Tracheobronchial perfusion during exercise in ponies

Tracheobronchial circulation during exercise has previously not been examined. Therefore blood flow to the trachea and bronchi (up to 7th generation of branching) was studied in seven healthy adult ponies at rest and during the 3rd and 10th min of exercise performed at a treadmill speed setting of 25 km/h. The ambient air temperature varied from 19 to 20 degrees C and humidity from 35 to 45%. To determine blood flow radionuclide-labeled 15-microns-diameter microspheres were injected into the left ventricle via a catheter advanced from the left carotid artery (exposed using local anesthesia), and a reference sample was obtained from the aorta. Adequate mixing of microspheres with blood was demonstrated by similar perfusion values for left and right kidneys. Exercise increased heart rate (194 +/- 9 and 200 +/- 7 beats/min) and mean aortic pressure (169 +/- 8 and 156 +/- 4 mmHg) of ponies at 3rd and 10th min. Tracheal blood flow (6.7 +/- 0.5 ml.min-1 x 100 g-1) of resting ponies was only one-third of the bronchial blood flow (21.6 +/- 4.9 ml.min-1 x 100 g-1) Significant changes in tracheal perfusion did not occur at 3rd or 10th min of exercise. Although bronchial perfusion also did not change at the 3rd min of exercise, it rose dramatically to 202.8 +/- 30.3 ml.min-1 x 100 g-1 during the 10th min. Concomitantly, renal blood flow decreased at 10th min of exertion. The large increase in bronchial blood flow at 10th min of exertion may have been necessitated by the need to help dissipate body heat.     

Dehydration increases the magnitude of selective brain cooling independently of core temperature in sheep

By cooling the hypothalamus during hyperthermia, selective brain cooling reduces the drive on evaporative heat loss effectors, in so doing saving body water. To investigate whether selective brain cooling was increased in dehydrated sheep, we measured brain and carotid arterial blood temperatures at 5-min intervals in nine female Dorper sheep (41 +/- 3 kg, means +/- SD). The animals, housed in a climatic chamber at 23 degrees C, were exposed for nine days to a cyclic protocol with daytime heat (40 degrees C for 6 h). Drinking water was removed on the 3rd day and returned 5 days later. After 4 days of water deprivation, sheep had lost 16 +/- 4% of body mass, and plasma osmolality had increased from 290 +/- 8 to 323 +/- 9 mmol/kg (P < 0.0001). Although carotid blood temperature increased during heat exposure to similar levels during euhydration and dehydration, selective brain cooling was significantly greater in dehydration (0.38 +/- 0.18 degrees C) than in euhydration (-0.05 +/- 0.14 degrees C, P = 0.0008). The threshold temperature for selective brain cooling was not significantly different during euhydration (39.27 degrees C) and dehydration (39.14 degrees C, P = 0.62). However, the mean slope of lines of regression of brain temperature on carotid blood temperature above the threshold was significantly lower in dehydrated animals (0.40 +/- 0.31) than in euhydrated animals (0.87 +/- 0.11, P = 0.003). Return of drinking water at 39 degrees C led to rapid cessation of selective brain cooling, and brain temperature exceeded carotid blood temperature throughout heat exposure on the following day. We conclude that for any given carotid blood temperature, dehydrated sheep exposed to heat exhibit selective brain cooling up to threefold greater than that when euhydrated.     

Ventilatory acclimatization to hypoxia is not dependent on cerebral hypocapnic alkalosis

