-d IDD compared with control (1.4 +/- 0.3 mg%). The increase in filtration of albumin is in excess of that attributable to hyperfiltration before increased albumin excretion early in diabetes. In 50-70-d IDD, absolute tubular reabsorption of albumin is decreased, correlating to the decrease in brush border height of the proximal tubule.     

Upper airway muscle activity in normal women: influence of hormonal status

Obstructive sleep apnea is a disorder with a strong male predominance. One possible explanation could be an effect of female hormones on pharyngeal dilator muscle activity. Therefore, we determined the level of awake genioglossus electromyogram (EMGgg) and upper airway resistance in 12 pre- and 12 postmenopausal women under basal conditions and during the application of an inspiratory resistive load (25 cmH2O . l-1 . s). In addition, a subgroup of eight postmenopausal women were studied a second time after 2 wk of combined estrogen and progesterone replacement in standard doses. Peak phasic and tonic genioglossus activity, expressed as a percentage of maximum, were highest in the luteal phase of the menstrual cycle (phasic 23.9 +/- 3.8%, tonic 10.2 +/- 1.0%), followed by the follicular phase (phasic 15.5 +/- 2.2%, tonic 7.3 +/- 0.8%), and were lowest in the postmenopausal group (phasic 11.3 +/- 1.6%, tonic of 5.0 +/- 0.6), whereas upper airway resistance did not differ. There was a weak but significant positive correlation between progesterone levels and both peak phasic (P < 0.05) and tonic (P < 0.01) EMGgg. Finally, there was a significant increase in EMGgg in the postmenopausal group restudied after hormone therapy. In conclusion, female hormones (possibly progesterone) have a substantial impact on upper airway dilator muscle activity.     

A two-dimensional Kolmorogov-Smirnov test for binned data

Exercise leads to marked increases in muscle insulin sensitivity and glucose effectiveness. Oral glucose tolerance immediately after exercise is generally not improved. The hypothesis tested by these experiments is that after exercise the increased muscle glucose uptake during an intestinal glucose load is counterbalanced by an increase in the efficiency with which glucose enters the circulation and that this occurs due to an increase in intestinal glucose absorption or decrease in hepatic glucose disposal. For this purpose, sampling (artery and portal, hepatic, and femoral veins) and infusion (vena cava, duodenum) catheters and Doppler flow probes (portal vein, hepatic artery, external iliac artery) were implanted 17 d before study. Overnightfasted dogs were studied after 150 min of moderate treadmill exercise or an equal duration rest period. Glucose ([14C]glucose labeled) was infused in the duodenum at 8 mg/kg x min for 150 min beginning 30 min after exercise or rest periods. Values, depending on the specific variable, are the mean +/- SE for six to eight dogs. Measurements are from the last 60 min of the intraduodenal glucose infusion. In response to intraduodenal glucose, arterial plasma glucose rose more in exercised (103 +/- 4 to 154 +/- 6 mg/dl) compared with rested (104 +/- 2 to 139 +/- 3 mg/dl) dogs. The greater increase in glucose occurred even though net limb glucose uptake was elevated after exercise (35 +/- 5 vs. 20 +/- 2 mg/min) as net splanchnic glucose output (5.1 +/- 0.8 vs. 2.1 +/- 0.6 mg/kg x min) and systemic appearance of intraduodenal glucose (8.1 +/- 0.6 vs. 6.3 +/- 0.7 mg/kg x min) were also increased due to a higher net gut glucose output (6.1 +/- 0.7 vs. 3.6 +/- 0.9 mg/kg x min). Adaptations at the muscle led to increased net glycogen deposition after exercise [1.4 +/- 0.3 vs. 0.5 +/- 0.1 mg/(gram of tissue x 150 min)], while no such increase in glycogen storage was seen in liver [3.9 +/- 1.0 vs. 4.1 +/- 1.1 mg/(gram of tissue x 150 min) in exercised and sedentary animals, respectively]. These experiments show that the increase in the ability of previously working muscle to store glycogen is not solely a result of changes at the muscle itself, but is also a result of changes in the splanchnic bed that increase the efficiency with which oral glucose is made available in the systemic circulation.     