We previously demonstrated that, in awake goats, 6 h of hypoxic carotid body perfusion during systemic normoxia produced time-dependent hyperventilation that is typical of ventilatory acclimatization to hypoxia (VAH). The hypocapnic alkalosis that occurred could have produced VAH by inducing cerebral vasoconstriction and brain lactic acidosis even though systemic arterial normoxia was maintained. In the present study we tested the hypothesis that hypocapnic alkalosis is a necessary component of VAH. Goats were prepared so that one carotid body could be perfused, from an extracorporeal circuit, with blood in which gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Using this preparation we carried out 4 h of hypoxic carotid body perfusion while maintaining systemic arterial (and brain) normoxia in awake goats. Expired minute ventilation (VE) was measured while CO2 was added to inspired air to maintain normocapnia. Carotid body PCO2 and PO2 were maintained near 40 Torr during the 4-h carotid body perfusion. Control mean VE was 8.65 +/- 0.48 l/min (mean +/- SE). With acute carotid body hypoxia (30 min) VE increased to 21.73 +/- 2.02 l/min (P less than 0.05); over the ensuing 3.5 h of carotid body hypoxia, VE progressively increased to 39.14 +/- 4.14 l/min (P less than 0.05). These data indicate that neither cerebral hypoxia nor hypocapnic alkalosis are required to produce VAH. After termination of the 4-h carotid body stimulation, hyperventilation was not maintained in these studies, i.e., there was no deacclimatization. This suggests that acclimatization and deacclimatization are produced by different mechanisms.     

Chronic push-pull brain perfusion in unrestrained rhesus macaques

A system was developed to permit perfusion of local brain regions and simultaneous peripheral blood sampling in free-moving caged monkeys. The system comprises a calvarial headpiece that contains multiple push-pull cannulas (PPC), a flexible stainless steel tether, a four-channel fluid swivel, and a surgical procedure for simultaneous multisite brain cannulation. Rhesus macaques were fitted surgically with an indwelling jugular catheter and PPC directed into the third ventricle, median eminence, and preoptic area. These animals were tethered for periods of 14-70 h during which brain perfusates and peripheral blood samples were collected at 10- to 30-min intervals through the tether-swivel assembly. Levels and pulsatile patterns of gonadotropin-releasing hormone in 10-min perfusate samples and luteinizing hormone and cortisol in sequential plasma samples were quantified by specific radioimmunoassays. The normal endocrine profiles in these animals suggest that this system provides a valuable method to study patterns of neurosecretions in an unrestrained simian.     

Influence of brain angiotensin on thermoregulation and hydromineral balance during pregnancy in rats.

During mammalian pregnancy, body temperature decreases and there are changes in fluid and electrolyte balance. Angiotensin signaling mechanisms in the brain have been shown to influence thermoregulation and body fluid balance in the nonpregnant state. We hypothesized that brain angiotensin is also implicated in adjusting these physiological systems in the pregnant rat. We compared core temperature and fluid regulation in three groups of pregnant rats: untreated rats, rats receiving continuous infusion of an AT(1) antagonist candesartan (5 microg.kg(-1).day(-1)) into a lateral cerebral ventricle to block brain AT(1) receptors, and rats receiving vehicle [artificial cerebrospinal fluid (aCSF)] vehicle. Untreated and aCSF-treated rats showed a decrease in colonic temperature (-0.5 and -0.8 degrees C respectively) by day 20 of gestation. However, rats treated with candesartan had increased colonic temperature compared with baseline (+0.9 degrees C), and their temperature was significantly higher on days 7 (P < 0.05), 17 (P < 0.05), and 20 (P < 0.001) compared with the other groups (aCSF and untreated). Daily food and water intakes and body weight were not different between the three groups. Similarly, litter sizes and pup weights were equal in all groups. Finally, the expected decreases in plasma Na(+) and osmolality during pregnancy were equivalent in all groups. This study suggests that brain angiotensin mediates the progressive decrease in body temperature that occurs during pregnancy. However, the changes in fluid balance associated with pregnancy are not dependent on brain angiotensin.     

Effect of human pancreatic polypeptide (HPP) on the release of anterior pituitary hormones

The effects of different doses of human pancreatic polypeptide (HPP) injected into the third ventricle was studied on plasma follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (Prl) and somatotropin (GH) in freely moving ovariectomized rats. Two hundred ng of HPP produced a significant decrease in plasma LH at 15, 30, and 60 min following microinjection. The LH-lowering effect of 400 and 800 ng of HPP developed at 5 min and persisted throughout the experiment. The strongest inhibition was observed at 15 and 30 min. No change in plasma FSH was detected at any time during the experimental period. Two hundred and 400 ng of HPP failed to influence the plasma Prl, while 800 ng resulted in a moderate but significant decrease in plasma Prl levels at 15 and 30 min following injection. Intraventricular microinjection of 400 ng of HPP decreased the GH level at 15 min and 800 ng caused a more pronounced decrease which was significant at 15, 30, and 60 min after the injection. The study suggested that HPP, either from the periphery if it can pass the blood brain barriers or produced in the brain, can influence pituitary function.     