Echocardiographic changes and alterations in lipid profile in cases of subclinical and overt hypothyroidism

Forty four patients (22 of overt hypothyroidism and 22 of subclinical hypothyroidism) and 11 controls underwent lipid profile evaluation and two dimensional echocardiography. Amongst the various parameters evaluated, mean Interventricular Septal (IVS) dimensions were significantly (p < 0.005) raised in overt hypothyroidism [IVS: end diastolic (ED) = 0.973 +/- 0.223 cm.; end systolic (ES) = 1.300 +/- 0.240 cm.] with respect to control group [IVS : ED = 0.747 +/- 0.118 cm.; ES = 1.073 +/- 0.173 cm.]. Mean Left Ventricular Posterior Wall (LVPW) thickness was also significantly (p < 0.005) raised in overt hypothyroidism [LVPW : ED = 0.944 +/- 0.200 cm.; ES = 1.350 +/- 0.243 cm.] in comparison with control group [LVPW : ED = 0.779 +/- 0.091 cm.; ES = 1.176 +/- 0.128 cm.]. Evidence of diastolic dysfunction was present in both subclinical (n = 2) and overt hypothyroidism (n = 6) while pericardial effusion was seen only in overt hypothyroidism (n = 10). Mean Serum cholesterol was significantly raised in both subclinical (192.13 +/- 47.40 mg%) (p < 0.05) and overt hypothyroidism (231.27 +/- 68.30 mg%) (p < 0.005) with respect to control group (157.63 +/- 37.69 mg%). In overt hypothyroid patients mean serum Triglyceride (235.59 +/- 137.53 mg%) (p < 0.05), LDL (126.09 +/- 54.99 mg%) (p < 0.05) and Apo-B (0.698 +/- 0.354 g/L) (p < 0.05) levels were significantly higher as compared to control group (serum triglyceride 165.45 +/- 49.15 mg%, LDL 88.72 +/- 38.75 mg%, Apo-B 0.474 +/- 0.176 g/L.     

Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality

Targeted disruption of the insulin receptor gene (Insr) in the mouse was achieved using the homologous recombination approach. Insr+/- mice were normal as shown by glucose tolerance tests. Normal Insr-/- pups were born at expected rates, indicating that Insr can be dispensable for intrauterine development, growth and metabolism. However, they rapidly developed diabetic ketoacidosis accompanied by a marked post-natal growth retardation (up to 30-40% of littermate size), skeletal muscle hypotrophy and fatty infiltration of the liver and they died within 7 days after birth. Total absence of the insulin receptor (IR), demonstrated in the homozygous mutant mice, also resulted in other metabolic disorders: plasma triglyceride level could increase 6-fold and hepatic glycogen content could be five times less as compared with normal littermates. The very pronounced hyperglycemia in Insr-/- mice could result in an increased plasma insulin level of up to approximately 300 microU/ml, as compared with approximately 25 microU/ml for normal littermates. However, this plasma level was still unexpectedly low when compared with human infants with leprechaunism, who lack IR but who could have extremely high insulinemia (up to > 4000 microU/ml). The pathogenesis resulting from a null mutation in Insr is discussed.     

Hemodynamic effects of medetomidine in the dog: a dose titration study

OBJECTIVE: To characterize the hemodynamic effects of medetomidine administered intravenously at doses ranging from 1 to 20 microg/kg, and to determine whether these effects are dose dependent. STUDY DESIGN: Prospective randomized multidose trial. ANIMALS: Twenty-five clinically normal male beagles (5 groups of 5), aged 1 to 4 years and weighing 13.5 +/- 1.7 kg. METHODS: Medetomidine, at a dose of 1, 2, 5, 10, or 20 microg/kg, was administered intravenously at time 0. Heart rate, arterial pressure, central venous pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure, body temperature, cardiac output, and packed cell volume were measured immediately before and at selected times after medetomidine administration (3, 7, 10, 20, 30, 40, 50, and 60 minutes in all groups, at 90 minutes for the 10 and 20 microg/kg groups, and at 120 minutes for the highest dose). Cardiac index, stroke index, rate-pressure product, systemic vascular resistance index, pulmonary vascular resistance index, and left and right ventricular stroke work indices were calculated. The degree of sedation was subjectively scored by an observer who was blinded to the treatment used. RESULTS: Heart rate, rate-pressure product, cardiac index, and left and right ventricular stroke work indices decreased below baseline values. Central venous pressure and systemic vascular resistance index increased above baseline measurements. Except in the 2 microg/kg group, after an initial and short lasting increase, a prolonged decrease in arterial pressure was observed. CONCLUSIONS: Hemodynamic changes were observed with the intravenous (IV) administration of medetomidine, at any dose. However, the two lowest doses (1 and 2 microg/kg) produced less cardiovascular depression. CLINICAL RELEVANCE: Medetomidine is an alpha-2 adrenoceptor agonist widely used in dogs, producing sedation, analgesia and cardiovascular depression. When using IV medetomidine, a reduction of the recommended dosage (ie, +/-30 to 40 microg/kg) by up to 6 times did not significantly influence the cardiovascular effects.     