Transmyocardial revascularization aggravates myocardial ischemia around the channels in the immediate phase

We examined whether transmyocardial revascularization (TMR) relieves myocardial ischemia by increasing regional perfusion via the transmural channels in acute canine experiments. Regional blood flow during transient coronary ligation (2 min) was compared before and 30 min after TMR, and at the third transient ischemia the mid-left ventricle (LV) was cut and immediately frozen along the short axis for the analysis of NADH fluorescence in the regions around the TMR channels. In low-resolution analysis (2-4 g tissue or 2-3 cm(2) area), regional perfusion was not significantly altered after TMR, and NADH fluorescence was observed throughout the ischemic region without significant spatial variation. High-resolution analysis (2.8 mg, 1 mm x 1 mm) revealed that the flow after TMR was lower, and NADH fluorescence was higher in the regions close to the channels (1-2 mm) than in the regions 3-4 mm away from them. Creating TMR channels did not improve the regional perfusion and rather aggravated the local ischemia in the vicinity of the channels in the immediate phase.     

Cerebral blood flow in the fetal guinea-pig

To measure brain blood flow in the fetal guinea-pig, radioactive microspheres were injected in the lateral saphenous vein whilst a reference sample of blood was withdrawn from the right axillary artery. Measurements were made near term of pregnancy, on the 60th-66th day, during anaesthesia with pentobarbitone and diazepam. Fetal blood pressure was 4.25 +/- 0.12 kPa and fetal heart rate was 250 +/- 7 beats per min. The arterial oxygen content varied between 1.9-5.1 mmol 1(-1). Blood flow to the whole brain (mean 1.13 +/- 0.14 ml min-1 g-1) was significantly correlated to the reciprocal of arterial oxygen content (r = 0.84). Four regions of the brain were examined: the cerebral hemispheres, the cerebellum, the thalamus and midbrain, and the pons and medulla. In each region blood flow was inversely related to arterial oxygen content (r = 0.80-0.83) but the rate of perfusion of the brain stem was greater than that of the cerebral hemispheres or cerebellum.     

Effect of exercise on epinephrine turnover in trained and untrained male subjects

The kinetics underlying plasma epinephrine concentrations were studied. Six athletes (T) and six sedentary males (C) were given intravenous infusions of 3H-labeled epinephrine, after which arterial blood was drawn. They rested sitting and bicycled continuously to exhaustion (60 min at 125 W, 60 min at 160 W, 40 min at 200 W, and 240 W to the end). Work time was 154 +/- 13 (SE) (T) and 75 +/- 6 (C) min. At rest, epinephrine clearance was identical [28.4 +/- 1.3 (T) vs. 29.2 +/- 1.8 (C) ml . kg-1 . min-1], but plasma concentration [1.42 +/- 0.27 (T) vs. 0.71 +/- 0.16 (C) nmol . l-1] and, accordingly, secretion [2.9 +/- 0.7 vs. 1.5 +/- 0.4 nmol . min-1] were higher (P less than 0.05) in T than C subjects. Epinephrine clearance was closely related to relative work load, decreasing from 15% above the basal level at 30% of maximal O2 uptake (VO2 max) to 22% below at 76% of VO2 max. Epinephrine concentrations increased much more with work intensity than could be accounted for by changes in clearance and were, at exhaustion, higher (P less than 0.05) in T (7.2 +/- 1.6) than in C (2.5 +/- 0.7 nmol . l-1) subjects despite similar glucose, heart rate, and hematocrit values. At a given load, epinephrine clearance rapidly became constant, whereas concentration increased continuously. Forearm extraction of epinephrine invalidated use of blood from a cubital vein or a hand vein arterialized by hot water in turnover measurements. During exercise, changes in epinephrine concentrations reflect changes in secretion rather than in clearance. Training may increase adrenal medullary secretory capacity.     