Enhancement of morphine-withdrawal and apomorphine-induced aggression by clonidine

The independence of indices of contractility to Starling effects was tested in 6 closed-chest dogs. After vagal and beta-receptors blockade, indices calculated with total left ventricular isometric pressure (TP), were shown to be strongly dependent of rises in end-diastolic pressure (LVEDP) induced by dextran infusion. At LVEDP of 14.6 +/- 1.5, 22.2 +/- 1.1 and 32.8 +/- 1.5 mm Hg (+/- SEM), the peak value of velocity of the contractile elements calculated with total pressure (peak VCE, TP) diminished by 21, 40 and 50%, and the extrapolated value of VCE, TP at zero total pressure (Vmax, TP) diminished by 15, 30 and 44%. In contrast, indices calculated with developed pressure (DP = TP-LVEDP) at the same LVEDP were much less influenced, particularly the extrapolated value of VCE, DP at zero DP (V max, DP5) and (peak dP/dt)/DP did not significantly change. During angiotensin infusion, expected decreases in TP indices secondary to LVEDP rises were partially masked by simultaneous increases in contractility, and DP indices tended to rise. On the other hand, with minimal changes in LVEDP, as during calcium injection and paired stimulation, increases in TP and DP indices demonstrate inotropic effects equally well. Our study also shows that, besides Vmax calculated with DP, the instantaneous ratio of peak dP/dt and DP can also be proposed as a simpler and thus more convenient index of contractility independent of volume changes.     

Ragweed sensitization alters pulmonary vascular responses to bronchoprovocation in beagle dogs

In ragweed (RW)-sensitized beagle dogs, we tested the hypothesis that reactivity of the pulmonary vasculature was enhanced with aerosolized histamine (Hist) and RW. Seven dogs were neonatally sensitized with repeated intraperitoneal RW injections, and 12 dogs were controls (Con). The dogs were anesthetized with intravenous chloralose, mechanically ventilated, and instrumented with femoral arterial and pulmonary artery catheters. Specific lung compliance (CLsp), specific lung conductance (Gsp), systemic vascular resistance index, and pulmonary vascular resistance index (PVRI) were measured before and after bronchoprovocation with Hist and RW. After Hist inhalation (5 breaths of 30 mg/ml), both Con and RW dogs had significant (P < 0.05) decreases in CLsp (-51 +/- 4 and -53 +/- 5%, respectively) and Gsp (-65 +/- 5 and -69 +/- 3%, respectively), but only RW-sensitized dogs had a significant increase in PVRI (38 +/- 10%). After RW inhalation (60 breaths of 0.8 mg/ml), only RW-sensitized dogs had significant increases (62 +/- 20%) in PVRI and decreases in Gsp (-77 +/- 4%) and CLsp (-65 +/- 7%). We conclude that, compared with Con, RW-sensitized beagle dogs have increased pulmonary vasoconstrictive responses with Hist or RW inhalation.     

Beh?et''s disease with acute inflammatory foci and localized secondary organizing pneumonia]

Both high and low affinity sulfonylurea receptors (SURs) reside on glucose responsive neurons where they influence cell firing and neurotransmitter release via the adenosinetriphosphate (ATP)-sensitive K+ (katp) channel. Here, the effect of diabetes on [3H] glyburide binding to SURs was assessed in male obesity-resistant Sprague-Dawley rats rendered diabetic with streptozotocin (65 mg/kg, i.p.). Additional streptozotocin-treated rats were supplemented with insulin (1.5 U/kg/ day). Streptozotocin reduced plasma insulin to 13% of control associated with hyperglycemia (25.3 +/- 1.7 mmol/l), while insulin lowered plasma glucose (9.56 +/- 1.78 mmol/l) to near control levels (7.65 +/- 0.22 mmol/l). Over 7 days, all streptozotocin-treated rats lost 12% of their initial body wt. while controls gained 1%. Despite equivalent wt. loss, streptozotocin-induced diabetes selectively increased high affinity [3H] glyburide binding in the hypothalamic dorsomedial nuclei (DMN) and ventromedial nuclei (VMN) and lateral area (LH). This was prevented by insulin injections. Low affinity binding was similarly increased in the DMN and VMN, as well as two amygdalar subnuclei but decreased in the substantia nigra, pars compacta. Insulin fully prevented these changes only in the DMN and one amygdalar nucleus and the substantia nigra. Therefore, binding to (SURs) appears to be generally upregulated in the face of hypoinsulinemia with hyperglycemia and this is prevented by insulin treatment. These and other data suggest that this combination of abnormalities in diabetes should have an adverse effect on the glucose sensing capacity of the brain.     

Etiopathogenesis of rheumatoid arthritis

We studied osmoregulation of plasma vasopressin in 5 patients with newly diagnosed diabetes mellitus. All patients showed typical symptoms of uncontrolled diabetes mellitus such as marked hyperglycemia, polyuria, and polydipsia, but did not have advanced diabetic complications. Vasopressin release was studied using 5% hypertonic saline infusion test twice: before treatment when the patient was hyperglycemic, and after treatment 1 to 2 months later when the patient was euglycemic. Plasma vasopressin was measured by a sensitive and specific radioimmunoassay. The mean basal plasma vasopressin value in the patients was significantly higher in the hyperglycemic compared with the euglycemic state (3.75 +/- 0.70 vs 1.18 +/- 0.46 pmol/l, respectively; P < 0.05). The relationship of plasma vasopressin with serum sodium, but not plasma osmolality, during hyperglycemia showed an apparent hypersecretion of vasopressin. In both cases, the sensitivity of the vasopressin response to osmotic stimuli was significantly decreased. During euglycemia, the sensitivity of vasopressin secretion to either sodium or osmolality was almost normal, although a slight rise in the osmostat was observed compared with normal subjects. Together, we found that the positive correlation of vasopressin with sodium or osmolality is maintained but significantly altered in patients with untreated diabetes mellitus. Especially noteworthy is the lowered threshold and decreased sensitivity of osmotically-induced vasopressin secretion during hyperglycemia, which may be caused by multiple factors such as diabetes-associated hypovolemia, osmogenic effects of glucose and other osmoles, depletion of the pool of vasopressin available for release, and the metabolic derangement of osmoreceptor/magnocellular neurons.     

Glucose production, utilization, and cycling in response to moderate exercise in obese subjects with type 2 diabetes and mild hyperglycemia

The glucoregulatory and hormonal responses to moderate-intensity exercise (50% VO2max for 45 min) were examined in subjects with type 2 diabetes and mild hyperglycemia. We studied seven obese subjects with type 2 diabetes and seven lean and seven obese control subjects (fasting plasma glucose levels, 7.5 +/- 0.5, 4.8 +/- 0.1, and 5.2 +/- 0.1 mmol/l, respectively). Glucose production, utilization, and cycling (flux between glucose and glucose-6-phosphate [G-6-P]) were measured with [6-(3)H]glucose and [2-(3)H]glucose using the constant specific-activity method. Insulin levels decreased normally during exercise in diabetic subjects. Plasma glucose levels decreased in diabetic subjects, but remained constant in control subjects. Basal glucose production was not different among groups and increased similarly during exercise. The decrease in plasma glucose in diabetic subjects was due to greater glucose utilization (867 +/- 83 vs. 726 +/- 143 micromol x m(-2) x min(-1); P < 0.05). This was a consequence of the mass effect of hyperglycemia, since glucose metabolic clearance increased similarly in all groups. Glucose cycling, expressed as a percentage of total glucose output (i.e., flux through G-6-P) was elevated at rest (P < 0.01), but decreased during exercise (P < 0.01). The catecholamine response to exercise was blunted in diabetic subjects, presumably indicating autonomic dysfunction. In conclusion, during moderate-intensity exercise in obese diabetic subjects with mild hyperglycemia, 1) insulin secretory responses were normally regulated; 2) glucose homeostasis was different from that in nondiabetic subjects because glucose levels decreased during exercise; 3) the decrease in plasma glucose was due to greater-than-normal rates of glucose utilization, which were sustained by hyperglycemia; and 4) elevated basal rates of glucose cycling decreased during exercise, presumably because exercise simultaneously lowered plasma glucose, was associated with a blunted catecholamine response, and accentuated an underlying defect in hepatic glucokinase activity in type 2 diabetes.     