The cardiovascular response to lower body negative pressure in humans depends on seal location

We tested whether seal location at iliac crest (IC) or upper abdomen (UA), before and during lower body negative pressure (LBNP), would affect thoracic electrical impedance, hepatic blood flow, and central cardiovascular responses to LBNP. After 30 min of supine rest, LBNP at -40 mm Hg was applied for 15 min, either at IC or UA, in 14 healthy males. Plasma density and indocyanine green concentrations assessed plasma volume changes and hepatic perfusion. With both sealing types, LBNP-induced effects remained unchanged for mean arterial pressure (-3.0+/-1.1 mm Hg), cardiac output (-1.0 l min(-1)), and plasma volume (-11 %). Heart rate was greater during UA (80.6+/-3.3 bpm) than IC (76.0+/-2.5 bpm) (p<0.01) and thoracic impedance increased more using UA (3.2+/-0.2 Omega) than IC (1.8+/-0.2 Omega) (p<0.0001). Furthermore, during supine rest, UA was accompanied by lower thoracic impedance (26.9+/-1.1 vs 29.0+/-0.8 Omega, p<0.001) and hepatic perfusion (1.6 vs 1.8 l.min(-1), p<0.05) compared to IC. The data suggest that the reduction in central blood volume in response to LBNP depends on location of the applied seal. The sealing in itself altered blood volume distribution and hepatic perfusion in supine resting humans. Finally, application of LBNP with the seal at the upper abdomen induced a markedly larger reduction in central blood volume and greater increases in heart rate than when the seal was located at the iliac crest.     

Central effects of atrial natriuretic peptide on plasma catecholamines, vasopressin, renin and beta-endorphin and on renal excretory functions in the dog

Atrial natriuretic peptide (ANP) has been identified in the central nervous system and its participation in regulation of various regulatory brain functions has been postulated. To elucidate whether central ANP influences endocrine systems related to blood pressure regulation and renal excretory functions, effects of infusion of ANP at a rate of 120 ng.min-1 into the third cerebral ventricle on plasma level of epinephrine (E), norepinephrine (NE), renin, vasopressin and beta-endorphin as well as on excretion of urine, sodium, potassium (UKV) solutes and free water (CH2O) were investigated in conscious dogs. Significant decrease of plasma E from 77.6 +/- 7.0 to 62.1 +/- 4.8 pg.ml-1 and of NE from 345.5 +/- 20.7 to 286.4 +/- 15.0 pg.ml-1 was found at the end of 30 min lasting ANP infusion. Significant elevation of PRA and UKV and a decrease in CH2O were found 60 min after ANP infusion. No significant changes in other variables were found. In time control experiments plasma hormones concentration and renal excretory functions were not significantly influenced. The results suggest that central ANP may affect the sympatho-adrenal outflow.     

Hypothalamic, rectal, and muscle temperatures in exercising dogs: effect of cooling

To investigate mechanisms that may be involved in the prolongation of exercise performance with body cooling hypothalamic (Thy), rectal (Tre), and exercising muscle (Tm) temperatures, as well as the heart rate, respiratory rate, blood lactic acid concentration ( [LA] ), and plasma osmolality (Osm) were measured in five dogs during exhaustive treadmill exercise at an ambient temperature (Ta) of 22 +/- 1 degree C without cooling (control) and with external cooling by use of ice packs. In both series of experiments, dehydration of animals was prevented. Compared with exercise with noncooling, exercise with cooling resulted in 1) increased exercise duration from 90 +/- 14 to 145 +/- 15 min (62%, P less than 0.05); 2) attenuated increases in Thy, Tre, and Tm; 3) decreased respiratory and heart rates; and 4) lowered LA. Significant negative correlations were found between both Tm and delta Tm attained at 60 min of the run and time of exercise until exhaustion (r = -0.72 and -0.74, respectively; P less than 0.02). This work failed to differentiate clearly changes or equilibrium levels of brain, core, or muscle temperature as separate factors affecting work tolerance. However, the inverse relationship between Tm reached at 60 min of the run (in both experiments) and the total duration of exercise indicates that sustained muscle hyperthermia may largely contribute to limitation of working ability.     

Central natriuretic peptides regulation of peripheral atrial natriuretic factor release

Atrial natriuretic factor (ANF) and C-type natriuretic peptide (CNP) receptors have been described in encephalic areas and nuclei related to the regulation of cardiovascular as well as sodium and water homeostasis. Stimulation of the anterior ventral third ventricular region of the brain modifies plasma ANF concentration, suggesting the participation of the central nervous system in the regulation of circulating ANF. The aim of this work was to study the effect of centrally applied ANF or CNP on plasma ANF. Normal and blood volume expanded rats (0.8 ml isotonic saline/100 g body weight) were intra cerebralventricularly injected with 1, 10 or 100 ng/μl/min ANF. Blood volume expanded animals were also centrally injected with the same doses of CNP. Blood samples were collected at 5 and 15 min. after intracerebralventricular administration of either ANF or CNP. Centrally applied ANF did not affect circulating ANF in normal blood volume rats. In blood volume expanded animals both ANF (1, 10 or 100 ng/μl/min) and CNP (1 ng/μl/min) decreased plasma ANF concentration after 15 min. Moreover, CNP (10 and 100 ng/μl/min) lowered circulating ANF levels not only at 15 min but also at 5 min. Neither ANF nor CNP elicited any change in mean arterial pressure and heart rate in normal and blood volume expanded rats. These results suggest the existence of a central regulation exerted by natriuretic peptides on circulating ANF levels. Furthermore, this is the first study reporting an effect on plasma ANF induced by centrally applied CNP.     

Possible negative ultra-short loop feedback of luteinizing hormone releasing hormone (LHRH) in the ovariectomized rat

To determine if LHRH might act within the brain to modify its own release, repeated blood samples were removed from conscious ovariectomized rats and minute doses of LHRH were injected into the third ventricle (3V). The effect of these injections on plasma LH and FSH was measured by radioimmunoassay (RIA). The higher dose of intraventricular LHRH (10 ng in 2 microliter) induced an increase in plasma LH within 10 min after its injection. Plasma LH decreased for the next 60 min. This was followed by restoration of LH pulses characteristic of the ovariectomized rat. This dose of LHRH slightly elevated plasma FSH concentrations. In stark contrast, a 10 fold lower dose of 1 ng of LHRH injected into the ventricle resulted in a highly significant decrease of plasma LH at 10 min following injection, followed by return of LH pulsations. There was no effect on the pulsatile release of FSH. The results are interpreted to mean that at the higher dose, sufficient LHRH reached the site of origin of the hypophyseal portal vessels in the median eminence so that it diffused into portal vessels and was delivered to the gonadotrophs to induce LH release. In contrast, the lower dose provided sufficient hypothalamic concentrations of the peptide to suppress the discharge of the LHRH neurons, thereby leading to a decline in plasma LH, indicative of an ultrashort-loop negative feedback of LHRH to suppress its own release.     

Acute renal response to LPS: impaired arginine production and inducible nitric oxide synthase activity

We have previously shown in rats that lipopolysaccharide (LPS) causes both decreased renal perfusion and kidney arginine production before nitric oxide (NO) synthesis, resulting in a >30% reduction in plasma arginine. To clarify the early phase effects of LPS, we asked the following two questions: 1) is the rapid change in renal arginine production after LPS simply the result of decreased substrate (i.e., citrulline) delivery to the kidney or due to impaired uptake and conversion and 2) is the systemic production of NO limited by plasma arginine availability after LPS? Arterial and renal vein plasma was sampled at 30-min intervals from anesthetized rats with or without citrulline or arginine (2 micromol.min(-1).kg(-1) iv) a dose with no effect on MAP, renal function, or NO production. Exogenous citrulline was quickly converted to arginine by the kidney, resulting in plasma levels similar to equimolar arginine infusion. Also, the increase in citrulline uptake resulted primarily from increased filtered load and reabsorption. In a separate series, citrulline was infused after LPS administration, verifying that citrulline uptake and conversion persists during impaired kidney function. Last, in rats given LPS, the elevation of plasma arginine had no discernable impact on mean arterial pressure, kidney function, or systemic NO production. This work demonstrates how arginine synthesis is normally "substrate limited" and explains how impaired kidney perfusion quickly results in decreased plasma arginine. However, contrary to in vitro studies, the significant reduction in extracellular arginine during the early phase response to LPS in vivo is not functionally rate limiting for NO production.     