Effects of diabetes and hyperglycemia on disaccharidase activities in the rat

BACKGROUND AND METHODS: To elucidate the effect of hyperglycemia on disaccharidase activities, the specific and total activities of the disaccharidases were measured in the intestinal mucosa and kidney cortex of diabetic and hyperglycemic rats. The diabetes was induced with an intraperitoneal injection of streptozotocin (60 mg/kg). The rats were made hyperglycemic with an intravenous instillation of a solution containing 40% dextrose monohydrate at a rate of 1.5 ml/h for 24 h. RESULTS: The blood glucose level was 387+/-45 mg/dl and 382+/-35 mg/dl (mean +/- standard deviation) in diabetic and hyperglycemic rats, respectively. In diabetic rats the intestinal maltase, sucrase, and lactase activities were significantly higher than those in control rats. Similarly, disaccharidase activities in hyperglycemic rats were significantly higher than those in control rats. The renal maltase activity in diabetic rats was significantly lower than that in control rats. The maltase activity in hyperglycemic rats, however, was not significantly different from that in control rats. CONCLUSIONS: These results suggest that 1) hyperglycemia directly increases the activities of intestinal maltase, sucrase, and lactase; 2) hyperglycemia does not influence renal maltase activity; and 3) hyperglycemia is partly responsible for increased activities of intestinal disaccharidases in diabetes mellitus.     

Cyclic motor activity of the gallbladder maintained in a pylorus-preserving gastrectomy in dogs

The gallbladder has cyclic motor activity (CMA), which is impaired after a conventional gastrectomy. We conducted experiments to determine whether or not a pylorus-preserving gastrectomy (PPG) could maintain gallbladder CMA. Six strain gauge force transducers were implanted into the gastrointestinal tract and gallbladder of six dogs, respectively. The motor activity of the gastrointestinal tract and gallbladder was recorded as a control. PPG was then carried out. The phasic contractions of the gallbladder, which were correlated with the antral contractions in the control state, were synchronized with contractions of the pylorus after PPG. Intravenous administration of CCK-OP (40 ng/kg) induced phasic contractions of the gallbladder at 4.6 +/- 0.2 c/min in 3 of the 6 days with gastric contractions. After PPG, the gallbladder had phasic contractions (4.5 +/- 0.2 c/m), which were synchronized with the contractions of the pylorus in all dogs regardless of the contractions in the remnant stomach. These findings suggest that gallbladder CMa has a closer relationship with the CMA of the pylorus than with the remnant stomach after PPG. Thus, a preservation of the pylorus at the time of gastric surgery will help in maintaining gallbladder function and coordination with the remnant stomach.     

Hemodynamic effects of sub-chronic NO synthase inhibition in conscious dogs: role of EDRF/NO in muscular exertion

Acute and chronic administration of nitric oxide (NO) synthase (NOS) inhibitors increase mean arterial blood pressure (MAP) in rats but their hemodynamic effects in other species remain unknown. Moreover, the role of NO in the control of exercise-induced vasodilation is still debated. To answer these questions, six dogs were instrumented for the continuous measurement of cardiac output (CO, electromagnetic flow probe on the aorta), MAP (aortic catheter) and left ventricular pressure (Konigsberg gauge). Total peripheral resistance (TPR) was calculated as MAP/CO ratio and dP/dt was used as an index of cardiac inotropism. The dogs were treated from day 0 (D0) to 7 (D7) by the NOS inhibitor, N omega-nitro-L-arginine (L-NNA), 20 mg/kg/day (IV). Such a dose regimen resulted in NOS inhibition evidenced (a) in vivo by a reduction of the hypotensive responses to graded doses of acetylcholine and bradykinin, (b) ex vivo by a decrease in the relaxation of the femoral artery to acetylcholine (EC 50 = 2.2 +/- 0.6 10(-7) M after L-NNA vs 2.2 +/- 0.8 10(-8) M in controls). One month after instrumentation, the dogs being conscious, MAP measured at rest remained unchanged following one week L-NNA treatment (from 90 +/- 2 at D0 to 91 +/- 5 mmHg at D7). However, TPR increased (from 3,600 +/- 290 at D0 to 6,300 +/- 510 dyn.s.cm-5 at D7) and CO decreased (from 2.1 +/- 0.2 at D0 to 1.2 +/- 0.1 l/min at D7) (all p < 0.01), partly as the result of a marked bradycardia (from 100 +/- 7 at D0 to 60 +/- 7 beats/min at D7). L-NNA induced-increase in TPR was completely reversed by a bolus injection of nitroglycerin (10 micrograms/kg). During treadmill exercise (12 km/h), heart rate (251 +/- 9 at D0 vs 226 +/- 11 beats/min at D7), CO (6.3 +/- 0.9 at D0 vs 4.3 +/- 0.7 l/min at D7) and stroke volume remained significantly lower, and TPR significantly higher (1,662 +/- 278 at D0 vs 2,621 +/- 489 dyn.s.cm-5 at D7) after L-NNA than in the control state. Thus, NOS inhibition in resting conscious dogs by L-NNA markedly increases peripheral resistance but does not increase arterial pressure. In addition, L-NNA blunts both exercise-induced peripheral vasodilation and increase in cardiac output, despite metabolic vasodilation.