Extra-adipocyte leptin release in human obesity and its relation to sympathoadrenal function

The link between the human sympathoadrenalmedullary system and the adipocyte hormone leptin is controversial. We measured total and regional norepinephrine spillover, epinephrine secretion rate, and extra-adipocyte leptin release in 22 lean [body mass index (BMI) < 26] and 20 obese (BMI > 28) normotensive men who underwent arterial and central venous catheterization. Because plasma clearance of leptin is primarily by renal removal, for men at steady state we could estimate whole body leptin release to plasma from renal plasma leptin extraction. Whole body leptin release was 1,950 +/- 643 (means +/- SE) ng/min in obese men and 382 +/- 124 ng/min in lean men (P < 0.05). Total and renal norepinephrine spillover rates correlated directly with whole body leptin secretion rate. Leptin is released from multiple nonadipocyte sites, which we tested by use of simultaneous arteriovenous blood sampling. We found a surprisingly large contribution of brain leptin release to the plasma leptin pool, 529 +/- 175 ng/min (> 40% whole body leptin release), with greater leptin release in obese than in lean men, 935 +/- 321 vs. 160 +/- 59 ng/min (P = 0.045). In parallel with leptin measurements, we also quantified brain serotonin turnover and jugular overflow of neuropeptide Y (NPY). Brain serotonin turnover was higher in obese than in lean men, 227 +/- 112 vs. 21 +/- 14 ng/min (P = 0.019), as was overflow of NPY from the brain, 12.9 +/- 1.4 vs. 5.3 +/- 2.2 ng/min (P = 0.042). These results suggest that leptin is released within the brain and at an increased rate in obese humans, in whom activation of brain serotonergic and NPY mechanisms also exists.     

Effects of temperature on the degradation and biliary secretion of asialoorosomucoid by the perfused rat liver: evidence for two intracellular pathways

We have utilized the in situ perfused rat liver under nonrecirculating conditions to examine the effect of temperature on the metabolism and biliary secretion of [125I]-asialoorosomucid (ASOR). In this manner we were able to follow the fate of a single round of internalized ligand. In control livers perfused at 37 degrees C, approximately 50% of [125I]-ASOR injected into the portal vein was extracted on first pass. Five minutes after the injection, radioactivity, which had been extracted initially, began to appear in the hepatic venous effluent. Within 25 min, 50% of the initially extracted radioactivity was released into the perfusion medium; the bulk of this radioactivity (greater than 95%) was soluble in trichloroacetic acid. In livers perfused at temperatures slightly less than 37 degrees C (30-35 degrees C), first-pass extraction of [125I]-ASOR was similar to that observed at 37 degrees C. However, a severalfold decrease in the rate of release of radioactivity from the liver into the perfusion medium was noted at the lower perfusion temperatures; whereas greater than 50% of the initially extracted radioactivity was released within 30 min from livers perfused at 37 degrees C, only 5% was released at 30 degrees C. At the lower perfusion temperature, a larger proportion of the released radioactivity was acid precipitable (24% vs. 5%). Some radioactivity also was recovered in the bile; of the total amount of radioactivity released from the liver in 30 min at 37 degrees C, approximately 5% was directed into the bile. At lower temperatures of perfusion, a greater fraction of the radioactivity that was released from the liver was directed into the bile (20% at 30 degrees C vs. 5% at 37 degrees C). The data imply that the endosomal pathway to the lysosome is highly sensitive to slight reductions in temperature while the transcytotic route into bile is less sensitive. Lower temperatures might prolong the residence time of ASOR in the prelysosomal endosomal compartments, and thereby increase the likelihood that undegraded ligand will be returned to the blood or be missorted into bile.     

Regional distribution of ethanol in rat brain

The cerebral distribution of a low ip dose of ethanol (ETOH) was studied using a double-barrelled, membrane-tipped perfusion cannula in rats. The cannulas were perfused with physiological solution in freely-moving animals at a rate of 19 μl/min for 5 min at 5, 10, and 15 min and subsequently at 15 min intervals for the remainder of 2 hrs after 1 g/kg ETOH. Peak blood ETOH levels (in mg/ 100 ml) after the single dose were 4 times those found in the lateral ventricle, 6–7 times those found in the reticular formation, cerebral cortex, and amygdala, and 9–11 times those found in the caudate and lateral hypothalamus. Peak levels were reached earliest in the lateral ventricle and reticular formation. In a related study, homogenized (“whole”) brain ETOH levels were found to be similar to blood levels while flushed (“bloodless”) brain ETOH levels were approximately 20% lower than those found in blood and “whole” brain. It is concluded that there is a significant differential distribution of ETOH in the rat brain after a low dose of ETOH, and that this unequal brain ETOH distribution may influence the behavioral effects of the drug.     

Role of brain histamine H1- and H2-receptors in neostigmine-induced hyperglycemia in rats.

We previously reported that when neostigmine, an inhibitor of acetylcholine esterase, was injected into the third cerebral ventricle, the concentration of hepatic venous plasma glucose was increased via central muscarinic receptors in anesthetized rats. To determine whether brain histamine receptors are involved in cholinergic system transmission with regard to central nervous system (CNS)-mediated glucoregulation, we examined the effects of the H1 receptor antagonist pyrilamine and the H2 receptor antagonist ranitidine on neostigmine-induced hyperglycemia in anesthetized rats. The injection of pyrilamine (5 x 10(-9)-5 x 10(-7) mol) into the third cerebral ventricle suppressed hyperglycemia induced by intraventricular injection of neostigmine (1 x 10(-9) mol) in a dose-dependent manner. Injection of ranitidine (5 x 10(-9)-5 x 10(-7) mol) into the third cerebral ventricle did not suppress the hyperglycemia induced by neostigmine, but enhanced it in a dose-dependent manner. These findings suggest that neostigmine-induced CNS-mediated hyperglycemia is transmitted by not only brain cholinergic muscarinic receptors but also in part by histamine H1 receptors.     

Molecular heterogeneity of canine cholecystokinin in portal and peripheral plasma

The release of molecular forms of cholecystokinin (CCK) into the portal and peripheral blood in response to an intraduodenal perfusion of sodium oleate (9 mmol X h-1) was studied in six conscious dogs with chronic portal vein catheters. Immunoreactive CCK as concentrated from 20 ml plasma by C18 SEP PAK cartridges and the pattern of molecular forms of CCK were studied by G50 gel filtration. CCK-like immunoreactivity (CCK-LI) was measured in the column eluates with antibody 5135, which measures gastrin and CCK equally and requires the intact carboxyl-terminus for full recognition. Gastrin was measured specifically with antibody 1611. Intraduodenal perfusion with oleate did not alter basal gastrin release. Release of CCK-LI by intraduodenal oleate was calculated by the increments of the integrated CCK-LI peaks over basal. Total CCK-like immunoreactivity (CCK-LI), calculated by integration of all CCK-LI peaks in gel filtration eluates, increased over basal by 12 fmol/ml in the portal and by 6 fmol/ml in the peripheral plasma after intraduodenal perfusion with sodium oleate. The main molecular forms eluted on gel filtration in positions of CCK33,39 and of CCK8. The pattern of CCK in the peripheral plasma was similar to that in the portal plasma except that in the peripheral plasma large molecular forms were more abundant than small forms. This finding was confirmed when CCK39 and CCK8 were infused either into the portal vein or into the peripheral vein and peripheral plasma CCK levels were measured. Elimination of CCK8 after portal vein infusion compared to peripheral vein infusion was about 3 times higher than that of CCK39. The abundance of large molecular forms of CCK in the circulating blood which are similar in potency to small forms, underlines their role in the physiology of CCK.